genetics 3 Flashcards

Question

N-acetyltransferase

Answer 1

It is an important phase II drug for Isoniazid for tuberculosis. If inactivation of this drug occurs too slow than peripheral neurophathy and bone marrow supression can occur. Those that metabolize it too fast, do not get the benefit of the drug.

Answer 2

Drugs: 6-mercaptopurine, 6-thioguanine, if you give these children with ALL (leukemia) standard doses you will KILL the child due to immunosuppression

Answer 3

Drugs: sulfonamide, dapsone, the mechanism is an x-linked enzyme, G6PD deficient individuals are susceptible to hemolytic anemia after drug exposures

Answer 4

Vitamin K is essential for blood clotting but must be enzymatically activated. This enzymatically activated form of vitamin K is a reduced form required for the carboxylation of glutamic acid residues in some blood-clotting proteins. The product of this gene encodes the enzyme that is responsible for reducing vitamin K 2,3-epoxide to the enzymatically activated form. Fatal bleeding can be caused by vitamin K deficiency and by the vitamin K antagonist warfarin, and it is the product of this gene that is sensitive to warfarin. In humans, mutations in this gene can be associated with deficiencies in vitamin-K-dependent clotting factors. In humans and rats it has also been associated with warfarin resistance different genotypes in confer different sensitivity ot warafin. Combining CPY2C9 and VKORC1 accounts for nearly half of the interindividual difference in warain dose requirment.

Answer 5

This condition mainly affects red blood cells. In affected individuals, a defect in an enzyme called glucose-6-phosphate dehydrogenase causes red blood cells to hemolysis. The most common medical problem associated with glucose-6-phosphate dehydrogenase deficiency is hemolytic anemia, which occurs when red blood cells are destroyed faster than the body can replace them. This type of anemia leads to paleness, yellowing of the skin and whites of the eyes (jaundice), dark urine, fatigue, shortness of breath, and a rapid heart rate. In people with glucose-6-dehydrogenase deficiency, hemolytic anemia is most often triggered by bacterial or viral infections or by certain drugs (such as some antibiotics and medications used to treat malaria). Hemolytic anemia can also occur after eating fava beans or inhaling pollen from fava plants (a reaction called favism). The G6PD gene provides instructions for making glucose-6-phosphate dehydrogenase. This enzyme is involved in the normal processing of carbohydrates. It also protects red blood cells from the effects of reactive oxygen species. Reactive oxygen species are byproducts of normal cellular functions. Chemical reactions involving glucose-6-phosphate dehydrogenase produce compounds that prevent reactive oxygen species from building up to toxic levels within red blood cells. As a result, reactive oxygen species can accumulate and damage red blood cells. Factors such as infections, oxidant drugs (sulfa), or ingesting fava beans can increase the levels of reactive oxygen species, causing red blood cells to be destroyed faster than the body can replace them. A reduction in the amount of red blood cells causes the signs and symptoms of hemolytic anemia. carriers of a G6PD mutation may be partially protected against malaria. This condition is inherited in an X-linked recessive pattern.

Answer 6

Thiopurine methyltransferase methylates thiopurine compounds. Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents and immunosuppressive drugs. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals. its role in the metabolism of the thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. TPMT catalyzes the S-methylation of thiopurine drugs. Defects in the TPMT gene leads to decreased methylation and decreased inactivation of 6MP leading to enhanced bone marrow toxicity which may cause myelosuppression, anemia, bleeding tendency, leukopenia & infection.

Answer 7

a large family of enzymes that are heme containing proteins in the liver and in the and intestinal epithelium. Fe2+ allows them to accept electrons from electron donors such as NAPH and use them for catalyzing different reactions, mostly adding one molecule of O from O2 to a C,N, or S. For many drugs, CYP450 adds a hydoxyl group to the molecule (phase I). This provides a site to add a sugar or acetyl group to detoxify the drug and make it easier to excrete (phase II). Most CYPs function to inactivate drugs, but rarely are needed for activation.

Answer 8

an enzyme that can glucuronidate many molecules including bilirubin extretion into bile and camptothecin (a chemotherapy drug). There is a lot of veriability in the metobilism and therefore risks to levels of toxicity.

Answer 9

a family of enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation. An absence or mutation of the pseudocholinesterase enzyme leads to a medical condition known as pseudocholinesterase deficiency. This is a silent condition that manifests itself only when people that have the deficiency receive the muscle relaxants succinylcholine or mivacurium during a surgery. The effects are varied depending on the particular drug given. When anesthetists administer standard doses of these anesthetic drugs to a person with pseudocholinesterase deficiency, the patient experiences prolonged paralysis of the respiratory muscles, requiring an extended period of time during which the patient must be mechanically ventilated. Eventually the muscle-paralyzing effects of these drugs will wear off despite the deficiency of the pseudocholinesterase enzyme. If the patient is maintained on a mechanical respirator until normal breathing function returns, there is little risk of harm to the patient.

Answer 10

by combining patients genotype at loci involved in postoperative complications with other relavent information, you can obtain better risk analysis. Some of these loci inclue glycoproteins concerned with platlet affregation and the coagulation cascade. C-reactive protein and interleukin-6 helps judge the risk of stroke

Answer 11

This family is responsible for breaking down 40% of all common drugs and there is less genetic variation in CYP3A4 than in other CYPs

Answer 12

a tricyclic antidepressant. the greater the number of copies of functional CYP2D6 genes, the faster it is metabolized and the faster it leaves the patients system

Answer 13

Can compare the frequency of disease in relatives of patients to see if higher than in general population. λs= risk of the disease in siblings of affected/ risk of disease in general population. Risk of disease in siblings of a type 1 diabetes patient is higher than risk in general population. Risk in general population ~ 0.4%. Risk to sibs of type 1 diabetes patient ~ 6%. lS ~ 15 for type 1 diabetes.

Answer 14

Proportion of variance in trait that is due to genetic variation. If heretibility is less than 50% it is considered low. the proportion of observed differences on a trait among individuals of a population that are due to genetic differences. Factors including genetics, environment and random chance can all contribute to the variation between individuals in their observable characteristics (in their "phenotypes"). Heritability thus analyzes the relative contributions of differences in genetic and non-genetic factors to the total phenotypic variance in a population. For instance, some humans in a population are taller than others; heritability attempts to identify how much genetics play a role in part of the population being taller. Heritability is measured by estimating the relative contributions of genetic and non-genetic differences to the total phenotypic variation in a population. Heritability measures the fraction of phenotype variability that can be attributed to genetic variation. This is not the same as saying that this fraction of an individual phenotype is caused by genetics. In addition, heritability can change without any genetic change occurring, such as when the environment starts contributing to more variation.

Answer 15

is a transcription factor that is highly expressed in the liver and is involved in the regulation of the expression of several liver-specific genes. Changes in the HNF1A gene cause diabetes by lowering the amount of insulin that is produced by the pancreas. It allows insulin to be produced normally in childhood but the amount of insulin reduces as you get older. HNF1A is one of a group of familial types of diabetes called maturity onset diabetes of the young (MODY). HNF1A accounts for 70% of MODY cases.

Answer 16

Different alleles in the same gene result in same trait. Different alleles in the same gene result in different traits. Example: Cystic Fibrosis. Many alleles appear to have very similar clinical progression of disease. Alleles can be grouped into classes; severity of lung and pancreatic involvement depends on allele class

Answer 17

if you have a severe/severe genotype 85% present with pancreatic insufficiency while mild/mild or mild/severe only 15% of panctreatic insufficiency. Such genotype is also related to pulmonary function in CF patients, patients with mild mutations have generally better lung functions than those carrying severe mutations. But when we deal with particular patient from both groups it is very difficult to predict if they will have severe or mild lung disease. We can see some patients from the severe group that have relatively good pulmonary function and vice versa. We expect therefore that contribution of these other factors that we were talking about is much stronger for lung disease than for pancreas.

Answer 18

Variants in different genes result in very similar clinical presentation. Classic example: Early onset Alzheimer disease (AD). Mutations in 3 different genes all result in identical clinical presentation of early-onset AD

Answer 19

environmentally caused phenotype that mimics the genetic version of the trait. Note that it can be argued that almost everything has some genetic component; intent here is that primary reason for the phenotype is not genetic. Example: Thalidomide-induced limb malformation vs. genetically-induced.

Answer 20

Risk factors: increasing age, obesity, physical inactivity, family history, prior gestational diabetes, impaired glucose tolerance (IGT). Associated with: LDL cholesterol, triglycerides, blood pressure. Control often attained with diet, exercise. Insulin resistance generally thought to precede insulin deficiency, but both often present at time of diagnosis. Control of type 2 diabetes can usually be attained by maintenance of a regimented diet and exercise program, suggesting that environment plays an important role in the pathogenesis of the disease. AGE: most individuals not affected until later in life. However, it is clear that obesity is not the whole story . Estimates of concordance rates for MZ twins: About 2 times those for dizygotic twins - 35%-100% Risk to 1st degree relatives of affected: ~ 3 to 4 times that of general population. Intermediate traits of blood glucose and insulin levels have heritability estimates as high as 50%

Answer 21

(also called the true positive rate, or the recall rate in some fields) measures the proportion of actual positives which are correctly identified as such (e.g. the percentage of sick people who are correctly identified as having the condition), and is complementary to the false negative rate. In medical diagnostics, test sensitivity is the ability of a test to correctly identify those with the disease (true positive rate), whereas test specificity is the ability of the test to correctly identify those without the disease (true negative rate). If 100 patients known to have a disease were tested, and 43 test positive, then the test has 43% sensitivity. If 100 with no disease are tested and 96 return a negative result, then the test has 96% specificity. Sensitivity and specificity are prevalence-independent test characteristics, as their values are intrinsic to the test and do not depend on the disease prevalence in the population of interest.[3] Positive and negative predictive values, but not sensitivity or specificity, are values influenced by the prevalence of disease in the population that is being tested.

Answer 22

sometimes called the true negative rate) measures the proportion of negatives which are correctly identified as such (e.g. the percentage of healthy people who are correctly identified as not having the condition), and is complementary to the false positive rate. A perfect predictor would be described as 100% sensitive (i.e. all sick are identified as sick) and 100% specific (i.e. all healthy are identified as healthy); however, theoretically any predictor will possess a minimum error bound known as the Bayes error rate.

Answer 23

are homologous sequences of nucleotides on the X and Y chromosomes. Pairing (synapsis) of the X and Y chromosomes and crossing over (recombination) between their pseudoautosomal regions appear to be necessary for the normal progression of male meiosis. Thus, those cells in which X-Y recombination does not occur will fail to complete meiosis. Structural and/or genetic dissimilarity (due to hybridization or mutation) between the pseudoautosomal regions of the X and Y chromosomes can disrupt pairing and recombination, and consequently cause male infertility. A high porportion of these genes are related to gonadal and genital development

Answer 24

In the presence of this gene, the medullary tissue forms typical testes with seminiferous tubules and Leydig cells that, under the stimulation of chorionic gonadotropin from the glacenta, become capable of androgen secretion. The spematogonia, derived from the primordial germ cells by successive mitosis, line the walls of the seminiferous tubules, where they reside together with supporting setoli cells. In males, leydig cells of the fetal testes produce androgen which stimulates the mesonephric ducts to form male genital ducts. the sertoli cells produce a hormone that suppresses formation of the paramesonephric ducts

Answer 25

if no y chromosome is present, the gonad begins to differentiate to form an ovary and the medulla regresses, and oogonia begin to develop within follicles. At about three months, oogonia enter meiosis I, but is arrested at dictyotene until ovulation occurs years later.

Answer 26

a paired organ found in mammals including humans during embryogenesis. In a male, it develops into a system of connected organs between the efferent ducts of the testis and the prostate, namely the epididymis, the vas deferens, and the seminal vesicle. The prostate forms from the urogenital sinus and the efferent ducts form from the mesonephric tubules. For this it is critical that the ducts are exposed to testosterone during embryogenesis. Testosterone binds to and activates androgen receptor, affecting intracellular signals and modifying the expression of numerous genes. In the mature male, the function of this system is to store and mature sperm, and provide accessory semen fluid. In the female, with the absence of anti-Müllerian hormone secretion by the sertoli cells and subsequent Müllerian apoptosis, the Wolffian duct regresses, and inclusions may persist. The epoophoron and Skene's glands may be present. Also, lateral to the wall of the vagina a Gartner's duct or cyst could develop as a remnant.

Answer 27

are paired ducts of the embryo that run down the lateral sides of the urogenital ridge and terminate at the sinus tubercle in the primitive urogenital sinus. The development of the paramesonephric (Müllerian) ducts is controlled by the presence or absence of "AMH", or Anti-Müllerian hormone (also known as "MIF" for "Müllerian-inhibiting factor", or "MIH" for "Müllerian-inhibiting hormone", or "APH" for Anti-Paramesonephric Hormone). In females, the paramesonephric ducts give rise to the uterine tubes, uterus, and upper portion of the vagina, while the mesonephric ducts degenerate due to the absence of male androgens. In contrast, the paramesonephric ducts begin to proliferate and differentiate in a cranial-caudal progression to form the aforementioned structures. During this time, the single-layered paramesonephric duct epithelium differentiates into other structures, ranging from the ciliated columnar epithelium in the uterine tube to stratified squamous epithelium in the vagina.

Answer 28

a rare sex chromosomal disorder. Usually, it is caused by unequal crossing over between X and Y chromosomes during meiosis in the father, which results in the X chromosome containing the normally-male SRY gene. When this X combines with a normal X from the mother during fertilization, the result is an XX male. Symptoms usually include small testes and subjects are invariably sterile. Individuals with this condition sometimes have feminine characteristics, with varying degrees of gynecomastia but with no intra-abdominal Müllerian tissue.

Answer 29

a type of hypogonadism in a person whose karyotype is 46,XY. The person is externally female with streak gonads, and left untreated, will not experience puberty. Such gonads are typically surgically removed (as they have a significant risk of developing tumors) and a typical medical treatment would include hormone replacement therapy with female hormones. The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation requires the action of several genes, of which one of the earliest and most important is SRY, the sex-determining region of the Y chromosome. Mutations of SRY account for many cases of Swyer syndrome. When such a gene is defective, the indifferent gonads fail to differentiate into testes in an XY (genetically male) fetus. Without testes, no testosterone or antimüllerian hormone (AMH) is produced. Without testosterone, the wolffian ducts fail to develop, so no internal male organs are formed. Also, the lack of testosterone means that no dihydrotestosterone is formed and consequently the external genitalia fail to virilize, resulting in normal female genitalia. Without AMH, the Müllerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina).

Answer 30

one of several proteins or their genes, which are coded from the AZF region on the human male Y chromosome.[1] Deletions in this region are associated with inability to produce sperm.

Answer 31

a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by its being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome (see dosage compensation). The choice of which X chromosome will be inactivated is random, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants in the organism. the choice of which x chromosome is to be inactivated is made early in development, thus females are mosaic. A fraction of the genes along the X chromosome escape inactivation on the Xi. The Xist gene is expressed at high levels on the Xi and is not expressed on the Xa.

Answer 32

it is contained in the x inactivation center in Xq13. it seems to be a key master regulatory locus for x inactivation and is only expressed from the allele on the inactive x.

Answer 33

unbalanced structural abnormalities of an x chromosome will cause that chromosome to be inactivated. Nonrandom inactivation is observed for most cases of x; autosome translocation. If the translocation is balanced, the noraml x chromosome is preferentially inactivated and the two parts of the translocated chromosome remain active so that the autosomal genes dont get inactivated. however, sometimes the break itself causes a mutation leading to an x-linked phenotype normaly only seen in males. in unbalanced offspring of unbalanced carriers, the translocated chromosome is inactivated to present partial trisomy.

Answer 34

refers to forms of intellectual disability which are specifically associated with X-linked recessive inheritance. As with most X-linked disorders, males are more heavily affected than females. Females with one affected X chromosome and one normal X chromosome tend to have milder symptoms. Unlike many other types of intellectual disability, the genetics of these conditions are relatively well understood.[2][3] It has been estimated there are ~200 genes involved in this syndrome; of these ~100 have been identified.

Answer 35

Aside from having an ambiguous-looking external genitalia, true hermaphroditism in humans differs from pseudohermaphroditism in that the person's karyotype has both XX and XY chromosome pairs (47XXY, 46XX/46XY, 46XX/47XXY or 45X/XY mosaic) and having both testicular and ovarian tissue. One possible pathophysiologic explanation of this rare phenomenon is a parthenogenetic division of a haploid ovum into two haploid ova. Upon fertilization of the two ova by two sperm cells (one carrying an X and the other carrying a Y chromosome), the two fertilized ova are then fused together resulting in a person having dual genitalial, gonadal (ovotestes) and genetic sex. Another common cause of hermaphroditism is the crossing over of the SRY from the Y chromosome to the X chromosome during meiosis. The SRY is then activated in only certain areas, causing development of testes in some areas by beginning a series of events starting with the upregulation of SOX9, and in other areas not being active (causing the growth of ovarian tissues). Thus, testicular and ovarian tissues will both be present in the same individual.

Answer 36

Mechanisms: Caused by genetic mutations (deletions, insertions, or rearrangements) that eliminate (or reduce) the function of the protein. Of the four major mechanisms, this is the most common genetic mechanism leading to human genetic disease. In general, many metabolic diseases (enzyme defect in a metabolic pathway) are due to loss of function mutations and these loss-of-function mutations are often (but not exclusively) inherited as autosomal recessive diseases as both alleles need to be damaged before the phenotype develops. Included in the ‘loss of function category’ are also mutations that lead to reduction of protein function (either reduction of protein produced or a protein that functions less well/efficiently). the mutation may be in coding region or mutations affecting gene regulation or dosage.

Answer 37

Complete loss of a protein: stop codon, frameshift, or deletion of multiple exons. DMD Xp21.2. Large deletions (multiple exons). Nonsense (stop) mutations / frameshift mutations à premature termination. (in-frame deletions -> milder Becker muscular dystrophy). Clinically: Boys with abnormal gait at 3-5 years, Calf pseudohypertrophy, Gower maneuver, Progressive involvement of respiratory muscles, Median age of death 18 years, Women may à cardiomyopathy. Large deletions (multiple exons) Nonsense (stop) mutations / frameshift mutations -> premature termination, (in-frame deletions -> milder Becker muscular dystrophy). X-linked inheritance. Frameshift deletions = major loss-of-function mechanism in Duchenne Muscular Dystrophy. In-frame deletions (and also missense mutations) = major loss-of (i.e. reduction)-function in Becker Muscular dystrophy.

