Chapter 5 Flashcards by Stephen Barna

Human genetic disorders can be classified into 3 categories

1) Disorders related to mutations in single genes with large effects, commonly referred to as ____ disorders

^** These disorders are rare, except in populations where they are maintained by strong selective forces like sickle cell anemia in areas where malaria is endemic. They have a ___ penetrance (the extent to which a particular gene is expressed in the phenotypes of individuals that carry it aka a high phenotype means those that posses the genes display the associated phenotypes for the genes)

A hereditary condition involving the abnormality in the structure of hemoglobin is an example of this type of disorder and is called hemoglobinopathy

2) ___ disorders arise from structural or numerical alterations in the autosomes (non sex chromosomes) and sex chromosomes

^** Like Mendelian disorders, they are rare but have ___ penetrance

3) The more common disorder is ___ disorders caused by interactions between multiple variant forms of genes (aka polymorphisms) and environmental factors

^** Since it takes several polymorphisms for a disease to occur, unlike mutant genes with large effects (aka high penetrance) that give rise to mendelian disorders, each polymorphism has a small effect and therefore ___ penetrance

Complex multigenic disorders are also referred to as multifactorial disorders and include atherosclerosis, diabetes mellitus, hypertension, and autoimmune disorders

4) There is also a 4th type of category that involves single gene disorders with NON-classical patterns of inheritance
^** Involves trinucleotide repeat mutations, mtDNA mutations (mitochondrial), and transmission influenced by genomic imprinting or gonadal mosaicism

1) Mendelian, high
2) Chromosomal, high
3) Complex multigenic (aka polygenic), low

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Mutations in the __ cell population can be passed on to offspring (these produce gametes aka sperm and ovums and contain 1 set of chromosomes), where as mutations in the ___ cell population can not (these are just cells that form the body of the organism and have diploid chromosome numbers aka any cell that is not a gamete, germ cell, gametocyte, or undifferentiated stem cell)

^** So even though somatic cell mutations can’t be passed on (cause hereditary disease), they can still cause cancers and some congenital malformations

Germ, Somatic

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There are different types of mutations

1) A ___ mutation within the coding sequence is a change in which a single base is substituted for a different base

There are three possible effects of a point mutation

A) A ___ mutation in when the code in a triplet of bases is altered, leading to the replacement of one amino acid by another in the gene product
^** If the new amino acid has similar biochemical properties, it is called a ___ mutation and a nonconservative missense mutation is one where the biochemical activity of the new amino acid is much different

B) A ___ mutation is when stop codon is produces and this affects translation

C) A ___ mutation is when no change in amino acid sequence occurs

1) Point

A) Missense
Conservative missense mutation
B) Nonsense
C) Silent

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In sickle cell anemia, the beta-globin chain of hemoglobin undergoes a CTC -> CAC point mutation, causing the amino acid ___ -> ___ substitution to occur

^** Realize this would be a nonconservative missense mutation

In ___, a severe form of anemia (lack of blood), the beta-globin chain has undergone a point mutation affecting a ___ sequence (CAG) and replacing the C with ___, to cause a stop codon to be formed and the beta-globin gene translation is prematurely terminated resulting in beta-globin deficiency

Factor V Leiden mutation is a ___ -> ___ amino acid substitution due to CGA->CAA and this causes resistance to activated ___ and since this anticoagulant pathway is lost, it causes blood clotting disorders (throbmophilia) and therefore high risk of developing DVTs

Glu (Glutamic acid) -> Val (Valine)

Beta-Thalassemia, glutamine (Gln), U

^** In other words Gln -> STOP

Gln (Glutamine) -> Arg (Arginine), protein C

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Remember, introns are the ___ sequences and exons are the __ sequences

Note that non-protein coding sequences (the introns) can also be mutated

If the mutation occurs in the promotor or enhancer region, ___ can not bind and transcription will be reduced or no longer occur