Answer 38

Reduction in amount of protein: deletion of copy. There can be transcription problems due to reduced or absent production of a globin mRNA because of deletions or mutations in regulatory or splice sites of a globin gene. There can also be translation issues due to nonfunctional or rapidly degraded mRNAs with nonsense or frameshift mutations

Answer 39

Somatic mutation leading to loss of tumor suppressor protein

Answer 40

due to deletion of PMP22 gene leading to a phenotype where patients have temporary (usually reversible) neuropathy when pressure is applied to various nerves. Just as your arm may go to sleep if left in a certain position, these patients are more sensitive to pressure on nerves and their limbs can ‘go to sleep’ for longer periods of time (hours, days, to months). there can be transcriptional issues due to increased postnatal transcription of one or more γ-globin genes. Deletion of PMP22 gene = Loss-of-function à Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). PMP22 protein is an integral membrane glycoprotein in nerves. Clinically: repeated focal pressure neuropathies (e.g. carpal tunnel syndrome and peroneal palsy with foot drop), First attack usually in 2nd-3rd decade, Recovery from acute neuropathy is often complete, Incomplete recovery -> mild disability, it is autosomal dominant

Answer 41

Nonsense (stop) mutations / frameshift mutations in COL1A1ààpremature termination. Reduced amount of normal COL1A1 (collagen) protein causing a ‘milder’ form of osteogenesis imperfect. Clinically characterized by increased fractures, brittle bones, and blue sclera.

Answer 42

Mechanisms: Caused by genetic mutations (often missense or sometimes promoter mutations) that enhance one or more normal functions of a protein (e.g. increased protein expression, increased half- life, decreased degradation, increased activity). Gain-of-function mutations caused by point mutations (missense mutations) often (but not always) show autosomal dominant inheritance patterns as carrying one mutant allele is sufficient to cause disease.

Answer 43

(Beta hemoglobin gene, Asp99Asn missense mutation): leads to a hemoglobin molecule which has higher than normal oxygen affinity, and is less able to unload oxygen in the tissues. Beta hemoglobin gene: Asp99Asn missense mutation, which has Higher oxygen affinity. In normal hemoglobin binding of oxygen allowing for shift from tense (deoxygenated) to relaxed (oxygenated) form. 99Asn mutation prevents this shift. Hemoglobin remains ‘locked’ in the relaxed state (which has higher oxygen affinity) = Gain Of Function. Consequences: Hb Kempsey unloads less oxygen in tissues, Body ‘thinks’ it needs more oxygen -> makes more red blood cells-> polycythemia

Answer 44

FGFR3 Gly380Arg mutation increases the normal signaling though intracellular tyrosine kinase domain (essentially having the receptor constitutively in the ‘turned-on’ state). Skull growth abnormal: midface hypoplasia (otits, sleep apnea)…small cranial foramina (hydrocephalus, brainstem compression (10% of patients), increased frequency of hypotonia, quadriparesis, failure to thrive, central apnea, and sudden death). Between 3% and 7% of patients die unexpectedly during their first year of life because of brainstem compression (central apnea) or obstructive apnea. Gain-of-function mutations, Advanced paternal age, De novo mutation. Age at onset: prenatal, Rhizomelic short stature, Megalencephaly, Spinal cord compression, (trident hand). Achondroplasia is a form of short-limbed dwarfism. However, in achondroplasia the problem is not in forming cartilage but in converting it to bone (a process called ossification), particularly in the long bones of the arms and legs. Achondroplasia is similar to another skeletal disorder called hypochondroplasia, but the features of achondroplasia tend to be more severe. Health problems commonly associated with achondroplasia include episodes in which breathing slows or stops for short periods (apnea), obesity, and recurrent ear infections. In childhood, individuals with the condition usually develop a pronounced and permanent sway of the lower back (lordosis) and bowed legs. Some affected people also develop abnormal front-to-back curvature of the spine (kyphosis) and back pain. A potentially serious complication of achondroplasia is spinal stenosis, which is a narrowing of the spinal canal that can pinch (compress) the upper part of the spinal cord. Spinal stenosis is associated with pain, tingling, and weakness in the legs that can cause difficulty with walking. Another uncommon but serious complication of achondroplasia is hydrocephalus, which is a buildup of fluid in the brain in affected children that can lead to increased head size and related brain abnormalities.

Answer 45

Patients with an extra copy of chromosome 21 have 3 total copies of the APP (21q21) leading to increased production of APP protein which contributes to early-onset Alzheimer disease in this patient population.

Answer 46

due to duplication of PMP22 gene (see HNPP) which leads to elevated PMP22 protein. Duplication of PMP22 gene = Gain-of-function à Charcot Marie Tooth Syndrome type IA (CMT1A). PMP22 protein is an integral membrane glycoprotein in nerves. Clinically: Demyelinating motor and sensory neuropathy, Often presents in lower extremities with weakness and muscle atrophy and mild sensory loss, Progressive; typical patterns on nerve conduction studies, is autosomal dominant

Answer 47

Mechanisms: Caused by genetic mutations (often missense) that confer a novel property on the protein, without necessarily altering its normal functions. Although the introduction of a novel property has sometimes been advantageous from an evolutionary standpoint, the majority of such changes result in a novel protein property that reduces fitness (i.e. can lead to disease). (relatively uncommon)

Answer 48

the Glu6Val mutation of the beta globin gene results in a hemoglobin molecule which transports oxygen essentially normally. However under low oxygen states the Val residue leads to polymerization of hemoglobin into long protein-fibers which deform and restrict the normally flexible red blood cells

Answer 49

A triplet repeat disorder where by expansion of CAG repeat ‘triplets’ in the gene increase the number of glutamine residues (the CAG codon codes for glutamine). Increased polyglutamine residues above a certain threshold leads to a novel toxic effect on the huntingtin protein. Expansion occurs in paternal allele

Answer 50

(relatively uncommon; seen in cancers) Mechanisms: Caused by genetic mutations that alter regulatory regions of a gene and alter either the timing (wrong time = heterochronic) or location (wrong place = ectopic) of expression. Cancers: a gene that is normally silent (for example in differentiated cells) is abnormally expressed (i.e. turned back ‘on’) and leads to abnormal proliferation. Oncogenes are examples of this situation.

Answer 51

the normal switch from fetal to adult hemoglobin does not occur and fetal hemoglobin, which has a higher affinity for oxygen, remains expressed beyond infancy. One mechanism for this is deletion of several genes in the beta hemoglobin locus, but retention of the fetal (γ) gene such that the γ-globin gene continues to be expressed because the β-globin gene is missing and the normal switch from γ to β cannot occur

Answer 52

transcription, translation, polypeptide folding, posttranslational modification, assembly of monomers into a holomeric protein, subcelular localization of the polypeptide or the holomer, cofactor of prosthetic group binding to the polypeptide, function of a correctly folded assembled and localized protein produced in normal amounts

Answer 53

More than 70 hemoglobinopathies are due to abnormal hemoglobins with amino acid substitutions or deletions that lead to unstable globins that are prematurely degraded, e.g., Hb Hammersmith

Answer 54

a lysosomal storage disease that is due to a failure to add a phosphate group to mannose residues of lysosomal enzymes. The mannose 6- phosphate residues are required to target the enzymes to lysosomes.

Answer 55

in some types, an amino acid substitution in a procollagen chain impairs the assembly of a normal collagen triple helix

Answer 56

a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease. in the carboxyl terminus of the LDL receptor, that impair the localization of the receptor to clathrin- coated pits, preventing the internalization of the receptor and its subsequent recycling to the cell surface

Answer 57

an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase. It is an inherited autosomal recessive trait. The enzyme cannot function due to poor or absent binding of the cofactor (pyridoxal phosphate) to the cystathionine synthase apoenzyme

Answer 58

caused by an impaired subunit interaction locks hemoglobin into its high oxygen affinity state, otherwise this protein is normal

Answer 59

In general mutations are relatively stable from generation to generation for most disorders. An exception to this can be found in the ‘unstable repeat expansion’ disorders. These genes contain tri, or tetra-nucleotide repeats which are believed to make the genes susceptible to slipped mispairing during DNA replication. The consequence of this is that the repeat numbers for each allele are prone to change from parent to offspring. An expansion of repeat numbers beyond certain thresholds can lead to clinical disease. Huntington disease, a progressive neurodegenerative condition is the classic example of this class of disease.

Answer 60

a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and behavioral symptoms. All humans have two copies of the Huntingtin gene (HTT), which codes for the protein Huntingtin (Htt). Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant Huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant. It is not inherited according to sex, but the length of the repeated section of the gene and hence its severity can be influenced by the sex of the affected parent. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the 3-letter genetic code (codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region. Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin. However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics. This altered form, called mHtt (mutant Htt), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these type of neurons, and are affected accordingly. Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to environment and other genes that modify the mechanism of HD. 36–39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms.