^** Along with that point mutation we talked about, non coding mutations here can cause alpha-thalassemia (hereditary anemia)

Since no transcription is occurring, noncoding regulatory RNAs can’t be formed including miRNAs, lnRNAs, transposons, telomeres, centromeres, etc…

If a point mutation occurs in the ___, defective splicing of intervening sequences can occur and results in the failure to form a mature mRNA and translation can’t occur and gene product is not synthesized

Non-coding (Think Introns stay IN), Coding (Think Exons Exit to code genes)

TFs

Intron

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If deletions or insertions occur in a pair of 3, the reading frame will remain intact and an abnormal protein with an extra or lacking one or more amino acid sequence will be synthesized

^** This 3 base deletion is often seen in the ____ disease affecting amino acid 508 which is ___, (so it is not a frameshift mutation) on chromosome ___****

If the deletion is not in a pair of 3, a ___ mutation occurs and therefore the reading frame is altered and results often in a variable number of incorrect amino acids followed by truncation due to a premature stop codon

^** This is seen in a single base deletion of the ABO A allele blood type -> ABO O allele blood type due to a shifted reading frame

Or seen in ___ disease where a 4 base insertion causes the HEXA allele (hexosaminidase A gene) to change leading to a frameshift mutation and often seen in Ashkenazi jews

Cystic fibrosis, Phe (phenylalanine), 7

Frame shift

Tay-Sachs (this disease destroys nerve cells in the brain and spinal cord)

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So thalassemia, which occurs due to problems with globin production can occur as alpha or beta, depending on the globin polypeptide chain that is altered

If the alpha chain undergoes a point mutation or deletion, depending on how many alleles are affected determines the severity of the disease

If one alpha allele is affected, the patient is a silent carrier

If 2 alleles are affected, the patient is still asymptomatic (alpha-thalassemia minor) and presents with mild ___cytic anemia and ___chromic RBCs

If 3 alleles are affected, the patient is said to have ___ disease and is symptomatic with moderate hemolytic, microcytic anemia and hypochromic RBCs. They often have ___megaly and Hb electrophoresis and protein chromatography show HbH

If 4 alleles are affected, the patient is incompatible with life and it’s called ___

Microcytic, hypocrhomic

Hb H diseas, Splenomegaly

Hydrops Fetalis

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The amplification of a sequence of three nucleotides is called trinucloetide-repeat mutations (single-gene disorders with non-classical patterns of inheritance) and while the sequences might vary in the different disorders, they ALL share the common nucleotides ___ and ___ and is commonly seen in ___ syndrome where the CGC repeats within the ___ gene and the expansion causes this gene to not be expressed leading to mental retardation

^** Another distinguishing feature is that these repeats are ___ aka the degree of amplification increasers during gametogenesis aka spermatogenesis and oogenesis aka creation of sperm and ovums)

C and G, Fragile X syndrome, FMR1 (Familial mental retardation)

Dynamic

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Some autosomal Mendelian disorders can have partial expression in the heterozygote form and full expression in the homozygote form

An example of this is Sickle Cell Anemia where in full blown SSA, the HbA hemoglobin is completely substituted by Hb__ and all cells are deformed with hemolytic anemia no matter the oxygen saturation

However, if the patient is heterozygous for the disorder, they are referred to as the ___ and only some Hb is HbS and the rest is HbA and only in unusual circumstances like decreased oxygen would the patient show signs of red cell sickling

HbS

Sickle cell trait

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When both alleles of a gene pair contribute to the phenotype, it is called ___ and histocompatibility (HLA genes) and blood groups are examples of this

Codominance

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___ is when a single mutation can affect different traits (that are or are not related) where as genetic ___ is when several mutations at different loci produce the same trait effect

Sickle Cell Anemia is an example of ___ because a single point mutation turns HbA -> HbS AND causes logjam in small vessels (aka differing end organ derangements)

Childhood deafness or diabetes mellitus is an example of ____

Pleiotropism, genetic heterogeneity

Pleiotropism

Genetic heterogeneity

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Mutations involving single genes follow 3 patterns of inheritance

___ disorders are manifested in the heterozygous state where only 1 gene is affected by at least 1 parent

These disorders appear in every generation and is evenly distributed in each generation (although more so in recessive)

Autosomal dominant disorders in patients can sometimes arise from parents who are not affected due to new mutations arising from either the egg or sperm and often seen in germ cells of old fathers

Some patients who inherit the autosomal dominant disorder can still not express any of the phenotypes associated with it and are said to have ___ of the mutation. If the mutation is expressed in all patients who have it, but the expression varies in severity among those it is called ___

^** Neurofibromatosis type 1 is an example of ___

The age of onset can also vary for autosomal dominant disorders like in Huntington’s disease

Autosomal dominant

Incomplete penetrance

Variable expressivity

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Most mutations lead to the reduced gene product or give rise to a dysfunctional or inactive protein and therefore whether the mutation gives rise to a dominant or recessive disease depends on if the remaining copy of the gene can compensate for the loss

If the gene can’t compensate for the loss, the mutation is dominant and there are some common patterns that these deleterious mutations fall into

1) Mutations involved in the regulation of complex metabolic pathways that are subject to feedback inhibition

^** In Familial hypercholesterolemia, which is an example of ___ for those who are heterozygous for the autosomal dominant mutation, ___ receptors are mutated and lost and results in a secondary elevation of ___ that predisposes a patient to ____ in affected heterozygotes

2) Mutations in key structural proteins such as collagen and cytoskeletal elements of the red cell’s membranes

^** This is seen in ___ where collagen and sever cytoskeletal abnormalities are seen and can occur if a single mutant collagen chain causes the entire collagen trimer to not be formed leading to decreased collagen. Since the mutant allele impairs the function of normal alleles, it is called ___

Variable expressivity, LDL, cholesterol, atherosclerosis (buildup of fats, cholesterol, and other substances in the artery walls)

Osteogenesis imperfect, dominant negative

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The transmission of disorders produced by gain of function mutations is almost ALWAYS ____ and illustrated in ___ disease where a trinucleotide-repeat gives rise to an abnormal protein in the gene called huntingtin that is toxic to neurons

Autosomal dominant, Huntingtons disease

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Mutations involving single genes follow 3 patterns of inheritance

When both alleles at a given gene locus are mutated, it leads to an ___ disease

Recessive traits can skip generations but there is an even distribution since it is autosomal

^** 25% chance (1 in 4 of having the trait)

If there is a mutant gene that occurs in very low frequency within a population, it is often from ____ if present in the proband (aka the starting for a genetic family study)

Recessive genes usually occur __ in life, ____ penetrance is common, many of the mutated genes encode for ___, expression tends to be more uniform than dominant disorders (even distribution between men and females) and unlike dominant disorders, new mutations are often not detected

^** So to recap, realize that in autosomal dominant disorders, ___ and ___s are involved and in autosomal recessive disorders, ___ are affected

*** Almost ALL inborn errors of metabolism are due to ____ disorders

Autosomal recessive

Consanguinity (blood relation)

Early, Complete (aka 100% of those who have it show it), enzymes

Receptors and Structural proteins, Enzymes

Autosomal recessive

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Name if the disorder is autosomal dominant or autosomal recessive Or X-linked recessive

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All sex-linked disorders are ___-linked and almost all are ___

^** They are all X linked since those mutations affecting the Y region affect spermatogenesis and cause the males with these to be infertile so it doesn’t get passed on

^** Aka most are X-linked recessive

There is no male-male transmission, but all daughters are either affected or carriers. Also more males are affected and are said to be ___ for the X-linked mutation. There is also an uneven distribution

X, recessive

Hemizygous (since the gene on the X does not correspond to the Y)