Answer 61

``` an important (and testable) concept that describes the clinical observation of disease severity worsening in subsequent generations. Genetic anticipation is explained by the mechanism of tri/tetra nucleotide repeat number expansions occurring from parent to offspring. The offspring inheriting an expanded disease allele is more likely to present earlier and progress faster. There are three principal pathogenic mechanisms for this to occur: 1) Expansion of noncoding repeats and loss of function, consequences are impaired transcription, mutant RNA is not made therefore mutant protein is not made. examples include fragile x and friedreich ataxia 2) Expansion of noncoding repeats conferring novel properties. RNA has novel property (abnormal RNA binds and soaks up RNA-binding proteins -> affects other gene products), Mutant RNA is made but Mutant protein not made. examples include Myotonic dystrophy types 1 and 2, Fragile X-associated tremor/ataxia syndrome (FXTAS) 3) Expansion of codons in exons. this causes novel property on expressed protein and both mutant RNA and protein is made which is toxic. Examples include Huntington disease and spinocerebellar ataxias. Most of these disorders have neurological consequences and are autosomal dominant in their inheritance pattern. Exceptions are Fragile X (X-linked), Friedreich ataxia (autosomal recessive), and some spinocerebellar ataxias (most are autosomal dominant, but recessive forms also reported) ```

Answer 62

Phenotype expressed only in people who have two mutant alleles of the same gene. Both parents of an affected child are obligated carriers of the disease-causing allele(s). Men and women are usually equally affected. Horizontal pedigree (affected individuals are usually siblings). Carriers are usually undetected, thus the birth of the first affected child is usually unexpected. The recurrence risk is 1 in 4 (25%) for each unborn child of the same couple. The probability of an unaffected sibling being a carrier is 2/3. The majority of mutant allele(s) are present in carriers instead of patients. Sometimes with a higher frequency within people of a small group (high-risk group). Increased incidence of parental consanguinity for a child affected by a rare AR disorder.

Answer 63

one who carries two different mutant alleles of the same gene.

Answer 64

Microcephaly and profound mental retardation if untreated during infancy. Neurobehavioral symptoms such as seizure, tremor, and gait disorders are common. High phenylalanine and low tyrosine levels in the plasma because the conversion from Phe to Tyr is impaired. High levels of phenylalanine metabolites in urine and sweat gives a characteristic “mousy” odor.

Answer 65

Disease frequency is 1/10,000 births (q2 = 1/10,000, q = 1%) among individuals of Northern European ancestry. Carrier frequency is about 1/50 (2pq ≈ 2q = 2%).

Answer 66

PKU is an inborn defect of phenylalanine metabolism. Most PKU cases are caused by defects in the PAH gene encoding phenylalanine hydroxylase, a liver enzyme that catalyzes the conversion of Phe to Tyr using molecular oxygen and a cofactor tetrahydrobiopterin (BH4). A small fraction of PKU patients (1~3%) have normal PAH but are defective in genes that are needed for the synthesis or regeneration of BH4, the cofactor of PAH. BH4 is also the cofactor for two other enzymes, tyrosine hydroxylase and tryptophan hydroxylase, both of which synthesize monoamine neurotransmitters. The high phenylalanine level in PKU damages the developing central nervous system in early childhood and interferes with the function of the mature brain, although the mechanism of damage is unclear. BH4-deficient PKU patients have problems caused by both hyperphenylalaninemia and neurotransmitter imbalance.

Answer 67

The PAH gene is at chromosome 12q22-24. Most mutations in PAH are partial or complete loss-of-function alleles. PAH gene exhibits high allelic heterogeneity; over 400 alleles have been identified. Most PKU patients are compound heterozygotes (i.e. having two different mutant alleles of the PAH gene). Severity of phenotype varies and probably reflects compound heterozygosity.

Answer 68

Guthrie test (aka Guthrie bacterial inhibition assay) for PKU was developed in the mid- 1960s. This test is based on the findings that thienylalanine inhibits the growth of the bacterium Bacillus subtilis and that such inhibition can be overcome by a high level of phenylalanine in the blood sample of a PKU baby. Mass Spectrometry is the current method of choice for many newborn screenings including PKU. A mass spectrometer simultaneously sorts many molecules in a blood specimen by weight (mass) and size, and also measures the quantity of each molecule. Phe/tyr ratio is also a good measure of PKU because phe is convereted to tyr by PAH, therefore without PAH the ratio is high. Timing of Test: The sensitivity of PKU screening is influenced by the age of the newborn when the blood sample is obtained. Phenylalanine level is typically normal in PKU babies at birth because of normal PAH in maternal supply and increases progressively with the initiation of protein feedings during the first days of life. Early detection and treatment is crucial to prevent irreversible damage to the developing brain. However, if tested too early (within 1-2 days of birth), some affected children can be missed. Newborns are tested first after birth and then again at their first pediatrician’s visit days later.

Answer 69

When treated early with low-phenylalanine diet, the mental retardation can be prevented. Phenylalanine is an essential amino acid and thus cannot be eliminated from the diet. The low-phenylalanine diet should be maintained throughout childhood and school years, and preferably the patient’s whole life. BH4-deficient PKU patients are treated with oral BH4, low-phenylalanine diet, and supplements (L-dopa and 5-hydroxytryptophan etc) to balance neurotransmitter levels.

Answer 70

It is important to maintain PKU women on a low-phenylalanine diet throughout their child- bearing years. PKU mothers who are not on a low-phenylalanine diet have a markedly increased risk of miscarriage and giving birth to children with congenital malformations, mental retardation, and growth impairment, irrespective of the genotypes of the children. These defects are caused by elevated phenylalanine levels in the maternal circulation during fetal development and thus termed maternal PKU.

Answer 71

ATD patients have a 20-fold increased risk of developing emphysema, with more severe symptoms among smokers. This disorder is late-onset, especially in non-smokers, but 80- 90% of deficient individuals will eventually develop disease symptoms. Many patients also develop liver cirrhosis and have increased risk of liver carcinoma due to the accumulation of a misfolded α1-AT mutant protein in the liver.

Answer 72

α1-antitrypsin deficiency is a common genetic disorder among Northern European Caucasians. Disease frequency is 1/2,500, carrier frequency ~1/25. The most common normal (wild-type) allele, the M allele, occurs with a frequency of 95%; thus 90% (0.952 =0.9025) of white Europeans have M/M genotype. Most ATD diseases are associated with two mutant alleles, the Z and S alleles. Individuals with Z/Z genotype have only 10-15% of normal α1-AT activity and account for most cases of the disease. Individuals with S/S genotype have 50-60% of normal α1-AT activity and usually do not express disease symptoms. Z/S compound heterozygotes have 30-35 % of normal α1-AT activity and may develop emphysema.

Answer 73

α1-antitrypsin (ATT or SERPINA1) is made in the liver and secreted into plasma. SERPINA1 is a member of serpins (serine protease inhibitor), which are suicide substrates that bind and inhibit specific serine proteases. The main target of SERPINA1 is elastase, which is released by neutrophils in the lung. When left unchecked, elastase can destroy the connective tissue proteins (particularly elastin) of the lung, causing alveolar wall damage and emphysema.

Answer 74

The SERPINA1 gene is on chromosome 14 (14q32.13). There are ~20 different mutant alleles, although the Z & S alleles account for most of the disease cases. The Z allele (Glu342Lys) encodes a misfolded protein that aggregates in the endoplasmic reticulum (ER) of liver cells, causing damage to the liver in addition to the lung. The S allele (Glu264Val) expresses an unstable protein that is less effective.

Answer 75

Sequence specific oligonucleotide probes can be used to distinguish the M, Z and S alleles in a target population and provide accurate prenatal diagnosis.

Answer 76

Smoking accelerates the onset of emphysema in ATD patients. Tobacco smoke damages the lung, prompting the body to send more neutrophils to the lung for protection. More neutrophils release more elastase, causing more severe lung damage.

Answer 77

Two approaches of delivering human SERPINA1 to the pulmonary epithelium are being studied: intravenous infusion and aerosol inhalation.

Answer 78

T-S is an inherited disorder that progressively destroys neurons in the brain and spinal cord. The most common form of T-S is an early-onset, fatal disorder apparent in infancy. T-S infants appear normal until the age of 3-6 months, when early symptoms such as muscle weakness, decreased attentiveness, and increased startle response appear. As the disease progresses, the T-S children experience symptoms of neurodegeneration including seizures, vision and hearing loss, diminishing mental function, and paralysis. An eye abnormality called “cherry-red spot” is a characteristic of T-S. Children of T-S usually live only till 3-4 years of age.

Answer 79

The Ashkenazic Jewish population is at 100-fold higher risk for T-S (~1/3,600) than the general population (~1/360,000). Other high-risk groups for T-S are certain French- Canadian communities of Quebec, the Old Order Amish community in Pennsylvania, and the Cajun population of Louisiana.

Answer 80

T-S is a lysosomal storage disease. Inability to degrade GM2 ganglioside results in up to 300-fold accumulation of this sphingolipid inside swollen lysosomes in neurons of the central nervous system. A defective hexosaminidase A (HexA) needed for in metabolizing GM2 is responsible for T-S. HexA is a heterodimer of αβ, which are encoded by the HEXA and HEXB genes, respectively. Although HexA is a ubiquitous enzyme, the impact of T-S is primarily in the brain where most of GM2 ganglioside is synthesized. Sandhoff disease (GM2 gangliosidosis type II) presents the same neurological symptoms as T-S. Sandhoff disease patients have defects in both Hexosaminidase A and Hexosaminidase B (HexB); Hex B is a homodimer of ββ. T-S is caused by a defective α subunit; only HexA activity is affected. Sandhoff disease is caused by a defective β subunit; both HexA and HexB activities are affected. The α subunit gene HEXA and the β subunit gene HEXB reside on chromosomes #15 and #5, respectively. AB-variant of Tay-Sachs is a rare form of T-S in which both HexA and HexB are normal but GM2 accumulates due to a defect in the GM2 activator protein (GM2-AP), which facilitates interaction between the lipid substrate and the HexA enzyme (α subunit) within the cell. Note: HexA and HexB refer to the two enzymes; HEXA and HEXB refer to two genes encoding the α and β subunit, respectively.

Answer 81

Over 100 HEXA mutations are known. The most common mutant allele (~80%) in the Ashkenazi Jewish population is a 4 bp insertion in exon 11 of HEXA, causing a frameshift and a premature stop codon in the coding sequence of the gene (i.e. it’s a null allele).

Answer 82

Enzymatic activity assay: both HexA and HexB enzymes are present in the serum. Their activities can be distinguished in such assays because only HexA is inactivated by heat. Carrier Screening: primarily among Ashkenazi Jewish population, the enzyme test has 97% accuracy because carriers have lower HexA enzyme levels in the blood. Prenatal screening: the enzyme test can also be performed on cultured amniotic fluid cells to detect T-S fetus when both parents are known to be carriers. Notably, this screening has reduced the number of T-S cases by about 95% over the past 30 years. DNA testing: The tests currently available can detect about 95% of carriers in the Ashkenazi Jewish population and about 60% of carriers among non-Jewish individuals. Therefore, some carriers will be missed by DNA test alone.

Answer 83

Juvenile and adult-onset forms of T-S are very rare with milder symptoms appearing in childhood, adolescence, or adulthood; the patients have decreased HexA activity.

Answer 84

The major form of adult hemoglobin (HbA) is a α2β2 tetramer of two α- and two β-globin chains. Each globin contains one heme group with a covalently linked iron that binds oxygen, so one HbA can simultaneously bind four oxygen molecules.

Answer 85

All of α and α-like genes are in the α-cluster on chromosome 16, while all of β and β-like genes are in the β-cluster on chromosome 11. All of these globin genes are likely to have arisen from a common ancestral gene via gene duplication events. There are two copies of α in the α-cluster but only one copy of β in the β-cluster. The genes in each cluster have the same 5’-to-3’ transcriptional orientation. At the molecular level the promoter and enhancer regions of these genes are very similar. α-cluster: zeta-alpha2-alpha1 (ζ-α2-α1). β-cluster: epsilon-gammaG-gammaA-delta-beta (ε-γG-γA-δ-β). Pseudogene: resembles a gene but makes no protein. ψζ, ψα, and ψβ are all pseudogenes. The 5'-to-3' spatial order of genes within each cluster coincides with the temporal order of their expression during development. The sequential expression of these genes during development is under the regulation of the Locus Control Region (LCR), which is located at the most upstream region of each cluster. It is currently thought that the distance between the LCR and a particular globin gene affects its expression.

Answer 86

are defined by their ability to enhance the expression of linked genes to physiological levels in a tissue-specific and copy number-dependent manner at ectopic chromatin sites. The concept derives from the idea that developmental and cell lineage-specific regulation of gene expression relies not only on gene-proximal elements such as promoters, enhancers, and silencers, but also on long-range interactions of various cis-regulatory elements and dynamic chromatin alterations. It is currently thought that the distance between the LCR and a particular globin gene affects its expression. The LCR presumably makes physical contact with the promoter and/or negative regulatory regions via specific transcriptional factors to influence gene expression by opening up the chromosome to TF through a DNase 1 hypersensitivity site. the LCR along with associated DNA binding proteins, interacts with genes of the locus to form a nuclear compartment called the active chromatic hub, where beta globin gene expression takes place. This hub moves from the 5' gene (ε-globin) to the δ and β globin genes in adults. Deletions of the entire LCR of the beta cluster cause beta-thalassemias, a condition in which zero β-globin synthesis leads to precipitation of the α-globin chains.

Answer 87

Adults have two Hb forms (made in the bone marrow): major form: HbA = α2β2 (97%), minor form : HbA2 = α2δ2 (2%), Note that δ level is much lower than β because δ has a weaker promoter. More Hb forms are present during embryonic and fetal development Embryonic hemoglobins (made in the yolk sac): ζ2ε2 = Hb Gower I α2ε2 = Hb Gower II ζ2γ2 = Hb Portland, Fetal hemoglobins (made in the liver): α2γ2 = HbF. Globin Switching: turn-off of ζ and ε, turn-on of α and γ during early embryogenesis, turn-offofγ,turn-on of β and δ around the time of birth. Significance of Globin Switching: HbF has higher affinity for O2 at low pO2 than HbA. Thus, HbF in fetal blood is better suited to bind O2 at the placenta (lower pO2) than HbA, which binds O2 at the lung (higher pO2).

Answer 88

~ 600 variants of hemoglobin. About half of them are clinically significant. The some different variants of hemoglobin include structural, thalassemias, and hereditary persistence of fetal hemoglobin

Answer 89

Mutations that alter the globin polypeptide properties without affecting its synthesis. Most structural variants are found in the β-globin chain. These mutations may alter O2 binding such as HbKemsey (too tight) and HbKansas (too weak), cause heme loss and denaturation of Hb, or make Hb less soluble such as HbS and HbC. Some can lead to serious red blood cell (RBC) diseases.

Answer 90

Disorders of imbalanced globin levels resulted from markedly reduced or no synthesis of one globin type. Can be caused by virtually all types of genetic mutations including deletions, missense and nonsense mutations, and defective transcriptional control. Note: A functional Hb tetramer is composed of two α (or α-like) chains and two β (or β-like) chains. Homotetramers (e.g. α4, β4, γ4) are poor O2 carriers and precipitate inside the RBC. Thalassemias are caused by an imbalance in the relative levels of the α and β globin chains, which leads to the precipitation of the globin in excess and decreases the life span of the RBC.

Answer 91

HPFH is a group of clinically benign conditions that impair the perinatal switch from γ- to β-globin synthesis, leading to continued high-level production of HbF in adults. HPFH may alleviate the severity of certain hemoglobinopathies and thalassemias, and is selected for in populations with a high prevalence of these conditions (which in turn are often selected for in areas where malaria is endemic). Thus, it has been found to affect Americans of African and Greek descent.

Answer 92

Most common among people of African origin, where carrier frequency is ~10%.it is a severe autosomal recessive hemolytic condition characterized by the red blood cells becoming grossly abnormal in shape under conditions of low o2 tension. Single base mutation at codon#6 in the β-globin gene changes glutamate to valine. HbS is 80% less soluble than HbA when not bound to O2, and polymerizes into long fibers that distort the RBC into a characteristic sickle shape. These sickled cells become lodged in the micro-capillaries and further exacerbate the sickling crisis.

Answer 93

A milder form of hemolytic anemia than sickle cell anemia. Caused by a single base mutation at codon#6 of the β-globin gene, changing glutamate to lysine. HbC is less soluble than HbA and tends to form crystals, reducing the deformability of RBC.

Answer 94

Both sickle cell anemia and hemoglobin CC disease are of autosomal recessive inheritance. Sickle cell trait (HbS trait) or hemoglobin C trait (HbC trait) describes the conditions expressed in individuals who are heterozygous of HbS/HbA and HbC/HbA, respectively. They are clinically normal except when under severe low pO2 stress.

Answer 95

Compound heterozygotes (βS/βC) have a milder anemia than sickle cell disease.

Answer 96

A recognition site (CCTNAGG) of the restriction enzyme MstII is destroyed in exon 1 by the A-to-T change in the βS mutant allele. The normal allele βA gives 1.15 kb + 0.20 kb fragments, whereas the βS mutant allele give one1.35 kb fragment. Note: MstII can distinguish between βA and βS but not between βA and βC.

Answer 97

Mostly caused by deletions of one or both copies of the α-globin gene in the α-cluster. Thus, γ- and β-globin are in excess. Affects the formation of both fetal and adult hemoglobins.

Answer 98

Common in Southeast Asia. Caused by deletion of both copies of α-globin genes in the α- cluster. Homozygous state (- -/- -) results in "hydrops fetalis" (stillborn). Most fetal hemoglobin is γ4 (Hb Bart’s) although there is enough ζ2γ2 (Hb Portland) to sustain fetal development. Heterozygotes (αα/--) have mild anemia, a.k.a. α-thalassemia-1 trait.

Answer 99

Common in Africa, Mediterranean, and Asia. Deletion of one of the two α-globin genes in the α-cluster. 50% decrease in α-globin synthesis. No disease phenotype in heterozygote (αα/α-, silent carrier). Mild anemia in homozygotes (α-/α-), a.k.a. α-thalassemia-2 trait.

Answer 100

Compound heterozygous individuals with only 25% of normal α-globin level. Severe anemia. a.k.a. HbH disease. About 5-30% of their hemoglobin is β4 (HbH), which precipitates.

Answer 101

Similar to alpha thalasemia, beta can cause hypochromic, microcytic anemia and the imbalance in globin synthesis leads to precipitation of the excess alpha chains, which in turn leads to damage of the red cell membrane. In contrast, the onset is not until a few months after birth, when beta globin normally replaces γ as the major non alpha chain. It is also usually due to single base pair substitutions rather than deletions (as in alpha). Show a wide range of severity and can be cause by virtually every possible type of mutation in the β-globin gene. High allelic heterogeneity means most patients with β-thalassemia are compound heterozygotes carrying two different mutant alleles of the β-globin gene. Categorization of β-thalassemias: Based on clinical conditions- thalassemia major vs thalassemia minor, Based on the molecular nature of the mutation – simple β-thalassemia vs complex thalassemia, Based on the biochemical nature of the diseases -β+-thalassemia vsβ0-thalassemia,

Answer 102

Characterized by severe anemia, in which most RBCs are destroyed before being released into the circulation. Thinning bone cortex, enlarged liver and spleen resulted from massive effort of blood production at these sites. Treat temporarily with blood transfusions; however, iron accumulation from repeated transfusion leads to organ failure. Iron chelation therapy (e.g. desferrioxamine) is used to reduce the complications of iron overload.

Answer 103

Clinically normal, carriers of one β-thalassemia allele.

Answer 104

Caused by mutations or deletions that impair the production of the β-globin chain alone. Other genes in the β-globin cluster unaffected. These mechanisms include promoter mutants, RNA splicing (in 5' GT or 3' AG), capping or tailling mutants, and frameshift or nonsense mutations

Answer 105

Caused by large deletions that remove the β-globin gene plus other genes in the β-cluster, or the LCR. Note that some deletions within β-cluster cause HPFH instead of thalassemia

Answer 106

Most common form of β-thalassemia (90% of the cases). Some β-globin is made so that some HbA is present. Decrease in β-globin synthesis can be caused by mutations affecting transcription, RNA processing, or protein stability.

Answer 107

Zero β-globin synthesis so that no HbA is present. Caused by deletion of the β-globin gene, nonsense or frameshift mutations at the 5’ of the coding region that lead to an early stop codon, or mutations that result in no RNA synthesis. [Hb] is ~5% of normal level (of which 95% is α2γ2 with 5% α2δ2), which is not enough for good survival.

Answer 108

No δ or β synthesis due to deletion of the coding sequences for both δ- and β-globin. Milder clinical phenotype than β0-thalassemia because the remaining γ gene(s) is still active after birth instead of switching off as would normally occur. Therefore, HbF (α2γ2) compensates for the absence of HbA (α2β2), about 5-18% of normal level of total hemoglobin production. Note: People with deletions that remove the δ and β genes (γ is intact) may have either δβ0- thalassemia or HPFH, depending on the range of the deletion.

Answer 109

No δ or β synthesis because of deletions of both genes. Increased γ-globin expression caused by either of the two following mechanisms: (1) extended deletion of additional downstream sequences, which likely brings a cis-acting enhancer element closer to the γ-globin gene, or (2) mutations in the promoter region of one of the two γ-globin genes that destroy the binding site of a repressor, thereby relieving postnatal repression of γ. HPFH individuals are disease free, since adequate levels of γ chains are still made due to the disruption of the perinatal globin switch from γ to β. 100% of hemoglobin is HbF (α2γ2), which is about 17-35% of normal level of total hemoglobin production. HPFH individuals have higher HbF (17-35%) level than δβ0-thalassemia individuals (5-18%). Understanding the mechanism of HPFH may make it possible to express HbF at high levels postnatally to treat patients of β-thalassemia and sickle cell anemia.

Answer 110