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Heterozygous females do not express the full phenotypic change because the other paired allele that is not affected and random inactivation of one X chromosome can protect them

However, females have the random inactivation of one of the X chromosomes, so if the normal X is inactive then full expression of the X-linked condition can occur

However, more commonly the normal X chromosome is only inactivated in some cells, so the female expresses the disorder partially such as in ____ deficiency which predisposes the patient to red cell hemolysis when receiving certain drugs and therefore the female is not only a carrier, but susceptible to drug induced hemolytic reactions

But realize that since there are still some normal cells, the severity of hemolytic reactions is almost always less in hetero females vs hemizygous males

G6PD (Glucose-6-phosphate dehydrogenase) deficiency

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Since mendelian disorders result from alterations involving single genes, these genetic defects can lead to the formation of abnormal proteins or reduced output of gene products and can be classified into 4 categories

1) Enzyme defects and their consequences

A) If an enzyme is defective, it can lead to ____ of the substance and tissue injury can occur if products of alternative minor pathways are toxic

^** Examples of this include ___ where the enzyme galactose 1-phosphate uridyltransferase (GALT) is defective and leads to the accumulation of galactose and subsequent tissue damage

Deficiency of degradative enzymes in the lysosomes, which results in accumulation of complex substrates called ____

B) Enzyme defects can lead to metabolic block and a decreased amount of ___

^** An example is seen in albinism where there is deficient ___ due to an enzyme defect in ___

If the end product feeds back to inhibit enzymes involved in early steps, then the overproduction of intermediates and their catabolic products can occur (some can be toxic) and a good example of this is ___ syndrome where HPRT gene is defective and leads to a buildup of uric acid

C) If an enzyme that is suppose to inactivate a tissue damaging substrate is defective, damage can occur

^** This is best seen in ___ deficiency where patients have a defect in serum alpha1-antitrypsin and therefore can’t inactivate the enzyme ___, which is a protease that disrupts connective tissue and destroys the elastin in the walls of the lung alveoli and therefore eventually leads to pulmonary emphysema or liver disease

A) Accumulation

Galactosemia

Lysosomal storage disease

B) End product

Melanin, Tyrosinase

Lesch-Nyhan

Alpha-1 antitrypsin, neutrophil elastase

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2) Defects in membrane receptors and transport systems

One example where the transport system is defective is _____ where a genetic defect in a receptor-mediated transport system occurs due to the ___ receptors not working properly and therefore no LDL is brought into the cells and therefore secondary synthesis of excess cholesterol occurs by complex intermediary mechanisms

Another example is ___ where the transport of chloride ions is defective and can lead to injury in the lungs and pancreas

Familial hypercholesterolemia, LDL

Cystic fibrosis

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3) Alterations in the structure, function, or quantity of nonenzyme proteins

Structural changes are best exemplified by ___ which are all characterized by defects in the structure of the globin molecule (like sickle cell)

Quantity alterations is best seen in ___ which are mutations in the globin gene that affects the amount of globin chains synthesized

Other genetic disorders involving structural proteins include decreased collagen leading to ___, decreased Fibrillin leading to ___, decreased Dystrophin leading to ___, and decreased spectrin leading to ___

Hemoglobinopathies

Thalassemias

Osteogenesis Imperfecta, Marfan Syndrome, Muscular Dystrophy (Duchenne/Becker), Hereditary Spherocytosis

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4) Mutations resulting in unusual reactions to drugs where certain defects are unmasked only after exposure to certain drugs and this area of genetics is called ___

The best example if in ___ deficiency where administration of antimalarial drug called primaquine causes a severe hemolytic anemia (decreased RBC count since they are destroyed and removed from blood stream)

Pharmacogenetics

G6PD

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Marfans syndrome is associated with defects in ___

This disease is a disorder of the ___ manifested by changes in the skeleton, eyes, and CV system

This disorder is mainly (70-85%) transmitted via ___ inheritance and the remainder is sporadic and arises from new mutations