The heterochronic expression of genes controls the timing of developmental events. heterochrony is defined as a developmental change in the timing of events, leading to changes in size and shape. There are two main components, namely (i) the onset and offset of a particular process, and (ii) the rate at which the process operates.

Answer 111

the expression of a gene in an abnormal place in an organism. This can be caused by a disease, or it can be artificially produced as a way to help determine what the function of that gene is.

Answer 112

the process which produces red blood cells (erythrocytes). the termporal switch of globin synthesis (moving down the chromosome in th same transcriptional orientation), is accompanied by chanes in the major site of synthesis. In the early fetus, erythropoiesis takes place in the mesodermal cells of the yolk sac. HbF (α2γ2) is the main oxygen transport protein in the human fetus. By the third or fourth month, erythropoiesis moves to the liver. After seven months, erythropoiesis occurs in the bone marrow. Beta chains are only synthesized in high levels only near the time of birth. δ synthesis continues after birth but never accounts for more than about 2% of adult hemoglobin. On the alpha chain the order is ζ, Ψ (both are psuedogenes), than α (all in fetal development).

Answer 113

also known as adult hemoglobin or α2β2, is the most common human hemoglobin tetramer, comprising over 97% of the total red blood cell hemoglobin. It consists of two alpha chains and two beta chains

Answer 114

a normal variant of hemoglobin A that consists of two alpha and two delta chains (α2δ2) and is found at low levels in normal human blood. Hemoglobin A2 may be increased in beta thalassemia or in people who are heterozygous for the beta thalassemia gene.

Answer 115

(also hemoglobin F, HbF, or α2γ2) is the main oxygen transport protein in the human fetus during the last seven months of development in the uterus and persists in the newborn until roughly 6 months old. Functionally, fetal hemoglobin differs most from adult hemoglobin in that it is able to bind oxygen with greater affinity than the adult form, giving the developing fetus better access to oxygen from the mother's bloodstream.

Answer 116

a single mutation in beta affects 50% of beta chains whereas a single alpha chain muation affects only 25% of the alpha chain. Howerver, the beta globin mutation has no prenatal consequence because gamma globin is the beta like chain in HB F, which constitutes three quarters of the total hemoglobin at term. alpha globin mutation can cause sevre phenotypes both prenataly and after birth.

Answer 117

the majority of mutant hemoglobin that cause this make hemoglobin tetramer unstable. The two best known varients that cause hemolysis, sickle cell globin and Hb c, are not unstable but cause the mutant globin proteins to assume unusual rigid structure.

Answer 118

have either increased or decreased o2 affinity or form methemoglobin (a form of globin incapable of reversible oxygenation

Answer 119

mutations in the coding region that reduce the abundance of the globin polypeptide. Most of these mutations impair the rate of synthesis of the mrna or the protein. Some variants cause extreme instability of the hemoglobin monomer

Answer 120

a group of abnormal Hb's in which a single amino acid substitution favors the formation of methemoglobin in spite of normal quantities of methemoglobin reductase. Methemoglobin is a form of hemoglobin that contains ferric [Fe3+] iron and has a decreased ability to bind oxygen.

Answer 121

consists of four gamma chains. It is moderately insoluble, and therefore accumulates in the red blood cells. It has an extremely high affinity for oxygen, resulting in almost no oxygen delivery to the tissues. It is produced in the disease alpha-thalassemia and in the most severe of cases, it is the only form of haemoglobin in circulation. In this situation, a fetus will develop hydrops fetalis and normally die before or shortly after birth, unless intrauterine blood transfusion is performed. Since Hemoglobin Barts is elevated in alpha thalassaemia, it can be measured, providing a useful screening test for this disease in some populations.

Answer 122

α thalassemia 3 gene deletion. The genotype is -/- -/α, Two unstable hemoglobins are present in the blood: Hemoglobin Barts (tetrameric γ chains) and Hemoglobin H (tetrameric β chains). Both of these unstable hemoglobins have a higher affinity for oxygen than normal hemoglobin, resulting in poor oxygen delivery to tissues. There is a microcytic hypochromic anemia with target cells and Heinz bodies (precipitated HbH) on the peripheral blood smear, as well as hepatosplenomegaly. The disease may first be noticed in childhood or in early adult life, when the anemia and hepatosplenomegaly are noted.

Answer 123

a condition in the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments.[1] By comparison, hydrops allantois or hydrops amnion are an accumulation of excessive fluid in the allantoic or amniotic space respectively.

Answer 124

Males with alpha thalassemia X-linked intellectual disability syndrome have intellectual disability and delayed development. Their speech is significantly delayed, and most never speak or sign more than a few words. Most affected children have weak muscle tone (hypotonia), which delays motor skills such as sitting, standing, and walking. Some people with this disorder are never able to walk independently. Alpha thalassemia X-linked intellectual disability syndrome results from mutations in the ATRX gene. This gene provides instructions for making a protein that plays an essential role in normal development. Although the exact function of the ATRX protein is unknown, studies suggest that it helps regulate the activity (expression) of other genes. Among these genes are HBA1 and HBA2, which are necessary for normal hemoglobin production. Mutations in the ATRX gene change the structure of the ATRX protein, which likely prevents it from effectively regulating gene expression. Reduced activity of the HBA1 and HBA2 genes causes alpha thalassemia. Abnormal expression of other genes, which have not been identified, probably causes developmental delay, distinctive facial features, and the other signs and symptoms of alpha thalassemia X-linked intellectual disability syndrome.

Answer 125

Allows introduction of genetic variation to propagate new genetic traits. This benefits organisms who Exist in a constantly-changing environment, Encounter & need to fend off disease (bacteria, viruses and parasites), Need to purge deleterious mutations. Variation Occurs due to each parent sharing half it’s genome and Occurs due to recombination during meiosis. You therefore need Sexual Dimorphism, where The phenotypic differences between males & females and Includes reproductive organs as well as body habitus differences

Answer 126

Only ONE copy of the majority of genes on the X chromosome is necessary for normal function. Two copies of some of the genes may actually be detrimental. In somatic cells of females (not males), one copy of the X chromosome randomly turned off in “Random X inactivation”, which occurs during the 1st week of embryogenesis. females are functionally mosaic for their x chromosomes- Half of their cells express the maternally-inherited X, half express the paternally-inherited X. This can also be demonstrated in some breeds of female cats

Answer 127

when more of the maternal or paternal x is turned off. ususally you would not know unless there was a disease on the chromosome that is one. This is more of a random thing that cannot be explained. Observed when a female shows signs or symptoms of an X-linked recessive condition, such as Duchene Muscular Dystrophy or Fragile X Syndrome. Instead of a random inactivation pattern more of the X chromosome with normal gene is turned off

Answer 128

No matter how many X chromosomes, there is still only one active X chromosome, the rest are inactivated some karyotypes include: 46,XX, 47,XXX, 47,XXY, 48,XXYY. There is a small subset of genes that are not turned off during x inactivation, which may account for the phenotype related to these conditions.

Answer 129

a congenital multiloculated lymphatic lesion that can arise anywhere, but is classically found in the left posterior triangle of the neck and armpits. This is the most common form of lymphangioma. It contains large cyst-like cavities containing lymph, a watery fluid that circulates throughout the lymphatic system. Microscopically, cystic hygroma consists of multiple locules filled with lymph. In the depth, the locules are quite big but they decrease in size towards the surface. Cystic hygroma can be associated with a nuchal lymphangioma or a fetal hydrops.

Answer 130

47, XXY. Can be seen in childhood. Symptoms include: Learning disabilities, Delayed speech and language, Tendency towards being quiet, Tall stature, Small testes, Reduced facial and body hair, Infertility, Hypospadias, Gynecomastia, Occurs in 1/500 – 1/1000 newborn boys

Answer 131

47,XYY symptoms include: Learning disabilities, Speech delays, Developmental delays, Behavioral and emotional difficulties, Autism spectrum disorders, Tall stature, Occurs in 1/1000 newborn boys

Answer 132

Triple X Syndrome 47,XXX, May have tall stature, Increased risk of Learning disabilities, Delayed speech, Delayed motor milestones, Seizures, Kidney Abnormalities. Occurs in 1/1000 newborn girls

Answer 133

Primary Sex Determination – Determination of the Gonads. Gonad Determination is Chromosomal. Generally, the presence of a normal Y chromosome results in a male individual. Likewise, the presence of a normal X chromosome and the absence of the Y chromosome results in a female individual. *Some* exceptions to this due to other genetic variants. Secondary Sex Determination: Gonadal development then determines secondary sex characteristics. Includes sex-specific organs: Penis, seminal vesicles & prostate gland or Vagina, cervix, uterus, fallopian tubes & mammary glands. Includes other phenotypic features: Body habitus & musculature, Hair growth, and Vocal Cartilage

Answer 134

4th week of conception: Primordial germ cells form in wall of yolk sac. 5th week of conception: Coelomic epithelium becomes genital ridge. 6th week of conception: Primordial germ cells migrate to the dorsal mesentary of the hindgut and enter the undifferentiated gonad, Epithelial cells of gonadal ridge proliferate and form primitive sex cords

Answer 135

7th week of conception: Differentiation of genital ridge into, Sertoli cells - eventually produce sperm, Leydig cells – interstitial cells. 8th week of conception: Leydig cells begin producing testosterone, Sertoli cells begin producing Anti-Mullerian Hormone (AMH), Primitive sex cords differentiate into: Testis cords & rete testis, eventually to become seminipherous tubules during puberty

Answer 136

7th – 8th week of conception: In the absence of SRY & in the presence of 2 X chromosomes, Primitive sex cords dissociate into irregular clusters, Medullary (primitive) cords regress and cortical (secondary) cords are formed:Destined to become follicular cells of the ovary, Follicular cells will eventually surround an oogonium which together are the primary ovarian follicle

Answer 137

Initially, 2 pairs of genital ducts in both males & females, including Mesonephric (Wolffian) duct and Paramesonephric (Mullerian) duct

Answer 138

Chemotactic factor causes tubules from mesonephric duct to penetrate the gonadal ridge. Essential for differentiation of the testis

Answer 139

SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Müllerian hormone (AMH) gene. SOX-9 also plays a pivotal role in male sexual development; by working with Sf1, SOX-9 can produce AMH in Sertoli cells to inhibit the creation of a female reproductive system. It also interacts with a few other genes to promote the development of male sexual organs. The process starts when the transcription factor Testis determining factor (encoded by the sex-determining region SRY of the Y chromosome) activates SOX-9 activity by binding to an enhancer sequence upstream of the gene. Next, Sox9 activates FGF9 and forms feedforward loops with FGF9 and PGD2. These loops are important for producing SOX-9; without these loops, SOX-9 would run out and the development of a female would almost certainly ensue. Activation of FGF9 by SOX-9 starts vital processes in male development, such as the creation of testis cords and the multiplication of Sertoli cells. The association of SOX-9 and Dax1 actually creates Sertoli cells, another vital process in male development.

Answer 140

Stimulates differentiation of the Sertoli & Leydic cells

Answer 141

Extracellular signaling factor responsible for differentiation of the ovary and is Inhibited by SOX9

Answer 142

A nuclear hormone receptor that is Up-regulated by WNT4 and Down regulates SOX9

Answer 143

Coactivator of the WNT pathway

Answer 144

At 3 weeks, originating from mesenchymal cells in the primitive streak, cells migrate to form a genital tubercle and genital swellings. Both originate from the urogenital sinus. Male structures: Androgen exposure (in this case Dihydrotestosterone) from the testis results in the formation of the following: Penis, Scrotum, Location of the urethral opening at the tip of the penis. Female structures: Estrogen exposure resulting from maternal and placental sources results in the formation of the following: Clitoris, Labia majora and minora, Lower 2/3 of the vagina

Answer 145

a body of tissue present in the development of the reproductive system. It forms in the ventral, caudal region of mammalian embryos of both sexes, and eventually develops into a phallus. In the human fetus, the genital tubercle develops around week 4 of gestation, and by week 9 becomes recognizably either a clitoris or penis.

Answer 146

in male embryos, they close over the urethral plate and fuse to form the spongy urethra and ventral aspect of the penis; in female embryos, the unfused urogenital folds develop into the labia minora.

Answer 147

are paired structures in the human embryo that represent the final stage of development of the caudal end of the external genitals before sexual differentiation. In both males and females, the two swellings merge: In the female, they become the posterior labial commissure. The sides of the genital tubercle grow backward as the genital swellings, which ultimately form the labia majora; the tubercle itself becomes the mons pubis. In contrast, the labia minora are formed by the urogenital folds. In the male, they become the scrotum.

Answer 148

An infant at stage 1 has a mildly large clitoris and slightly reduced vaginal opening size. This degree may go unnoticed or may be simply assumed to be within normal variation. Stages 2 and 3 represent progressively more severe degrees of virilization. The genitalia are obviously abnormal to the eye, with a phallus intermediate in size and a small vaginal opening. Stage 4 looks more male than female, with an empty scrotum and a phallus the size of a normal penis, but not quite free enough of the perineum to be pulled onto the abdomen toward the umbilicus (i.e., what is termed a chordee in a male). The single small urethral/vaginal opening at the base or on the shaft of the phallus would be considered a hypospadias in a male. X-rays taken after dye injection into this opening reveal the internal connection with the upper vagina and uterus. This common opening can predispose to urinary obstruction and infection. Stage 5 denotes complete male virilization, with a normally formed penis with the urethral opening at or near the tip. The scrotum is normally formed but empty. The internal pelvic organs include normal ovaries and uterus, and the vagina connects internally with the urethra as in Stage 4. These infants are not visibly ambiguous are usually assumed to be ordinary boys with undescended testes. In most cases, the diagnosis of CAH is not suspected until signs of salt-wasting develop a week later.

Answer 149

On this 1st day of life: Obtain FISH studies for Sex Chromosomes and a Karyotype (or Chromosomal Microarray), Order hormone studies: LH, FSH, Testosterone, Dihydrotestosterone, +/- AMH. Consider ultrasound study to Evaluate for gonads & uterus and Surgical consult with Urology. Consider consultation with a specialized Disorders of Sexual Development team, if available, Endocrinology, Genetics, Urology, Psychology. Regardless of the results of the studies ordered, the answer to the family’s question is not necessarily straight forward. Issues to be considered: Underlying genetics, Family cultural and social perspective, Medical & surgical outcomes, Risks for tumor development, Fetal brain development in the context of hormone exposure/ future gender identity, Future sexuality, Future fertility

Answer 150

46, XY, X-linked gene, AR. Mutation causes abnormality of the androgen receptor. Even though the body makes androgens (testosterone), it doesn’t necessarily recognize or respond to it. Phenotypes range from mild under-virilization (Partial AIS) to full sex reversal (Complete AIS). Previously called “Testicular feminization”

Answer 151

46, XY. Mutation causes decreased ability of the body to convert testosterone to dihydrotestosterone. Phenotype shows undervirilized male with increased virilization at the time of puberty

Answer 152

46, XY or 46, XX, Y-linked gene in normal situations. Deletion or absence of the gene results in full 46, XY sex reversal and a phenotypically normal female. Ectopic presence of the SRY gene in a 46, XX individual results in a phenotypically normal male. Mutations in the SRY gene in a 46, XY individual results in decreased or absent production of Anti Mullerian hormone & under virilization of a male

Answer 153

Sex reversal with 46, XY. Due to mutations in the WT1 gene. Both cause different types of chronic kidney disease Diffuse mesangial sclerosis and Focal segmental glomerulosclerosis. Increased risk for Wilms Tumor. WT1 – transcription factor for SRY gene

Answer 154

The most common cause of ambiguous genitalia in 46, XX. 21-hydroxylase deficiency. Complicated by salt wasting in the first few weeks of life and with times of metabolic stress leading to Decreased sodium and chloride and Increased potassium

Answer 155

Unequal crossing over between two highly homologous repeats on chromosome 17p12 can result in: 3 copies of the PMP22 gene with the CMT1A phenotype or the reciprocal with 1 copy of the PMP22 gene with the HNPP phenotype.

Answer 156

an autosomal dominant disease that results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP-22). The PMP-22 protein is a critical component of the myelin sheath. Overexpression of this gene causes the structure and function of the myelin sheath to be abnormal. Patients experience weakness and atrophy of the muscles of the lower legs beginning in adolescence; later they experience hand weakness and sensory loss. Interestingly, a different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP-22 genes. In this case, abnormally low levels of the PMP-22 gene result in episodic, recurrent demyelinating neuropathy.

Answer 157

Clinically: Brittle bones, increased fractures (non-deforming), blue sclerae, normal stature. First fracture may occur with diapering, but more typically once infant begins to walk (and fall), Affected individuals may have anywhere from a few fractures to more than 100M, Progressive hearing loss in adults. The structure of type I procollagen. Note that type I procollagen is composed of two proα1(I) chains and one proα2(I) chain. OI Type I: Premature termination codons (nonsense and frameshift) in COL1A1 -> mRNA unstable -> mRNA degraded -> reduction of normal COL1A1 protein Autosomal Dominant. Funtionaly these patients make a lower amount of this triple helix of collagen. In Osteogenesis type I, loss of function mutations -> ½ the amount of total collagen trimers, but it is all normal -> mild phenotype

Answer 158

In Osteogenesis types II, III, IV novel property mutations à relatively ‘normal’ amount of total collagen trimers, but ½ is abnormal à severe phenotype. Lesson: better to have ½ the amount of normal collagen (type I), than produce abnormal collagen trimers (types II-IV)

Answer 159

type 2 results from mutations in the CNBP gene. The protein produced from the CNBP gene is found primarily in the heart and in skeletal muscles, where it probably helps regulate the function of other genes. Similar changes in the structure of the DMPK and CNBP genes cause the two forms of myotonic dystrophy. In each case, a segment of DNA is abnormally repeated many times, forming an unstable region in the gene. The mutated gene produces an expanded version of messenger RNA, which is a molecular blueprint of the gene that is normally used to guide the production of proteins. The abnormally long messenger RNA forms clumps inside the cell that interfere with the production of many other proteins. These changes prevent muscle cells and cells in other tissues from functioning normally, which leads to the signs and symptoms of myotonic dystrophy.

Answer 160

Myotonic dystrophy is characterized by progressive muscle wasting and weakness. People with this disorder often have prolonged muscle contractions (myotonia) and are not able to relax certain muscles after use. For example, a person may have difficulty releasing their grip on a doorknob or handle. Also, affected people may have slurred speech or temporary locking of their jaw. The muscle weakness associated with type 1 particularly affects the lower legs, hands, neck, and face. Myotonic dystrophy type 1 is caused by mutations in the DMPK gene. The protein produced from the DMPK gene may play a role in communication within cells. It appears to be important for the correct functioning of cells in the heart, brain, and skeletal muscles (which are used for movement).

Answer 161

an autosomal recessive inherited disease that causes progressive damage to the nervous system. It manifests in initial symptoms of poor coordination such as gait disturbance; it can also lead to scoliosis, heart disease and diabetes, but does not affect cognitive function. The disease progresses until a wheelchair is required for mobility. Its incidence in the general population is roughly 1 in 50,000. Friedreich's ataxia is an autosomal recessive disorder that occurs when the FXN gene contains amplified intronic GAA repeats. The FXN gene encodes the protein frataxin. GAA repeat expansion causes frataxin levels to be reduced. Frataxin is an iron-binding protein responsible for forming iron–sulphur clusters. One result of frataxin deficiency is mitochondrial iron overload which can cause damage to many proteins. The exact role of frataxin in normal physiology remains unclear. The gene is located on chromosome 9. The mutant gene contains expanded GAA triplet repeats in the first intron; in a few pedigrees, point mutations have been detected. Because the defect is located in an intron, the mutation causes gene silencing through induction of a heterochromatin structure in a manner similar to position-effect variegation. Maternal expansion is more likely

Answer 162

a naturally occurring essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases. A deficit in tetrahydrobiopterin biosynthesis and/or regeneration can result in phenylketonuria (PKU) from excess L-phenylalanine concentrations or hyperphenylalaninemia (HPA), as well as monoamine and nitric oxide neurotransmitter deficiency or chemical imbalance. The chronic presence of PKU can result in severe brain damage, including symptoms of mental retardation, microcephaly, speech impediments such as stuttering, slurring, and lisps, seizures or convulsions, and behavioral abnormalities, among other effects.

Answer 163

it is a protease inhibitor and is a suicide substrate of the serine protease elastase

Answer 164

is released and activated by neutrophils at the airway, destroing elastin in the connective tissue for elastin remodeling

Answer 165

the most abundant (40% to 75%) type of white blood cells in mammals and form an essential part of the innate immune system. They are formed from stem cells in the bone marrow. They are short-lived and highly motile.

Answer 166

The HEXA gene provides instructions for making one part (subunit) of an enzyme called beta-hexosaminidase A. Specifically, the protein produced from the HEXA gene forms the alpha subunit of this enzyme. One alpha subunit joins with one beta subunit (produced from the HEXB gene) to form a functioning enzyme. Beta-hexosaminidase A plays a critical role in the brain and spinal cord (central nervous system). This enzyme is found in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, beta-hexosaminidase A forms part of a complex that breaks down a fatty substance called GM2 ganglioside.

Answer 167

The GM2A gene provides instructions for making a protein called the GM2 ganglioside activator. This protein is necessary for the normal function of an enzyme called beta-hexosaminidase A, which plays a critical role in the brain and spinal cord (central nervous system). Beta-hexosaminidase A and the GM2 ganglioside activator protein work together in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, the activator protein binds to a fatty substance called GM2 ganglioside and presents it to beta-hexosaminidase A to be broken down.

Answer 168

Hexosaminidase A and the cofactor GM2 activator protein catalyze the degradation of the GM2 gangliosides and other molecules containing terminal N-acetyl hexosamines. Hexosaminidase A is a heterodimer composed of an alpha subunit (this protein) and a beta subunit. The alpha subunit polypeptide is encoded by the HEXA gene while the beta subunit is encoded by the HEXB gene. Gene mutations in the gene encoding the beta subunit (HEXB) often result in Sandhoff disease; whereas, mutations in the gene encoding the alpha subunit (HEXA, this gene) decrease the hydrolysis of GM2 gangliosides, which is the main cause of Tay–Sachs disease.

Answer 169

Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II).

Answer 170

Also called Tay-Sachs Disease, AB Variant. Mutations in the GM2A gene cause GM2-gangliosidosis, AB variant. The GM2A gene provides instructions for making a protein called the GM2 ganglioside activator. This protein is required for the normal function of an enzyme called beta-hexosaminidase A, which plays a critical role in the brain and spinal cord. Beta-hexosaminidase A and the GM2 ganglioside activator protein work together in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, the activator protein binds to a fatty substance called GM2 ganglioside and presents it to beta-hexosaminidase A to be broken down. Mutations in the GM2A gene disrupt the activity of the GM2 ganglioside activator, which prevents beta-hexosaminidase A from breaking down GM2 ganglioside. As a result, this substance accumulates to toxic levels, particularly in neurons in the brain and spinal cord. Progressive damage caused by the buildup of GM2 ganglioside leads to the destruction of these neurons, which causes the signs and symptoms of the AB variant. Because the AB variant impairs the function of a lysosomal enzyme and involves the buildup of GM2 ganglioside, this condition is sometimes referred to as a lysosomal storage disorder or a GM2-gangliosidosis.

Answer 171

also known as Sandhoff-Jatzkewitz disease, variant 0 of GM2-Gangliosidosis or Hexosaminidase A and B deficiency, is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B. These catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2, its derivative GA2, the glycolipid globoside in visceral tissues, and some oligosaccharides. Accumulation of these metabolites leads to a progressive destruction of the central nervous system and eventually to death. The rare autosomal recessive neurodegenerative disorder is clinically almost indistinguishable from Tay-Sachs disease, another genetic disorder that disrupts beta-hexosaminidases A and S. There are three subsets of Sandhoff disease based on when first symptoms appear: classic infantile, juvenile and adult late onset.

Answer 172

ζ to alpha, ε to gamma (around 6 weeks), gamma to beta | at birth

Answer 173

Hbc changes it to positve-> slows it downt the most. Hbs changes it to neutral-> slows down, HbA is normaly negative so it moves the quickes to the positive anode.

Answer 174

a disease state in which the proportion of blood volume that is occupied by red blood cells increases. Blood volume proportions can be measured as hematocrit level. It can be due to an increase in the number of red blood cells ("absolute polycythemia") or to a decrease in the volume of plasma ("relative polycythemia"). Polycythemia is sometimes called erythrocytosis, but the terms are not synonymous because polycythemia refers to any increase in red blood cells, whereas erythrocytosis only refers to a documented increase of red cell mass.

Answer 175

an abnormal Hb of molecular formula α2Aβ2102Asn→Thr; found in association with familial cyanosis due to decreased oxygen affinity of this Hb.

Answer 176

a condition in which red blood cells are unusually small as measured by their mean corpuscular volume. Thalassemia can cause microcytosis. Depending upon how the terms are being defined, thalassemia can be considered a cause of microcytic anemia, or it can be considered a cause of microcytosis but not a cause of microcytic anemia.

Answer 177

a generic term for any type of anemia in which the red blood cells (erythrocytes) are paler than normal. (Hypo- refers to less, and chromic means color.) A normal red blood cell will have an area of pallor in the center of it; in hypochromic cells, this area of central pallor is increased. This decrease in redness is due to a disproportionate reduction of red cell hemoglobin (the pigment that imparts the red color) in proportion to the volume of the cell. In many cases, the red blood cells will also be small (microcytic), leading to substantial overlap with the category of microcytic anemia. The most common causes of this kind of anemia are iron deficiency and thalassemia.

Answer 178

an acquired form of alpha-thalassemia (see this term) characterized by a myelodysplastic syndrome (MDS) or more rarely a myeloproliferative disease (MPD) associated with hemoglobin H disease. ATMDS is due to acquired somatic mutations in the ATRX gene (Xq21.1). There is also evidence that acquired deletions of chromosome 16p may be causative. These defects result in significant down-regulation of alpha-globin gene expression.

Answer 179

point mutations in the underlying DNA or errors during transcription can activate a cryptic splice site in part of the transcript that usually is not spliced. This results in a mature messenger RNA with a missing section of an exon. In this way, a point mutation, which usually only affects a single amino acid, can manifest as a deletion in the final protein.

Answer 180

an abnormal hemoglobin with a single point mutation in the β chain. At position 26 there is a change in the amino acid, from glutamic acid to lysine. Hemoglobin E has been one of the less well known variants of normal hemoglobin. It is very common in Southeast Asia but has a low frequency amongst other races. HbE can be detected on electrophoresis.

Answer 181

Incomplete dominance is a form of intermediate inheritance in which one allele for a specific trait is not completely dominant over the other allele. This results in a third phenotype in which the expressed physical trait is a combination of the dominant and recessive phenotypes. Incomplete dominance is similar to, but different from co-dominance. In co-dominance, an additional phenotype is produced, however both alleles are expressed completely. Co-dominance is exemplified in AB blood type inheritance.

Answer 182

are genes that are present in both sexes of sexually reproducing species but are expressed in only one sex and remain 'turned off' in the other. In other words, sex-limited genes cause the two sexes to show different traits or phenotypes, despite having the same genotype. This term is restricted to autosomal traits, and should not be confused with sex-linked characteristics, which have to do with genetic differences on the sex chromosomes (see sex-determination system). Sex-limited genes are also distinguished from sex-influenced genes, where the same gene will show differential expression in each sex. Sex-influenced genes commonly show a dominant/recessive relationship, where the same gene will have a dominant effect in one sex and a recessive effect in the other (for example, male pattern baldness).

Answer 183

females who are heterozygous may or may not emonstrate the disease, depending on the pattern of random x inactivation and the porportion of cells in pertinent tissues that have the mutant allele n the avtive vs. inactive chromosome. There can also be homozygous affected females.

Answer 184

when a female carrier of a recessive x-linked allele has a phenotypic expression of the disease. This event depends on skewed x inactivation in pertinent tissues. Also females will have different degress of disease penetrance and expression

Answer 185

people with the condition in each generation, males and females affected in roughly equal proportions, all forms of transmission present (male to female, male to male, female to male and female to female).

Answer 186

the incidence of the trait is much higher in males than females. Heterozygous females are usually unaffected but some may express the condition with vaiable severity as determined by the pattern of x inactivation. The gene reponsible for the condition is transmitted from an affected man through all his daughters. any of his daughters sons has a 50% chance of inheriting it. the mutant allele is ordinarily never transmitted directly from father to t son, but it is transmitted by an affected male to all his daughters. the mutant allele may be transmitted through a series of female carriers; if so the affected males in a kindred are related through females. a significant proportion of isolated cases are due to new mutation.

Answer 187

affected males with noraml mates have no affected sons and no normal daughters. Both male and female offspring of female carriers have 50% risk of inheriting the phenotype. The pedigree pattern is similar to that seen with autosomal dominant inheritance. affected females are about twice as comen as affected males but affected females typically have milder (although variable) expression of the phenotype.

Answer 188

the inferitance pattern seen with genes in the pseudoautosomal region of the x and y chromosomes that can exchange regularly between the two sex chromosomes and therefore mimic autosomal inheritance.

Answer 189

Somatic mosaicism occurs when the somatic cells of the body are of more than one genotype. In the more common mosaics, different genotypes arise from a single fertilized egg cell, due to mitotic errors at first or later cleavages. The most common form of mosaicism found through prenatal diagnosis involves trisomies. Although most forms of trisomy are due to problems in meiosis and affect all cells of the organism, there are cases where the trisomy occurs in only a selection of the cells. This may be caused by a nondisjunction event in an early mitosis, resulting in a loss of a chromosome from some trisomic cells. Generally this leads to a milder phenotype than in non-mosaic patients with the same disorder. But mosaicism need not necessarily be deleterious. Revertant somatic mosaicism is a rare recombination event in which there is a spontaneous correction of a mutant, pathogenic allele. In revertant mosaicism, the healthy tissue formed by mitotic recombination can outcompete the original, surrounding mutant cells in tissues like blood and epithelia that regenerate often.

Answer 190

the precursor (germline) cells to ova and spermatazoa are a mixture (mosaic) of two or more genetically different cell lines. The cause is usually a mutation that occurred in an early stem cell that gave rise to all or part of the gonadal tissue.

Answer 191

In disorders caused by trinucleotide repeat expansions, an abnormally large allele that is not associated with clinical symptoms but that can expand into a full mutation when transmitted to offspring (Full mutations are associated with clinical symptoms of the disorder.)

Answer 192

A unique feature of mtDNA is that, at cell division, the mtDNA replicates and sorts randomly among mitochondria. In turn, the mitochondria sort randomly among daughter cells. Therefore, in cells where heteroplasmy is present, each daughter cell may receive different proportions of mitochondria carrying normal and mutant mtDNA.

Answer 193

a cell that has a uniform collection of mtDNA: either completely normal mtDNA or completely mutant mtDNA.

Answer 194

A cell can have some mitochondria that have a mutation in the mtDNA and some that do not. This is termed heteroplasmy. The proportion of mutant mtDNA molecules determines both the penetrance and severity of expression of some diseases.

Answer 195

The DNA found in mitochondria, the energy-producing organelles of cells, is often analyzed to trace evolutionary pathways. Mitochondrial DNA (mtDNA) has a high "substitution" or mutation rate, compared with other sites in our genome. mtDNA is transmitted only from mother to child, and can be inherited intact over thousands of generations. Mutations in the mtDNA sequence can be used to reconstruct the maternal lineage of populations.

Answer 196

the enlargement of red blood cells with near-constant hemoglobin concentration, and is defined by a mean corpuscular volume (MCV) of greater than 100 femtolitres (the precise criterion varies between laboratories).

Answer 197

an erythrocyte that is normal in size, shape, and color.

Answer 198

The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1; this gene) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions.

Answer 199

The human β-globin locus is composed of five genes located on a short region of chromosome 11, responsible for the creation of the beta parts (roughly half) of the oxygen transport protein Hemoglobin. This locus contains not only the beta globin gene but also delta, gamma-A, gamma-G, and epsilon globin. Expression of all of these genes is controlled by single locus control region (LCR), and the genes are differentially expressed throughout development. The order of the genes in the beta-globin cluster is: 5' - epsilon – gamma-G – gamma-A – delta – beta - 3'. The arrangement of the genes directly reflects the temporal differentiation of their expression during development, with the early-embryonic stage version of the gene located closest to the LCR. If the genes are rearranged, the gene products are expressed at improper stages of development.

Answer 200

is a normal variant of hemoglobin A that consists of two alpha and two delta chains (α2δ2) and is found at low levels in normal human blood. Hemoglobin A2 may be increased in beta thalassemia or in people who are heterozygous for the beta thalassemia gene. HbA2 exists in small amounts in all adult humans (1.5-3.1% of all hemoglobin molecules) and is increased in people with Sickle-cell disease. Its biological importance is not yet known.

Answer 201

Hemoglobin S: Homozygous SS disease “Sickle Cell Anemia”, S heterozygous: AS, sickle trait. Sickle Syndromes: Hemoglobin SC hemoglobinopathy, SB° thalassemia, SB+ thalassemia. Hemoglobin C: Homozygous CC hemoglobinopathy, Heterozygous C, e.g. AC, or C trait, C-Beta thalassemia. Hemoglobin E: Homozygous EE, Heterozygous AE, Combination: E-Beta thalassemia

Answer 202

α thalassemia, β thalassemia, γ thalassemia, Δ thalassemia

Answer 203

Clinically significant only at birth and usually over by 6 months of life.

Answer 204

Not significant by itself but can be a problem if β-d thalassemia.

Answer 205

S, C, α (mostly trait 1) and β thalassemia

Answer 206

α (mostly trait 2) and β thalassemia and E

Answer 207

β thalassemia and S

Answer 208

α, β thalassemia and E

Answer 209

Thalassemia is a disorder in which a reduced rate of one or more of the globin chain synthesis leads to imbalanced globin chain production, defective hemoglobin production and damage to the red cells and their precursors.

Answer 210

α thalassemia 2 gene deletion

Answer 211

Hemoglobin Constant Spring is a variant in which a mutation in the alpha globin gene produces an alpha globin chain that is abnormally long. The quantity of hemoglobin in the cells is low for two reasons. First, the messenger RNA for hemoglobin Constant Spring is unstable. Some is degraded prior to protein synthesis. Second, the Constant Spring alpha chain protein is itself unstable. The result is a thalassemic phenotype. (The designation Constant Spring derives from the isolation of the hemoglobin variant in a family of ethnic Chinese background from the Constant Spring district of Jamaica.)

Answer 212

β thalassemia major, 2 severely abnormal or absent genes

Answer 213

B0/B+, 2 mildly moderately abnormal genes

Answer 214

β+/β or β0/β, also know as beta thal minor, 1 abnormal gnee, 1 normal gene

Answer 215

The direct effects of BTM on other organs and tissues in the body are due to the deleterious effects of the profound anemia, the byproducts of hemolysis, and the intramedullary and extramedullary expansion of erythroid marrow progenitors. However, in actual practice, patients exhibit both direct and indirect abnormalities of a number of organ systems. Indirect effects include the accumulation of end-organ damage due to iron overload either from blood transfusions or accelerated iron turnover, blood-borne infections (eg, viral hepatitis from blood transfusions), or progressive diversion of caloric resources to bone marrow expansion. dense skill/ marrow expansion, englarged spleen, osteopenia/ bone changes-Skeletal abnormalities are dramatic in these patients and frequently lead to marked changes in the facial structure and body habitus, producing the characteristic "chipmunk facies" and delayed skeletal maturation. Skeletal changes are due largely to the expansion and invasion of erythroid bone marrow, which widen the marrow spaces, attenuate the cortex, and produce osteoporosis. iron overload, and short growth and endocrine failure

Answer 216

Red cell transfusions, Iron chelators, Vitamin C, Splenectomy/cholecystectomy, Bone marrow transplant

Answer 217

Autosomal dominant. Most common skeletal dysplasia. 1 in 15,000-40,000 newborns. 80% new mutation rate. These explain autosomal dominant disorder seen in a child without affected parents. Small stature: Males 4’ 3” and Females 4’, Rhizomelic limb shortening, Short fingers, Genu varum, Trident hands, Large head/frontal bossing, Midfacial retrusion, Small Foramen Magnum/Craniocervical instability

Answer 218

also called bow-leggedness, bandiness, bandy-leg, and tibia vara), is a physical deformity marked by (outward) bowing of the leg in relation to the thigh, giving the appearance of an archer's bow. Usually medial angulation of both femur and tibia is involved.

Answer 219

Fibroblast Growth Factor Receptor 3. Regulates bone growth by limiting the formation of bone from cartilage. Chromosome 4p16.3 nucleotide 1138. Amino acid substitution 1138G>A. Mutation increases the activity of the protein interfering with skeletal development. Nucleotide 1138 of the FGFR3 gene has the highest new mutation rate known in man. is mutated in achondroplasia

Answer 220

Men over the age of 40 are noted to have a higher rate of children with de-novo autosomal dominant conditions: Achondroplasia, Apert Syndrome, Crouzon Syndrome, Pfeiffer Syndrome. Large number of cell divisions during spermatogenesis increases the mutation rate. Older men have decreased ability to repair mutations

Answer 221

Retinoblastoma, BRCA mutation, Huntington Disease

Answer 222

Retinoblastoma is a rare type of eye cancer that usually develops in early childhood, typically before the age of 5. This form of cancer develops in the retina, which is the specialized light-sensitive tissue at the back of the eye that detects light and color. Malignant tumor of the retina, 1 in 15,000 live births, RB1 on chromosome 13, Retinoblastoma Associated protein regulates the cell cycle, 90% penetrance. Mutations in the RB1 gene are responsible for most cases of retinoblastoma. RB1 is a tumor suppressor gene, which means that it normally regulates cell growth and keeps cells from dividing too rapidly or in an uncontrolled way. Most mutations in the RB1 gene prevent it from making any functional protein, so it is unable to regulate cell division effectively. As a result, certain cells in the retina can divide uncontrollably to form cancerous tumors. Some studies suggest that additional genetic changes can influence the development of retinoblastoma; these changes may help explain variations in the development and growth of tumors in different people

Answer 223

Neurofibromatosis type 1 is a condition characterized by changes in skin coloring (pigmentation) and the growth of tumors along nerves in the skin, brain, and other parts of the body. The signs and symptoms of this condition vary widely among affected people. The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many cells, including nerve cells and specialized cells surrounding nerves (oligodendrocytes and Schwann cells). Neurofibromin acts as a tumor suppressor, which means that it keeps cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the NF1 gene lead to the production of a nonfunctional version of neurofibromin that cannot regulate cell growth and division. As a result, tumors such as neurofibromas can form along nerves throughout the body. It is unclear how mutations in the NF1 gene lead to the other features of neurofibromatosis type 1, such as café-au-lait spots and learning disabilities. Autosomal dominant, 1 in 3000 births, 50% new mutation rate. NIH Diagnostic Criteria 2 or more of the following: 6 or more café-au-lait spots, 2 or more neurofibromas, 1 plexiform neurofibroma, Freckling in the axillary or inguinal area, Optic glioma, 2 or more Lisch Nodules, Distinctive osseous lesions, Affected first degree relative. Although considered dominant must have a mutation in both genes to show the phenotype

Answer 224

Osteogenesis imperfecta (OI) is a genetic disorder that causes a person's bones to break easily, often from little or no apparent trauma. OI is also called "brittle bone disease." OI varies in severity from person to person, ranging from a mild type to a severe type that causes death before or shortly after birth. In addition to having fractures, people with OI also have teeth problems (dentinogenesis imperfecta), and hearing loss when they are adults. People who have OI may also have muscle weakness, loose joints (joint laxity) and skeletal malformations. Type I OI is the mildest form of the condition. People who have type I OI have bone fractures during childhood and adolescence often due to minor trauma When these individuals reach adulthood they have fewer fractures. Autosomal dominant, 1 in 30,000-50,000. COL1A1: Collagen type 1 alpha 1, Chromosome 7q21.3, Reduced production of pro-alpha 1 chains that reduces the type 1 collagen production by half, Molecular and biochemical testing available

Answer 225

The COL1A1 gene provides instructions for making part of a large molecule called type I collagen. Collagens are a family of proteins that strengthen and support many tissues in the body, including cartilage, bone, tendon, skin, and the white part of the eye (the sclera). Type I collagen is the most abundant form of collagen in the human body. Osteogenesis imperfecta is the most common disorder caused by mutations in the COL1A1 gene. More than 400 COL1A1 gene mutations that cause osteogenesis imperfecta have been identified. Most of the mutations that are responsible for osteogenesis imperfecta type I, the mildest form of this disorder, reduce the production of pro-α1(I) chains. With fewer pro-α1(I) chains available, cells can make only half the normal amount of type I collagen. A shortage of this critical protein underlies the bone fragility and other characteristic features of osteogenesis imperfecta type I. Several kinds of mutations in the COL1A1 gene cause the more severe forms of osteogenesis imperfecta, including types II, III, and IV. In addition to more severe bone problems, features of these conditions can include blue sclerae, short stature, hearing loss, respiratory problems, and a disorder of tooth development called dentinogenesis imperfecta. Some of the mutations that cause severe forms of osteogenesis imperfecta delete segments of DNA from the COL1A1 gene, resulting in an abnormally shortened, often nonfunctional pro-α1(I) chain. Other genetic changes alter the sequence of amino acids in the pro-α1(I) chain, usually replacing the amino acid glycine with a different amino acid. In some cases, amino acid substitutions alter one end of the protein chain (called the C-terminus), which interferes with the assembly of collagen molecules. These COL1A1 gene mutations lead to the production of abnormal versions of type I collagen. When this abnormal collagen is incorporated into developing bones and other connective tissues, it causes the serious health problems associated with severe forms of osteogenesis imperfecta.