This is an ___ (cell membrane or extracellular?) mutation where this disease occurs via the inheritance of an defective extracellular glycoprotein called ___ and this leads to the loss of fibrillin (a glycoprotein essential for the formation of elastic fibers found in connective tissue) which causes 2 problems

1) Loss of structural support in ___ rich connective tissue (Discussed in next notecard)
2) Excess activation of ___ signaling due to the loss of microfibrils since normal microfibrils sequester (hide) TGF-Beta and therefore control its availability

^** We conclude this because patients with no FBN1 mutations but instead gain-of-function TGF-Beta mutations exhibit Marfan syndrome (MFS2) and also in rats with FBN1 mutations, if you provide antibodies to TGF-Beta you prevent aorta and mitral valve alterations

Structural proteins

Connective tissue

Autosomal dominant

Extracellular

Fibrillin-1

1) Microfibril
2) TGF-Beta

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Fibrillin is a major component of ____ (a general term to describe the structure of a protein) found in the ECM and forms a scaffolding on which ____ is deposited to form elastic fibers (so in other words, elastic fibers are composed of MF and TE)

^** These fibers are abundant in the heart, ligaments, and periorbital regions

Fibrillin occurs as FBN1 and FBN 2

Mutations in ___ gives rise to Marfan’s syndrome and mutations in ___ gives rise to Congenital Contractural arachnodactyly (an autosomal dominant disorder with skeletal abnormalities)

Most of the FBN1 mutations are ___ mutations that give rise to abnormal fibrillin-1 and this can inhibit polymerization of fibrillin fibers (aka the dominant negative effect since it is impairing the function of normal alleles) and weaken the connective tissue called ___insufficiency

Microfibrils, Tropoelastin

FBN1, FBN2

Missense

Haploinsufficiency

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In Marfan Syndrome, the bone overgrowth and myxoid (tumors of connective tissue) changes in mitral valves are attributed to not tissue elasticity changes, but ___ ^** Excess TGF-Beta can have deleterious effects on vascular smooth muscle development and increase MMPs that destroy the ECM

TGF-Beta

The morphological characteristics of Marfan syndrome include 1) Unusually tall with long extremities and long tapering fingers and toes 2) Ligaments in the hands and feet are lax and therefore the patient is double jointed (thumb can hyperextend back to wrist) 3) The head appears long aka ___ (long-headed) with bossing of frontal eminences and prominent supraoribital ridges 4) Spinal deformities can appear (kyphosis, scoliosis, rotation or slipping of the dorsal/lumbar vertebra) 5) Chest is deformed (Pectus carinatum or pectus excavatum) 6) Ocular changes and most common is bilateral subluxation or dislocation of the lens called ___ * *****^ This is important, if bilateral ectopia lentis is observed, THINK MARFAN SYNDROME 7) Cardiovascular lesions including ___ valve prolapse (which can lead to floppy valves and lead to mitral regurgitation.... and more importantly, dilation of the ____ due to ___ (also called familial thoracic aortic aneurysm) which is a term to describe disorders of large arteries and is a CLINICAL IMPORTANT problem that can lead to death if an aortic dissection ruptures In this disease, cystic medionecrosis causes loss of the aortic tunica ___ support (aka weakening of the tunica media) resulting in progressive dilation of the aortic valve ring and root of the aorta giving rise to severe aortic incompetence TGF-Beta excess signaling can also contribute to aortic dilation in the tunica _____ (outer most layer) ****Weakening of the aorta predisposes the patient to an tunica ___ (inner most layer aka an intimal tear) tear which can then cause an intramural hematoma that cleaves the layers of the tunica ___ to produce an ___ and as the aortic layers are cleaved the hemorrhage can eventually rupture through the aortic wall and cause death ^** In other words, the patient is predisposed to an intimal tear, when this tear occurs blood starts to flow onto the media layer. Then the media layer tears allowing blood to flow through the media layer in a "false lumen" so one more time, aortic dissections occur when blood separates the laminar planes of the media to form a blood-filled channel in the aortic wall Finally, note that there is a large amount of variation in this disease and therefore diagnosis is based on the "revised Ghent criteria" that must include ___ of the four major organ systems (skeletal, CV, ocular, and skin) and ___ minor involvement of another organ Treatment includes perscribing ___ to reduce heart rate and organ wall stress