Answer 226

a genetic disorder of human connective tissue. It has various expressions ranging from mild to severe: the most serious complications are defects of the heart valves and aorta, which often lead to early death. The syndrome also may affect the lungs, eyes, dural sac surrounding the spinal cord, the skeleton, and the hard palate. People with Marfan tend to be unusually tall, with long limbs and long, thin fingers and toes. Marfan syndrome is caused by mutations in the FBN1 gene on chromosome 15, which encodes the glycoprotein fibrillin-1, a component of the extracellular matrix. Fibrillin-1 protein is essential for the proper formation of the extracellular matrix, including the biogenesis and maintenance of elastic fibers. The extracellular matrix is critical for both the structural integrity of connective tissue, but also serves as a reservoir for growth factors. Elastin fibers are found throughout the body, but are particularly abundant in the aorta, ligaments and the ciliary zonules of the eye; consequently, these areas are among the worst affected. It can also be caused by a range of intravenous crystal treatments in those susceptible to the disorder. Systemic disorder of connective tissue, Ocular, Skeletal, Cardiovascular. the major sign that would lead a doctor to consider an underlying condition is a dilated aorta or an aortic aneurysm. Sometimes, no heart problems are apparent until the weakening of the connective tissue (cystic medial degeneration) in the ascending aorta causes an aortic aneurysm or aortic dissection, a surgical emergency. An aortic dissection is most often fatal and presents with pain radiating down the back, giving a tearing sensation.

Answer 227

a displacement or malposition of the eye's crystalline lens from its normal location. A partial dislocation of a lens is termed lens subluxation or subluxated lens; a complete dislocation of a lens is termed lens luxation or luxated lens.

Answer 228

an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels. Approximately 50% of people with this disease will develop end stage kidney disease and require dialysis or kidney transplantation. Progression to end stage kidney disease usually happens in the 4th to 6th decades of life. Autosomal dominant polycystic kidney disease occurs worldwide and affects about 1 in 400 to 1 in 1000 people. Two PKD genes, PKD1 and PKD2, encode membrane proteins that localize to a non-motile cilium on the renal tube cell. Polycystin-2 encoded by PKD2 gene is a calcium channel that allows extracellular calcium ions to enter the cell. Polycystin-1, encoded by PKD1 gene, is thought to be associated with polycystin-2 protein and regulates polycystin-2's channel activity. The calcium ions are important cellular messengers, which trigger complicated biochemical pathways that lead to quiescence and differentiation. Malfunctions of polycystin-1 or polycystin-2 proteins, defects in the assembly of the cilium on the renal tube cell, failures in targeting these two proteins to the cilium, and deregulations of calcium signaling all likely cause the occurrence of PKD. Autosomal dominant, 1 in 1000 births, 5% new mutation rate. Bilateral renal cysts, Cysts in other organs, Vascular abnormalities, End stage renal disease in 50% by 60 years old

Answer 229

a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease. The high cholesterol levels in FH are less responsive to the kinds of cholesterol control methods that are usually more effective in people without FH (such as dietary modification and statin tablets), because the body's underlying biochemistry is slightly different. However, treatment (including higher statin doses) can often be successful. Many people have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. People who have one abnormal copy (are heterozygous) of the LDLR gene may have premature cardiovascular disease at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, inherited in an autosomal dominant pattern, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births. Very low new mutation rate

Answer 230

a deposition of yellowish cholesterol-rich material that can appear anywhere in the body in various disease states. They are cutaneous manifestations of lipidosis in which lipids accumulate in large foam cells within the skin. They are associated with hyperlipidemias, both primary and secondary types.

Answer 231

The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45 kb, and the protein gene product contains 839 amino acids in mature form. A single abnormal copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes accelerated atherosclerosis in childhood, including its complications. The plasma LDL levels are inversely related to the activity of LDL receptor (LDLR). Homozygotes have LDLR activity of less than 2%, while heterozygotes have defective LDL processing with receptor activity being 2–25%, depending on the nature of the mutation. Over 1000 different mutations are known.

Answer 232

Apolipoprotein B, in its ApoB100 form, is the main apolipoprotein, or protein part of the lipoprotein particle. Its gene is located on the second chromosome (2p24-p23) and is between 21.08 and 21.12 Mb long. FH is often associated with the mutation of R3500Q, which causes replacement of arginine by glutamine at position 3500. The mutation is located on a part of the protein that normally binds with the LDL receptor, and binding is reduced as a result of the mutation. Like LDLR, the number of abnormal copies determines the severity of the hypercholesterolemia.

Answer 233

Mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene were linked to autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report. The gene is located on the first chromosome (1p34.1-p32) and encodes a 666 amino acid protein that is expressed in the liver. It has been suggested that PCSK9 causes FH mainly by reducing the number of LDL receptors on liver cells.

Answer 234

Expansion of a segment of DNA consisting of three or more nucleotides, CAG CAGCAGCAGCAGCAG, Slipped Mispairing, Anticipation, Parental Transmission Bias, AD, AR and X-linked transmission

Answer 235

Mispairing of bases in regions of repetitive DNA replication coupled with inadequate DNA repair systems. As the repeat grows longer the probability of subsequent mispairing increases

Answer 236

Severity and/or onset of disease increases in next generation

Answer 237

Trinucleotide expansion more prone to occur in gametogenesis of the male or the female

Answer 238

a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and behavioral[1] symptoms. It typically becomes noticeable in mid-adult life. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease used to be called Huntington's chorea. Symptoms of the disease can vary between individuals and even among affected members of the same family, but usually progress predictably. The earliest symptoms are often subtle problems with mood or cognition. A general lack of coordination and an unsteady gait often follows. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral symptoms.[1] Physical abilities are gradually impeded until coordinated movement becomes very difficult. Mental abilities generally decline into dementia. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy to around twenty years from the point at which symptoms begin. There is no cure for HD, and full-time care is required in the later stages of the disease. Existing pharmaceutical and non-drug treatments can relieve many of its symptoms. All humans have two copies of the Huntingtin gene (HTT), which codes for the protein Huntingtin (Htt). The gene is also called HD and IT15, which stands for 'interesting transcript 15'. Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant Huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant: mutation of either of a person's HTT genes causes the disease. It is not inherited according to sex, but the length of the repeated section of the gene and hence its severity can be influenced by the sex of the affected parent. Instability is greater in spermatogenesis than oogenesis; maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length. Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingting.

Answer 239

a symptom of a small handful of certain neuromuscular disorders characterized by delayed relaxation (prolonged contraction) of the skeletal muscles after voluntary contraction or electrical stimulation.

Answer 240

The DMPK gene provides instructions for making a protein called myotonic dystrophy protein kinase. Although the specific function of this protein is unknown, it appears to play an important role in muscle, heart, and brain cells. This protein may be involved in communication within cells. It also appears to regulate the production and function of important structures inside muscle cells by interacting with other proteins. For example, myotonic dystrophy protein kinase has been shown to turn off (inhibit) a specific subunit (PPP1R12A) of a muscle protein called myosin phosphatase. Myosin phosphatase is an enzyme that plays a role in muscle tensing (contraction) and relaxation.

Answer 241

Hereditary hypophosphatemic rickets is a disorder related to low levels of phosphate in the blood (hypophosphatemia). Phosphate is a mineral that is essential for the normal formation of bones and teeth. In most cases, the signs and symptoms of hereditary hypophosphatemic rickets begin in early childhood. The features of the disorder vary widely, even among affected members of the same family. Mildly affected individuals may have hypophosphatemia without other signs and symptoms. More severely affected children experience slow growth and are shorter than their peers. They develop bone abnormalities that can interfere with movement and cause bone pain. The most noticeable of these abnormalities are bowed legs or knock knees (a condition in which the lower legs are positioned at an outward angle). These abnormalities become apparent with weight-bearing activities such as walking. If untreated, they tend to worsen with time. Hereditary hypophosphatemic rickets can result from mutations in several genes. Mutations in the PHEX gene, which are responsible for X-linked hypophosphatemic rickets, occur most frequently. Mutations in other genes cause the less common forms of the condition. PHEX: Regulates fibroblast growth factor. Inhibits the kidneys ability to reabsorb phosphate into the blood stream

Answer 242

X-linked dominant Fragile X syndrome (x linked dominant) is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females. Affected individuals usually have delayed development of speech and language by age 2. Most males with fragile X syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with fragile X syndrome may also have anxiety and hyperactive behavior such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with fragile X syndrome have features of autism spectrum disorders that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome. Most males and about half of females with fragile X syndrome have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macroorchidism) after puberty. Mutations in the FMR1 gene cause fragile X syndrome. The FMR1 gene provides instructions for making a protein called fragile X mental retardation 1 protein, or FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses, which are specialized connections between nerve cells. Synapses are critical for relaying nerve impulses. Nearly all cases of fragile X syndrome are caused by a mutation in which a DNA segment, known as the CGG triplet repeat, is expanded within the FMR1 gene. Normally, this DNA segment is repeated from 5 to about 40 times. In people with fragile X syndrome, however, the CGG segment is repeated more than 200 times. The abnormally expanded CGG segment turns off (silences) the FMR1 gene, which prevents the gene from producing FMRP. Loss or a shortage (deficiency) of this protein disrupts nervous system functions and leads to the signs and symptoms of fragile X syndrome. Males and females with 55 to 200 repeats of the CGG segment are said to have an FMR1 gene premutation. Most people with a premutation are intellectually normal. In some cases, however, individuals with a premutation have lower than normal amounts of FMRP. As a result, they may have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience emotional problems such as anxiety or depression. Some children with a premutation may have learning disabilities or autistic-like behavior. The premutation is also associated with an increased risk of disorders called fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS).

Answer 243

X-linked Dominant, a rare genetic postnatal neurological disorder of the grey matter of the brain[2] that almost exclusively affects females but has also been found in male patients. The clinical features include small hands and feet and a deceleration of the rate of head growth (including microcephaly in some). Repetitive stereotyped hand movements, such as wringing and/or repeatedly putting hands into the mouth, are also noted.[3] People with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures.[4] They typically have no verbal skills, and about 50% of individuals affected do not walk. Scoliosis, growth failure, and constipation are very common and can be problematic. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in high levels. The MECP2 protein is likely to be involved in turning off ("repressing" or "silencing") several other genes. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of mental retardation in females.

Answer 244

This condition is inherited in an X-linked recessive pattern. It is characterized by neurological and behavioral abnormalities and the overproduction of uric acid. Uric acid is a waste product of normal chemical processes and is found in blood and urine. Excess uric acid can be released from the blood and build up under the skin and cause gouty arthritis (arthritis caused by an accumulation of uric acid in the joints). Uric acid accumulation can also cause kidney and bladder stones. The nervous system and behavioral disturbances experienced by people with Lesch-Nyhan syndrome include abnormal involuntary muscle movements, such as tensing of various muscles (dystonia), jerking movements (chorea), and flailing of the limbs (ballismus). People with Lesch-Nyhan syndrome usually cannot walk, require assistance sitting, and generally use a wheelchair. Self-injury (including biting and head banging) is the most common and distinctive behavioral problem in individuals with Lesch-Nyhan syndrome. Mutations in the HPRT1 gene cause Lesch-Nyhan syndrome. The HPRT1 gene provides instructions for making an enzyme called hypoxanthine phosphoribosyltransferase 1. This enzyme is responsible for recycling purines, a type of building block of DNA and its chemical cousin RNA. Recycling purines ensures that cells have a plentiful supply of building blocks for the production of DNA and RNA. When this enzyme is lacking, purines are broken down but not recycled, producing abnormally high levels of uric acid. For unknown reasons, a deficiency of hypoxanthine phosphoribosyltransferase 1 is associated with low levels of a chemical messenger in the brain called dopamine. Dopamine transmits messages that help the brain control physical movement and emotional behavior, and its shortage may play a role in the movement problems and other features of this disorder. However, it is unclear how a shortage of hypoxanthine phosphoribosyltransferase 1 causes the neurological and behavioral problems characteristic of Lesch-Nyhan syndrome.

Answer 245

X-linked recessive, Spectrum of muscle disease from mild to severe, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, DMD-associated dilated cardiomyopathy

Answer 246

a recessive X-linked form of muscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and eventual death. The disorder is caused by a mutation in the dystrophin gene, the largest gene located on the human X chromosome, which codes for the protein dystrophin, an important structural component within muscle tissue that provides structural stability to the dystroglycan complex (DGC) of the cell membrane. While both sexes can carry the mutation, females rarely exhibit signs of the disease. Duchenne muscular dystrophy (DMD) is caused by a mutation of the dystrophin gene at locus Xp21. Dystrophin is responsible for connecting the cytoskeleton of each muscle fiber to the underlying basal lamina (extracellular matrix) through a protein complex containing many subunits. The absence of dystrophin permits excess calcium to penetrate the sarcolemma (cell membrane). Alterations in these signalling pathways cause water to enter into the mitochondria which then burst. In skeletal muscle dystrophy, mitochondrial dysfunction gives rise to an amplification of stress-induced cytosolic calcium signals and an amplification of stress-induced reactive-oxygen species (ROS) production. In a complex cascading process that involves several pathways and is not clearly understood, increased oxidative stress within the cell damages the sarcolemma and eventually results in the death of the cell. Muscle fibers undergo necrosis and are ultimately replaced with adipose and connective tissue.

Answer 247

an X-linked recessive inherited disorder characterized by slowly progressive muscle weakness of the legs and pelvis. It is a type of dystrophinopathy, which includes a spectrum of muscle diseases in which there is insufficient dystrophin produced in the muscle cells, resulting in instability in the structure of muscle cell membrane. This is caused by mutations in the dystrophin gene, which encodes the protein dystrophin. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, but in Duchenne muscular dystrophy no functional dystrophin is produced making DMD much more severe than BMD. The disorder is inherited with an X-linked recessive inheritance pattern. The gene is located on the X chromosome. Since women have two X chromosomes, if one X chromosome has the non-working gene, the second X chromosome will have a working copy of the gene to compensate. Because of this ability to compensate, women rarely develop symptoms. However, they may do so due to mosaicism. For example, carrier females of mutations are at increased risk for dilated cardiomyopathy. Since men have an X and a Y chromosome and because they don't have another X to compensate for the defective gene, they will develop symptoms if they inherit the non-working gene.

Answer 248

Dilated cardiomyopathy presenting between 20-40 years of age. Early death. No skeletal muscle involvement. No Dystrophin in the myocardium

Answer 249

X-linked recessive, I in 4000 male births, 10% carrier females affected. Spontaneous bleeds into joints, muscles or intracranial, Excessive bruising, Prolonged bleeding after injury or incision, Delayed wound healing. Mutation: F8, Factor VIII, Chromosome Xq28, Deficiency of Factor VIII, 22A inversion causes 50%

Answer 250

Group of disorders caused by dysfunction of the respiratory chain. These disorders tend to affect tissues that heavily rely on oxidative phosphorylation, brain, retina, skeletal muscle and heart

Answer 251

The features of Kearns-Sayre syndrome usually appear before age 20, and the condition is diagnosed by a few characteristic signs and symptoms. People with Kearns-Sayre syndrome have progressive external ophthalmoplegia, which is weakness or paralysis of the eye muscles that impairs eye movement and causes drooping eyelids (ptosis). Affected individuals also have an eye condition called pigmentary retinopathy, which results from breakdown (degeneration) of the light-sensing tissue at the back of the eye (the retina) that gives it a speckled and streaked appearance. The retinopathy may cause loss of vision. In addition, people with Kearns-Sayre syndrome have at least one of the following signs or symptoms: abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects), problems with coordination and balance that cause unsteadiness while walking (ataxia), or abnormally high levels of protein in the fluid that surrounds and protects the brain and spinal cord (the cerebrospinal fluid or CSF). Kearns-Sayre syndrome is a condition caused by defects in mitochondria, which are structures within cells that use oxygen to convert the energy from food into a form cells can use. This process is called oxidative phosphorylation. Although most DNA is packaged in chromosomes within the nucleus (nuclear DNA), mitochondria also have a small amount of their own DNA, called mitochondrial DNA (mtDNA). This type of DNA contains many genes essential for normal mitochondrial function. People with Kearns-Sayre syndrome have a single, large deletion of mtDNA, ranging from 1,000 to 10,000 DNA building blocks (nucleotides). The cause of the deletion in affected individuals is unknown.

Answer 252

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy). The signs and symptoms of this disorder most often appear in childhood following a period of normal development, although they can begin at any age. Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Most affected individuals experience stroke-like episodes beginning before age 40. These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function (dementia). Most people with MELAS have a buildup of lactic acid in their bodies, a condition called lactic acidosis. Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. Less commonly, people with MELAS may experience involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes, and hormonal imbalances.

Answer 253

Myoclonic epilepsy with ragged-red fibers (MERRF) is a disorder that affects many parts of the body, particularly the muscles and nervous system. In most cases, the signs and symptoms of this disorder appear during childhood or adolescence. The features of MERRF vary widely among affected individuals, even among members of the same family. MERRF is characterized by muscle twitches (myoclonus), weakness (myopathy), and progressive stiffness (spasticity). When the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells are called ragged-red fibers. Other features of MERRF include recurrent seizures (epilepsy), difficulty coordinating movements (ataxia), a loss of sensation in the extremities (peripheral neuropathy), and slow deterioration of intellectual function (dementia). People with this condition may also develop hearing loss or optic atrophy, which is the degeneration (atrophy) of nerve cells that carry visual information from the eyes to the brain. Affected individuals sometimes have short stature and a form of heart disease known as cardiomyopathy. Less commonly, people with MERRF develop fatty tumors, called lipomas, just under the surface of the skin. Mutations that cause MERRF impair the ability of mitochondria to make proteins, use oxygen, and produce energy. These mutations particularly affect organs and tissues with high energy requirements, such as the brain and muscles.

Answer 254

Leber hereditary optic neuropathy (LHON) is an inherited form of vision loss. Although this condition usually begins in a person's teens or twenties, rare cases may appear in early childhood or later in adulthood. For unknown reasons, males are affected much more often than females. The genes associated with LHON each provide instructions for making a protein involved in normal mitochondrial function.

Answer 255

Both genes and environmental factors play major roles in virtually all diseases. We have no systematic ways to discover environmental risk factors, but we can systematically discover disease genes. Genes for Mendelian (single-gene) disorders are fairly deterministic (confer disease yes/no). However, most genes for common diseases confer relatively small risks (odds ratios; Ors). Discovery of disease genes provides clues to pathogensis, most appropriate treatment, screening/surveillance of high-risk individuals. Highly predictive genetic testing may be difficult or impossible

Answer 256

Discover risk genes for common diseases, specific risk variants, high-risk combinations. Carry out accurate DNA-based predictive diagnostics of disease susceptibilities based on individualized genetic risks. Apply optimized individualized treatments or preventatives based on genetic diagnosis of disease susceptibilities and pharmacogenetic analysis of optimized drug efficacy/specificity. However, low ORs of most disease susceptibility genes identified make accurate prediction difficult/impossible in most cases

Answer 257

Odds Ratio (OR) =Risk of disease having a given gene variant / Risk of disease not having a given gene variant

Answer 258

Mapping requires polymorphic DNA Markers. Except for sequencing entire genomes, we don’t have technology to score all genetic differences in individuals/families. Instead, we “genotype” polymorphic DNA “markers” (any scoreable difference) at known genomic positions. Surrogates for disease mutations; some polymorphisms cause disease; most don’t. Commonly used marker types: microsatellites, single-nucleotide polymorphisms (SNPs), copy-number variations (CNVs)

Answer 259

A haplotype is a collection of specific alleles (particular DNA sequences) in a cluster of tightly-linked genes on a chromosome that are likely to be inherited together. Put in simple words, haplotype is the group of genes that a progeny inherits from one parent. A second meaning of the term haplotype is a set of single-nucleotide polymorphisms (SNPs) on a single chromatid of a chromosome pair that are associated statistically. It is thought that these associations, and the identification of a few alleles of a haplotype sequence, can unambiguously identify all other polymorphic sites in its region. Such information is very valuable for investigating the genetics of common diseases, and has been investigated for the human species by the International HapMap Project.

Answer 260

Recombination breaks macro-patterns of polymorphic genotypes on the same chromosome into haplotypes. Recombination is not truly random, so very close polymorphism genotypes carried on the same chromosome cluster into ~10-50 kb haplotype blocks in which SNP alleles are in linkage disequilibrium (LD; marker alleles within blocks tend to be co-inherited, because recombination within blocks is uncommon). LD blocks 2X smaller in African than Caucasian or Asian pops. because African pop. is more ancient. If you genotype enough SNPs to identify the haplotype, you can impute other variation that wasn’t genotyped

Answer 261

linkage disequilibrium is the non-random association of alleles at two or more loci, that descend from single, ancestral chromosomes. Linkage disequilibrium is wholly a measurement of proximal genomic space. It is necessary to refer to this as gametic phase disequilibrium or simply gametic disequilibrium because it is described through DNA recombination. In other words, linkage disequilibrium is the occurrence of some combinations of alleles or genetic markers in a population more often or less often than would be expected from a random formation of haplotypes from alleles based on their frequencies. It is a second order phenomenon derived from linkage, which is the presence of two or more loci on a chromosome with limited recombination between them. The amount of linkage disequilibrium depends on the difference between observed allelic frequencies and those expected from a homogenous, randomly distributed model. Populations where combinations of alleles or genotypes can be found in the expected proportions are said to be in linkage equilibrium.

Answer 262

a hypothesis driven approach, studies the gene directly. Depends on biological hypothesis (biological candidate) or positional hypothesis / information (positional candidate, ‘hit’ from GWAS or other mapping method). Sometimes successful in mendelian disorders. in common (complex) disorders most useful when candidates are positives from GWAS. pathogenic sequence variants not obvious, often occuring in normal individuals. most hypothesis are wrong

Answer 263

(test gene/causal variant indirectly). Most common type of “genetic study” > Depends on a priori biological hypothesis (biological candidate) or positional hypothesis (positional candidate). Most powerful for common risk alleles with small to moderate effects (Ors) (i.e. “complex”, polygenic traits). Most a priori biological hypotheses wrong/ Fatal flaws lead to false-positives! Concepts: 1. Causal disease variation in candidate gene ‘tagged’ by local haplotype of polymorphic DNA markers in 2. Depends on LD: DNA sequence variations close together on the same piece of DNA will tend to not be separated by recombination over long periods, and so will be non-randomly co-inherited Approach (Case-Control study design): 1. Genotype marker in candidate gene in cases and in controls 2. Compare allele frequencies in cases versus controls

Answer 264

Conceptually simple. Can be done with reasonable-sized number of cases and controls (hundreds). Uses simple statistics (Chi-square, Fisher exact test); p < 0.05, 0.01, etc. If test multiple variants, must apply multiple-testing correction. Real association does not imply causation by the associated variant, but does imply at least LD with a causal mutation. ALMOST ALWAYS YIELDS FALSE-POSITIVES Two fatal flaws: 1. True multiple-testing correction must include all tests, even those done by others and perhaps never published 2. Background genetic variation may vary among populations. Therefore, must ethnically match cases & controls; otherwise, observed differences in allele frequencies may reflect different genetic backgrounds of cases vs. controls, not disease association. However, even in “homogeneous” population, occult population differences (“stratification”) can lead to false-positives. about 96% of published confirmed genetic associations turn out to be false- positives due to stratification and publication bias of positve results

Answer 265

the presence of a systematic difference in allele frequencies between subpopulations in a population possibly due to different ancestry, especially in the context of association studies. Population stratification is also referred to as population structure, in this context. The basic cause of population stratification is nonrandom mating between groups, often due to their physical separation (e.g., for populations of African and European descent) followed by genetic drift of allele frequencies in each group. In some contemporary populations there has been recent admixture between individuals from different populations, leading to populations in which ancestry is variable (as in African Americans). Over tens of generations, random mating can eliminate this type of stratification. In some parts of the globe (e.g., in Europe), population structure is best modeled by isolation-by-distance, in which allele frequencies tend to vary smoothly with location. Population stratification can be a problem for association studies, such as case-control studies, where the association could be found due to the underlying structure of the population and not a disease associated locus. By analogy, one might imagine a scenario in which certain small beads are made out of a certain type of unique foam, and that children tend to choke on these beads; one might wrongly conclude that the foam material causes choking when in fact it is the small size of the beads. Also the real disease causing locus might not be found in the study if the locus is less prevalent in the population where the case subjects are chosen. For this reason, it was common in the 1990s to use family-based data where the effect of population stratification can easily be controlled for using methods such as the TDT. But if the structure is known or a putative structure is found, there are a number of possible ways to implement this structure in the association studies and thus compensate for any population bias. Most contemporary genome-wide association studies take the view that the problem of population stratification is manageable, and that the logistic advantages of using unrelated cases and controls make these studies preferable to family-based association studies.

Answer 266

hypothesis free approach. Search genome for segments disproportionately co-inherited along with disease through “multiplex families” (families with multiple cases of a disease). Assumes affected relatives within a family share disease susceptibility genes “identical by descent”. Can discover new, unknown genes. Can provide very fine localization. Best for Mendelian traits (uncommon alleles with strong effects); less powerful for “complex traits”. the principle depends on recombination. Loci close near each other on a chromosome tend not to be separated by recombination vs. loci far apart

Answer 267

The unit of genetic distance/recombination. 1 cM = 1% recombination between two loci per meiosis. Average 2.44 chiasmata/chromosome/meiosis; each chromosome has at least one recombination event per meiosis. Therefore, even two loci on the same chromosome >50 cM apart appear “unlinked” (i.e. inherited as if on different chromosomes). Statistical measure is LOD (log of odds) score

Answer 268

LOD= Log10 (likelihood of data if loci linked at x cM/ likelihood of data if loci unlinked. It is significance is LOD >3.0 is considered proof of linkage/gene localization

Answer 269

another case control association study. It is hypothesis free approach. Same as candidate gene case-control association study, but tests hundreds of thousands/millions of markers (SNPs) across entire genome. Search for SNPs with significantly different allele frequencies in cases versus controls. You know number of tests performed genomewide; can perform appropriate multiple-testing correction. Still need to match cases and controls ethnically, but because entire genome is represented, can detect and correct for population stratification. Very large number of SNPs tested (hundreds of thousands to millions) presents huge multiple-testing problem; requires at least ~1000 cases and ~1000 controls. “Significant” associations require confirmation by independent replication by follow-up association study of specific SNPs. Requires no hypotheses about pathogenesis; can discover new genes, fine localization. Most effective for common alleles with small to moderate effect sizes (ORs)

Answer 270

Combined Hypothesis-based and hypothesis-free approaches. High-throughput DNA sequencing including: Biological candidate genes, GWAS signals (specific genes or genes within regions), Full-genome or Exome (~1% of genome) sequencing. Must distinguish potentially causal variants from non-pathological variation (1000 Genomes Project & UK10K data will help). Prioritize for follow-up functional analyses

Answer 271

In Mendelian disorders of large effect, findings thus far suggest one or a very small number of variants within coding genes underlie the entire condition. Because of the severity of these disorders, the few causal variants are presumed to be extremely rare or novel in the population, and would be missed by any standard genotyping assay. Exome sequencing provides high coverage variant calls across coding regions, which are needed to separate true variants from noise. A successful model of Mendelian gene discovery involves the discovery of de novo variants using trio sequencing, where parents and pro band are genotyped.

Answer 272

Genetic Diseases, where the root cause of the disease is a pathogenic abnormality of the DNA, are generally incurable with today’s medicines. In other words, we are currently unable to correct DNA defects at the level of the genome for an entire organism. However, many genetic conditions are treatable and the morbidity and mortality of many genetic diseases can be reduced by a variety of approaches

Answer 273

Just because a disease is ‘genetic’ does not imply that it is untreatable or that only a ‘genetic-based’ therapy will work. For example, Trisomy 21 is one of the most frequently recognized causes of mental retardation. Improved care by pediatricians and pediatric specialists (especially correction of severe cardiac defects) has markedly improved survival with this diagnosis. In 1983 the median age of death for patients with Trisomy 21 was 25 years; by 1997 the median age had risen to 49. None of this improvement in survival can be attributed to genetic therapies that fixed the underlying disease. For congenital heart defects (many of which have an underlying genetic basis) there are estimated to now be more adults dying from congenital heart disease than children.

Answer 274

Hyperphenylalaninemia-elevated serum levels of phenylalanine due to: PAH gene mutations (Classic PKU, Variant PKU, Non-PKU hyperphenylalaninemia). Treat with low phenylalanine diets. Impaired tetrahydrobiopterin (BH4) recycling (PCD / DHPR mutations) Impaired BH4 synthesis (GTP-CH / 6-PTS mutations). Treat with low phenylalanine diet, L-dopa, 5-HT, carbidopa +/- folinic acid +/- BH4

Answer 275

now >2 dozen diseases for which dietary and/or medication therapy can be applied. Majority of metabolic diseases manifest autosomal recessive inheritance. Newborn screening (done by heel stick test on ~all newborns) is done to diagnose early or pre-clinical disease in newborns and allow for early therapy, before permanent morbidity occurs. General Uses and Indications: Diagnosed metabolic diseases where disease is due to deficiency of essential compound(s) and/or accumulation of toxic compound(s). Many of these are in amino acid catabolic pathwaysààrequires dietary restriction of > 1 amino acids. Benefits: Effective in many cases, ‘leaky’ mutations can have relatively liberal diets, Problems: lifelong compliance, expensive, need trained nutritionist, need to maintain growth, illness can lead to secondary metabolic crises, can cause fetal damage, long-term prognosis on therapy not always known

Answer 276

Strategy depends on underlying defect and mechanism of pathology. General Uses and Indications: Can be proposed for conditions where the genetic mutation causes a protein abnormality that is amendable to therapy by pharmacologic manipulation and/or protein replacement therapy (PRT). Benefits: Can be quite effective in correcting enzyme deficiencies, especially when the targeted protein is needed in the plasma/serum (extracellular). Problems: Expensive, Delivery of injected (extracellular) protein to specific organs and/or intracellular compartments is challenging, risk of immune response to recombinant protein, delivery across blood-brain barrier is challenging (neurological symptoms if present, often do not improve), protein replacement does not always correct existing cellular/tissue damage.

Answer 277

Alpha-1 antitrypsin is a plasma protein that inhibits elastase (balances the tissue destructive properties of elastase). ~100,000 homozygotes in USààelevated risk of COPD and liver disease. Conceptually, the disease is a deficiency -> recombinant protein replacement therapy (PRT) can mitigate the effects of the disease. Most effective therapy remains avoidance of smoking

Answer 278

Fabry disease is an X-linked condition due to deficiency of alpha-galactosidase Accumulation of glycosphingolipids causes widespread microvascular damage Neuron damage: neurologic pain crises in childhood. Sweat gland damage: reduced sweating, risk of heat stroke. Renal damage: progressive renal failure (cause of death prior to renal transplanation). Vascular damage: risk of heart attacks and stroke. Cardiovascular: hypertrophy of cardiac tissue also seen. Recombinant enzyme replacement therapy appears to mitigate some aspects of the disease. Approved in the United States -> annual cost $150-200,000 / patient (lifelong)

Answer 279

For some genetic conditions, medications can be used to alter gene expression can ameliorate the severity of disease. Butyrate given to sickle cell patients increases the expression fetal hemoglobin which could reduce the polymerization of Hemoglobin S which leads to complications in Sickle Cell anemia. In circumstances where a genetic mutation causes a primary problem of dysfunction of a single organ system, transplantation can potentially ameliorate disease. The bulk of the experience has been with hepatic or bone marrow transplantation. Other organs (lung, heart, pancreas) have also occurred on a more limited level for some diseases.

Answer 280

Definition: introduction of DNA (or RNA) molecules into human cells to treat an acquired or inherited disease. A current goal is to strive to perform only somatic gene therapy and to avoid any introduction of recombinant genes into the germline of a patient. So ‘gene therapy’ is designed to be non- heritable. General Uses and Indications: Gene therapy is currently not widely used or available, although 100s of studies (in animal and human models) are underway. Approach: Can be ex vivo (insertion of DNA/RNA occurs outside the patient in cells/tissues which are then given to the patient) or in vivo (DNA/RNA constructs injected/delivered directly to the patient).

Answer 281

Recessive inheritance for severe congenital. Parents typically carriers. Loss of function mutations predominate. Autosomal dominant for nonsyndromic progressive deafness with childhood onset (hearing ~normal at birth). One parent typically affected

Answer 282

Allelic heterogeneity with both dominant and recessive inheritance patterns. MAJOR PHENOTYPIC FEATURES: Congenital deafness in the recessive form. Progressive childhood deafness in the dominant form. ~ 1/2 congenital deafness = genetic. Of genetic: 3/4 nonsyndromic, 1/4 syndromic. Non Syndromic: GJB2 mutations most common -> ½ of all nonsyndromic autosomal recessive deafness. Conductive: anatomy. Nervous: sensiorineural. Diagnose with newborn screening Patient: hearing aids, cochlear implant. Future sibs/offspring: genetic testing and counseling. GJB2 gene mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB1. DFNB1 deafness is inherited in an autosomal recessive manner, which means that two copies of the GJB2 gene in each cell are altered. GJB2 gene mutations probably alter gap junctions, which may disturb the level of potassium ions in the inner ear. Levels of potassium ions that are too high may affect the function and survival of cells that are needed for hearing. Researchers have also identified several GJB2 gene mutations that cause another form of nonsyndromic deafness called DFNA3, which is inherited in an autosomal dominant manner. This type of inheritance means that one copy of the GJB2 gene in each cell is altered. These mutations replace one amino acid in connexin 26 with an incorrect amino acid. It remains unclear how these GJB2 gene mutations lead to DFNA3-associated hearing loss. The altered connexin 26 protein probably inhibits the assembly of gap junctions or their normal function, which could disrupt the conversion of sound waves to nerve impulses.

Answer 283

the transgene must be delivered/targeted to the appropriate cells and not to inappropriate cells. You do not have to express the transgene in its ‘normal’ location. For example, Factor VIII is typically made by the liver and secreted into the blood to help maintain normal clotting (Factor VIII deficiency àà hemophilia A). Some limited success has been seen injecting transgene into muscle tissue and having muscle tissue secret transgenic Factor VIII.

Answer 284

the transgene must lead adequate expression (in terms of level or expression (how much transgenic product is made) and duration (how long does the effect last). Often the goal is not to achieve ‘normal’ physiological levels of a transgenic protein.

Answer 285

the toxic side-effects of the transgene must be acceptable.

Answer 286

Delivery: Several delivery mechanisms are currently being studied. Viral: Adenoviral and Retroviral. Non-Viral: Liposomal, protein-DNA conjugates, injection of naked DNA, artificial chromosomes Note: Current gene therapy efforts are largely directed at gene ‘replacement / deficiency’ models, where a gene (protein) is missing or non-functional. Approaches to correct diseases due to dominant negative and/or gain of function mutations are expected to be more challenging.

Answer 287

RNA viruses, Integrate into cell genome with Minimal host immune reactions, nsert size of transgene limited to ~7-8kb Infect only dividing cells (cannot reach quiescent tissues). Risk of insertional mutagenesis /gerrmline integration), Efficient at infecting dividing cells, As these integrate into genomic DNA, the transgene can be passed to daughter cells

Answer 288

DNA Viruses, Wide variety of cell types can be infected, Transgene insert size ~35-36kb Stable and easy to get high titers, Does NOT integrate into cell genome, Expression can be very transient Risk of malignant transformation, Lower risk of insertional mutatgenesis, Immune reactions can be severe Can infect non-dividing cells, Higher titers are possible, Typically short-lived effect; not passed to daughter cell lines

Answer 289

Several approaches: Liposomes, direct DNA , "non-viral gene therapy approach, nsert size can be very large Could deliver mini-chromosomes Minimal host immune response, Low efficiency, Transient expression, Safest?: does not integrate into host genome, Often degraded by cellular mechanisms (non-specific uptake is inefficient process), Typically short-lived effect; not passed to daughter cell lines"

Answer 290

Gene Therapy: Currently, limited examples, Enzyme replacement: Lysosomal storage diseases, alpha-1-antitrypsin, Protein Replacement: Factor replacement in hemophilia

Answer 291

Farnesyl Transferase Inhibitors: Showing promise in Lamin A/C mutations in Progeria, a premature aging syndrome. Lamin A/C mutation leads to a mutant lamin A/C protein (‘progerin’) that is targeted to the nuclear membrane by Farnesyl groups àà pathological effects at nuclear membrane. Farnesyl transferase inhibitors appear to reduce progerin sequestration at the nuclear membrane. Marfan Syndrome: FBN1 mutations now known to increase cytokine transforming growth factor beta (TGF-ß)ààmany pathologic findings. Angiotensin II Receptor Blockers (ARBs) can block some of the TGF-ß effect. In Marfan mice ARBs block aortic root enlargement. In Marfan patients (small numbers) ARBs slowed rate of aortic root enlargement.

Answer 292

Imatinib (Gleevec) for treatment of chronic myelogenous leukemia where a chromosome 9:22. translocation joins parts of two genes (BCR and ABL) into a fusion gene -> fusion transcript ->fusion protein called BCR-ABL that can be inhibited by Imatinib. Pharmacologic chaperones: bind to mutant proteins and favorably change the properties of the mutant protein (e.g. stabilize, restore function, improve targeting, etc.)

Answer 293

Suppression of nonsense (stop codon) signals: Allows for some ‘read-through’ of truncation mutations. Aminoglycosides (antibiotics) do this non-specifically. Manipulation of pre-mRNA splicing: Small interfering RNA (siRNA) can selectively degrade mRNA transcripts, microRNAs can suppress protein translation, Anti-sense oligonucleotides can suppress splicing

Answer 294

Analyzing an individual's genetic material to determine predisposition to a particular health condition or to confirm a diagnosis of genetic disease. Examining a sample of blood or other body fluid or tissue for biochemical, chromosomal, or genetic markers that indicate the presence or absence of genetic disease. Many ‘tests’ provide information about genetic status/risk without directly testing DNA. Examples: biochemical tests (amino aids, organic acids as in phenylketonuria or maple syrup urine disease), enzyme activity assays (Gaucher disease), protein electrophoresis (sickle cell disease), lipid levels (familial hypercholesterolemia), X-rays (achondroplasia), ultrasound (polycystic kidney disease, hypertropic cardiomyopathy), sweat chloride test (cystic fibrosis), skin examination (albinism), medical history, family history, etc.

Answer 295

General Uses and Indications: Suspected abnormality of chromosome number or structure (deletion, insertion, rearrangements). Frequently obtained from pregnant women > 35 years (amniocentesis or chorionic villus sampling), from patients with congenital abnormalities (dysmorphisms, structural organ defects, mental and/or growth retardation), from families with multiple miscarriages and/or fertility problems, and directly from certain cancer biopsies. Can Diagnose: aneuploidies (abnormal chromosome number), chromosome deletions, duplications, and insertions of moderate to large size (>3,000-5,000 kb / 3-5 Mb), and rearrangements. Cannot Diagnose: single gene deletions, point mutations, small deletions, duplications, and insertions, methylation defects, trinucleotide repeat abnormalities.

Answer 296

General Uses and Indications: Used to diagnose deletions, some translocations, and abnormalities of copy number. Often used to detect cytogenetic changes that are at or beyond the limits of resolution obtained by high-resolution chromosomal analysis. FISH for duplications works better on cells in interphase than metaphase (metaphase the chromatin is very compact). Can Diagnose: recognized microdeletion syndromes, recognized chromosomal rearrangements (in cancers), and gene copy numbers (cancers). Also useful in diagnosing anueploidies (e.g. trisomy 13, 18, 21) in the prenatal setting. Cannot Diagnose: deletions, rearrangements that are not specifically tested for (i.e. FISH probes are specifically designed for each condition). FISH is not always able to detect duplications of gene regions. Point mutations and small deletions cannot be diagnosed with this approach. Examples of Microdeletion Syndromes: Cri-du-chat, Smith-Magenis, DiGeorge (22qdel), Williams syndrome, Wolf-Hirschhorn, Prader-Willi syndrome, Angelman syndrome.

Answer 297

Expression Arrays, Chromosomal Microarray Analysis (CMA)

Answer 298

Used to test the RNA expression of genes (i.e. which genes are turned ‘on’ or ‘off’). These are semi-quantitative and test the activity of genes (see figure) rather than just the presence or absence of a gene or genetic variant (expression arrays). These have a small, but likely growing role, in oncology.

Answer 299

These have a big role in clincal genetics currently. These look for chromosomal DNA losses and gains (so called ‘deletion/duplication’ studies). Sometimes this is also called array comparative genomic hybridization (aCGH) analysis. General Uses and Indications of CMA: CMA has become fairly standard for looking for small genomic deletions/insertions. You can think of this as a superior method to looking for chromosomal gains than losses than traditional chromosomal analysis because the resolution of the CMA is vastly superior to chromosomal analysis. The probe size used these days is between 100-200 Kb so they can pick up smaller changes than can be appreciated by chromosome analysis. Currently, some labs use >~200 Kb for deletions and >~400 Kb for duplications. Can Diagnose: aneuploidies, unbalanced chromosomal rearrangements, chromosome deletions and duplications > 200 Kb and 400 Kb, respectively. Cannot Diagnose: Deletions/Duplications below the resolution of CMA, nucleotide mutations, balanced chromosomal rearrangements.

Answer 300

Widely used method of mutation detection based on Sanger-Gilbert method. Able to identify the genetic mutation causing many disease conditions. General Uses and Indications: Used to identify sequence changes (mutations) in specific genes. In general you need the following: You must know or suspect a specific genetic diagnosis, The gene must have been identified, The mutation must be detectable by sequencing (deletions, insertions, rearrangements are not always found by sequencing), The mutation must be located in a region of the gene that is actually sequenced (promoter and deep-intronic mutations often missed by commercial tests). Can Diagnose: Mutations in known genes (mutation can be previously reported or can be novel), polymorphic variants, small (1 to ~100 nucleotide) deletion/insertions. Ideal for looking at the sequence of a known disease gene. Cannot Diagnose: The technique is very specific, assaying only the region of the gene(s) for which the test has been designed. Frequently, many clinical genetic tests do NOT routinely sequence all parts of a gene (e.g. promoters, introns). This means that although the approach is often very specific, clinical sensitivity is frequently below 100% (this is an important concept to understand). This technique cannot easily detect larger deletions/insertions, rearrangements, and most chromosomal abnormalities.

Answer 301

Uses massively-parallel sequencing of individual DNA molecules and is likely to replace PCR based DNA sequencing within a few years (and is actually already in clinical use as of early 2012).

Answer 302

Genetic testing is used for several purposes: diagnosis, risk estimation, pregnancy planning, population screening. Test interpretation often depends on the context in which the test is performed. A genetic test which gives a ‘normal’ (or ‘wild-type’) genetic sequence is often referred to a ‘negative result’ by clinicians. [Watch out for the patient who thinks that a ‘negative’ result is bad.] Be aware that a ‘normal’ result (or ‘no pathogenic mutation detected’) does not always rule out a particular disease. For example, a DNA sequencing test that sequences exons of a gene will miss any disease causing mutations located in introns. A genetic test which gives an ‘abnormal’ (or ‘mutant’ genetic sequence for example) is often referred to as being ‘positive’ or ‘mutant’ by clinicians (again, be wary of patient confusion). Note: technically a mutation refers to ANY DNA sequence change which differs from the reference (‘wild-type’) sequence. Thus, many genetic changes that are benign changes can be called ‘mutations’. In clinical medicine, be aware that many clinicians don’t strictly apply this definition and use ‘mutation’ only when referring to disease causing changes. A polymorphism is defined as a genetic mutation which is present in 1% of the population studied. While most polymorphisms do not influence biological traits or disease risk, some polymorphisms have been linked with risks of disease.

Answer 303

result is one where the information from a genetic test definitively diagnoses or excludes the disease in question. Put another way, an informative genetic test result is one that is reliably either a true positive or true negative result (ruling-in or ruling-out disease/risk, respectively).

Answer 304

result usually refers to a situation where the genetic test result is normal, but it is not possible to definitively exclude disease/disease risk. A non-informative genetic test result leaves open the possibility that an underlying pathogenic mutation exists, but was missed/not detected by the test.

Answer 305

multiple mutations in a particular gene (or at a particular loci) can cause disease. (Allelic heterogeneity in the research setting can also refer to the present of multiple non-pathogenic polymorphisms within a gene) Example: Cystic fibrosis is an autosomal recessive disease caused my mutations in one gene, CFTR. Over 1,000 different mutations have been reported. Cystic fibrosis shows allelic heterogeneity but is genetically homogenous (e.g. NO Genetic Heterogeneity).

Answer 306

multiple genes (when mutated) associated with the same phenotype. Example: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in at least 10 different genes. HCM shows both allelic and genetic heterogeneity. A genetic test which cannot completely account for all possible allelic and genetic heterogeneity in a particular disorder can lead to non-informative results.

Answer 307

a rare genetic syndrome in which affected children are predisposed to develop Wilms tumour (a tumour of the kidneys), Aniridia (absence of the coloured part of the eye, the iris), Genitourinary anomalies, and Retardation.[1] The G is sometimes instead given as "gonadoblastoma," since the genitourinary anomalies are tumours of the gonads (testes or ovaries).

Answer 308

If disease diagnosis is already suspected on clinical grounds then test is ‘confirmational’. If symptoms are present, but clear diagnosis is unknown, test results can diagnose the underlying and current disease.

Answer 309

Patient (or in case of prenatal testing, a developing baby) has some underlying ‘risk’ of disease (based on family history or ethnic background). The genetic test result further classifies the risk of a future disease

Answer 310

Multiple endocrine neoplasia is a group of disorders that affect the body's network of hormone-producing glands (the endocrine system). Hormones are chemical messengers that travel through the bloodstream and regulate the function of cells and tissues throughout the body. Multiple endocrine neoplasia typically involves tumors (neoplasia) in at least two endocrine glands; tumors can also develop in other organs and tissues. These growths can be noncancerous (benign) or cancerous (malignant). If the tumors become cancerous, the condition can be life-threatening. Mutations in the MEN1 gene cause multiple endocrine neoplasia type 1. This gene provides instructions for producing a protein called menin. Menin acts as a tumor suppressor, which means it normally keeps cells from growing and dividing too rapidly or in an uncontrolled way. Although the exact function of menin is unknown, it is likely involved in cell functions such as copying and repairing DNA and regulating the activity of other genes. When mutations inactivate both copies of the MEN1 gene, menin is no longer available to control cell growth and division. The loss of functional menin allows cells to divide too frequently, leading to the formation of tumors characteristic of multiple endocrine neoplasia type 1. It is unclear why these tumors preferentially affect endocrine tissues.

Answer 311

one of the latest pharmacological approaches to lysosomal storage diseases. It fixes defective protein as an alternative to Stop codon suppression treatment. These chaperones are minute molecules that can enter the central nervous system ( via Blood Brain Barrier). Once in the CNS, they attach to the enzyme (inactive form) and fix it so that it takes the correct functional shape. Limitation of the therapy is that it only works with certain mutations : Gaucher's disease, Fabry disease, Pompe disease and Late-onset Tay-Sachs disease. Lack of bio-marker and the potential to reduce the enzyme function if given incorrect dose are challenging aspects of current clinical trials.

Answer 312

cofactor, replace extracellular protein, replace intracellular protein, replace intracellular protein, target intracellular protein.

Answer 313

Fabry disease is an inherited disorder that results from the buildup of a particular type of fat, called globotriaosylceramide, in the body's cells. Beginning in childhood, this buildup causes signs and symptoms that affect many parts of the body. Characteristic features of Fabry disease include episodes of pain, particularly in the hands and feet (acroparesthesias); clusters of small, dark red spots on the skin called angiokeratomas; a decreased ability to sweat (hypohidrosis); cloudiness of the front part of the eye (corneal opacity); problems with the gastrointestinal system; ringing in the ears (tinnitus); and hearing loss. Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Some affected individuals have milder forms of the disorder that appear later in life and affect only the heart or kidneys. Fabry disease is caused by mutations in the GLA gene. This gene provides instructions for making an enzyme called alpha-galactosidase A. This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells. Alpha-galactosidase A normally breaks down a fatty substance called globotriaosylceramide. Mutations in the GLA gene alter the structure and function of the enzyme, preventing it from breaking down this substance effectively. As a result, globotriaosylceramide builds up in cells throughout the body, particularly cells lining blood vessels in the skin and cells in the kidneys, heart, and nervous system. The progressive accumulation of this substance damages cells, leading to the varied signs and symptoms of Fabry disease. Because females have two copies of the X chromosome, one altered copy of the gene in each cell usually leads to less severe symptoms in females than in males, or may cause no symptoms at all.

Answer 314

In normal conditions, the LMNA gene codes for a structural protein called prelamin A. There is a farnesyl functional group attached to the carboxyl-terminus of its structure. The farnesyl group allows prelamin A to attach temporarily to the nuclear rim. Once the protein is attached, the farnesyl group is removed. Failure to remove this farnesyl group permanently affixes the protein to the nuclear rim. Without its farnesyl group, prelamin A is referred to as lamin A. Lamin A, along with lamin B and lamin C, makes up the nuclear lamina, which provides structural support to the nucleus. Farnesyltransferase inhibitors (FTIs) are drugs that inhibit the activity of an enzyme needed in order to make a link between progerin proteins and farnesyl groups. This link generates the permanent attachment of the progerin to the nuclear rim. In progeria, cellular damage can be appreciated because that attachment takes place and the nucleus is not in a normal state. Lonafarnib is an FTI, which means it can avoid this link, so progerin can not remain attached to the nucleus rim and it now has a more normal state. Showing promise in Lamin A/C mutations in Progeria, a premature aging syndrome. Lamin A/C mutation leads to a mutant lamin A/C protein (‘progerin’) that is targeted to the nuclear membrane by Farnesyl groups -> pathological effects at nuclear membrane. Farnesyl transferase inhibitors appear to reduce progerin sequestration at the nuclear membrane

Answer 315

The FGFR3 gene provides instructions for making a protein called fibroblast growth factor receptor 3. This protein plays a role in several important cellular processes, including regulation of cell growth and division, determination of cell type, formation of blood vessels, wound healing, and embryo development. Two mutations in the FGFR3 gene cause more than 99 percent of cases of achondroplasia, which is a form of short-limbed dwarfism. Both mutations lead to the same change in the FGFR3 protein, glycine is replaced with the amino acid arginine at protein position 380 (written as Gly380Arg or G380R). Researchers believe that this genetic change causes the receptor to be overly active, which leads to the disturbances in bone growth that occur in this disorder. FGFR3 is a transmembrane tyrosine kinase receptor -> binds fibroblast growth factors -> initiates a signaling cascade -> ~ inhibits bone growth. FGFR3 c.1138 G>A Gly380Arg = gain-of-function mutations that cause ligand-independent activation of FGFR3. FGFR3 turned ON -> inappropriately inhibits bony growth. c.1138G is ~#1 most mutable nucleotide in human gene à nearly 100% of achondroplasia (single gene / single nucleotide). De novo mutations of FGFR3 guanine 1138 occur exclusively in the father's germline and increase in frequency with advanced paternal age (>35 years)

Answer 316

Hypochondroplasia is a form of short-limbed dwarfism. This condition affects the conversion of cartilage into bone, particularly in the long bones of the arms and legs. Hypochondroplasia is similar to achondroplasia, but the features tend to be milder. Hypochondroplasia is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most people with hypochondroplasia have average-size parents; these cases result from a new mutation in the FGFR3 gene. In the remaining cases, people with hypochondroplasia have inherited an altered FGFR3 gene from one or two affected parents. Individuals who inherit two altered copies of this gene typically have more severe problems with bone growth than those who inherit a single FGFR3 mutation. People with hypochondroplasia have short arms and legs and broad, short hands and feet. Other characteristic features include a large head, limited range of motion at the elbows, a sway of the lower back (lordosis), and bowed legs. These signs are generally less pronounced than those seen with achondroplasia and may not be noticeable until early or middle childhood.

Answer 317

Systems outside the ears are involved. General: Intellectual disability, seizures, dysmorphic syndromes. Specific: With retinitis pigmentosa suggests Usher (AR)syndrome. With thyroid goiter suggests Pendred (#2 AR) syndrome. With arrhythmia or sudden death suggests Jervell and Lange-Nielson (AR) syndrome. With white forelock suggests Waardenburg (#1 AD)syndrome. With 8th nerve schwannomas suggests Neurofibromatosis type II

Answer 318

retinitis pigmentosa, Usher syndrome is inherited as an autosomal recessive trait. Usher syndrome is the most common condition that affects both hearing and vision. A syndrome is a disease or disorder that has more than one feature or symptom. The major symptoms of Usher syndrome are hearing loss and an eye disorder called retinitis pigmentosa, or RP. RP causes night-blindness and a loss of peripheral vision (side vision) through the progressive degeneration of the retina. The retina is a light-sensitive tissue at the back of the eye and is crucial for vision. As RP progresses, the field of vision narrows—a condition known as “tunnel vision”—until only central vision (the ability to see straight ahead) remains. Many people with Usher syndrome also have severe balance problems.

Answer 319

thyroid goiter, Pendred syndrome is a disorder typically associated with hearing loss and a thyroid condition called goiter. A goiter is an enlargement of the thyroid gland, which is a butterfly-shaped organ at the base of the neck that produces hormones. If a goiter develops in a person with Pendred syndrome, it usually forms between late childhood and early adulthood. In most cases, this enlargement does not cause the thyroid gland to malfunction.

Answer 320

With arrhythmia or sudden death, Jervell and Lange-Nielsen syndrome is a condition that causes profound hearing loss from birth and a disruption of the heart's normal rhythm (arrhythmia). This disorder is a form of long QT syndrome, which is a heart condition that causes the heart (cardiac) muscle to take longer than usual to recharge between beats. Beginning in early childhood, the irregular heartbeats increase the risk of fainting (syncope) and sudden death.

Answer 321

white forelock, Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Although most people with Waardenburg syndrome have normal hearing, moderate to profound hearing loss can occur in one or both ears. The hearing loss is present from birth (congenital). People with this condition often have very pale blue eyes or different colored eyes, such as one blue eye and one brown eye. Sometimes one eye has segments of two different colors. Distinctive hair coloring (such as a patch of white hair or hair that prematurely turns gray) is another common sign of the condition. The features of Waardenburg syndrome vary among affected individuals, even among people in the same family.

Answer 322

Neurofibromatosis type 2 is a disorder characterized by the growth of noncancerous tumors in the nervous system. The most common tumors associated with neurofibromatosis type 2 are called vestibular schwannomas or acoustic neuromas. These growths develop along the nerve that carries information from the inner ear to the brain (the auditory nerve). Tumors that occur on other nerves are also commonly found with this condition. With 8th nerve schwannomas

Answer 323

X-Linked: Premutation Triplet repeat expansion (CGG 55-200), Age at onset: Adulthood, Ataxia, tremor, Memory loss, parkinsonism, peripheral neuropathy, Men >> women. Premature Ovarian Failure, X-linked, Premutation Triplet repeat expansion, Women (not men)

Answer 324

The FMR1 gene product, FMRP, is expressed in many cell types but most abundantly in neurons. FMRP may chaperone a subclass of mRNAs from the nucleus to the translational machinery. More than 99% of FMR1 mutations are expansions of a (CGG)n repeat sequence in the 5' untranslated region of the gene. In normal alleles of FMR1, the number of CGG repeats ranges from 6 to approximately 50. In disease-causing alleles or full mutations, the number of repeats is more than 200. Alleles with more than 200 CGG repeats usually have hypermethylation of the CGG repeat sequence and the adjacent FMR1 promoter, causing fragile x. Hypermethylation inactivates the FMR1 promoter, causing a loss of FMRP expression. Full mutations arise from premutation alleles (approximately 59 to 200 CGG repeats) with maternal transmission of a mutant FMR1 allele but not with paternal transmission; in fact, premutations often shorten with paternal transmission. Because the length of an unstable CGG repeat increases each generation if it is transmitted by a female, increasing numbers of affected offspring are usually observed in later generations of an affected family; this phenomenon is referred to as genetic anticipation. The risk of premutation expansion to a full mutation increases as the repeat length of the premutation increases. Not all premutations, however, are equally predisposed to expand. Although premutations are relatively common, progression to a full mutation has been observed only on a limited number of haplotypes; that is, there is a haplotype predisposition to expansion. This haplotype predisposition may relate partly to the presence of a few AGG triplets embedded within the string of CGG repeats; these AGG triplets appear to inhibit expansion of the string of CGG repeats, and their absence in some haplotypes, therefore, may predispose to expansion.

Answer 325

a condition that results in the partial or complete inability of the cell to respond to androgens. The unresponsiveness of the cell to the presence of androgenic hormones can impair or prevent the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty, but does not significantly impair female genital or sexual development. As such, the insensitivity to androgens is clinically significant only when it occurs in genetic males (i.e. individuals with a Y-chromosome, or more specifically, an SRY gene). Clinical phenotypes in these individuals range from a normal male habitus with mild spermatogenic defect or reduced secondary terminal hair, to a full female habitus, despite the presence of a Y-chromosome.

Answer 326

In population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci, that descend from single, ancestral chromosomes.[1] Linkage disequilibrium is wholly a measurement of proximal genomic space. It is necessary to refer to this as gametic phase disequilibrium[2] or simply gametic disequilibrium because it is described through DNA recombination. In other words, linkage disequilibrium is the occurrence of some combinations of alleles or genetic markers in a population more often or less often than would be expected from a random formation of haplotypes from alleles based on their frequencies. It is a second order phenomenon derived from linkage, which is the presence of two or more loci on a chromosome with limited recombination between them. The amount of linkage disequilibrium depends on the difference between observed allelic frequencies and those expected from a homogenous, randomly distributed model. Populations where combinations of alleles or genotypes can be found in the expected proportions are said to be in linkage equilibrium.

Answer 327

A haplotype is a contraction for haploid genotype. A haplotype is a collection of specific alleles (particular DNA sequences) in a cluster of tightly-linked genes on a chromosome that are likely to be inherited together.[1][2] Put in simple words, haplotype is the group of genes that a progeny inherits from one parent.

Answer 328

22q11.2 deletion syndrome has many possible signs and symptoms that can affect almost any part of the body. The features of this syndrome vary widely, even among affected members of the same family. Common signs and symptoms include heart abnormalities that are often present from birth, an opening in the roof of the mouth (a cleft palate), and distinctive facial features. People with 22q11.2 deletion syndrome often experience recurrent infections caused by problems with the immune system, and some develop autoimmune disorders such as rheumatoid arthritis and Graves disease in which the immune system attacks the body's own tissues and organs. Affected individuals may also have breathing problems, kidney abnormalities, low levels of calcium in the blood (which can result in seizures), a decrease in blood platelets (thrombocytopenia), significant feeding difficulties, gastrointestinal problems, and hearing loss. Skeletal differences are possible, including mild short stature and, less frequently, abnormalities of the spinal bones.

genetics 3 Flashcards

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