Dolichocephalic Ectopia Lentis Mitral, Ascending aorta, cystic medionecrosis Media, adventitia (aka externa) Intima, Media, aortic dissection 2, 1 Beta blockers

Another disease that affects connective tissue and multiple organ systems is Ehlers-Danlos syndromes (EDS) This syndrome results from some defect in the structure or synthesis of ___ ^** Note other defects like osteogenesis imperfecta, Alport syndrome, and epidermolysis bullosa are also affected by collagen synthesis Also note that this set of diseases can be inherited by ALL 3 mendelian patterns Since these syndromes contain collagen defects, tissues rich in collagen are the most affected including the skin, ligaments, and joints Since fibers lack adequate tensile strength, the ___ is hyperextensible (since it is easily stretchable it is therefore very fragile and vulnerable to trauma) and the ___ are hypermobile (this fact predisposes patients to joint dislocations)

Fibrillar collagen Skin, joints

Name the EDS type based on the clinical findings and also name the mode of inheritance and gene defect associated with it 1) Rupture of the colon and large arteries, think skin, bruising, and small joint hyperextensibility 2) Ocular fragility with rupture of cornea and retinal detachment, hypotonia (low muscle tone), joint laxity, and congenital scoliosis 3) Diaphragmatic hernia (abdominal organs move into chest through opening in diaphragm), skin and joint hypermobility, atrophic scars, and easy bruising 4) Joint hypermobility, pain, and dislocations 5) Severe joint hypermobility, skin changes (mild), scoliosis, and bruising 6) Severe skin fragility, cutis laxa (skin becomes inelastic and hangs loosely or folds), bruising

1) Vascular (IV aka 4) - AD - COL3A1 2) ***** Kyphoscoliosis (VI) - AR - Lysyl hydroxylase****** 3) Classic (I and II) - AD - COL5A1, COL5A2 4) Hypermobility (III) - AD - Unknown cause 5) Arthrochalasia (VIIa, VIIb) - AD - COL1A1, COL1A2 6) Dermatosparaxis (VIIc) - AR - Procollagen N-peptidase

In the kyphoscoliosis EDS type, remember there is a defect with the ___ enzyme With no lysyl hydroxylase, there is no hydroxylation of lysine residues which results in reduced levels of hydroxylysine which is essential for ___ collagen fibers and therefore this lack of cross-linking results in decreased structural stability ^** So realize that this EDS is due to a defect in an ENZYME The vascular EDS type is from abnormalities of type ___ collagen (hence the gene defect is COL3A1) There are 3 different mutations that can lead to this form of EDS which is what makes it genetically heterogeneous... It is important to realize that unlike kyphoscoliosis EDS, this type of EDS is due to a mutation involving a ___ rather than an enzyme The 3 types of mutations can be 1) Affects the rate of synthesis for ___ chains 2) Affects the secretion of ____ 3) Causes the synthesis of structurally abnormal ___ Since Vascular EDS is a structural protein defect, it makes sense that this is an AD inheritance and that severe structural defects like an increase in the vulnerability to spontaneous ruptures in organs exists

Lysyl hydroxylase cross-linking type 3 Structural protein 1) Pro-alpha1 (III) chains 2) Type 3 procollagen 3) Type 3 collagen ^** Note the mechanisms for collagen synthesis is on page 23

Arthrochalasia and dermatosparaxis EDS is due to a fundamental defect in the conversion of ___ to ___ which involves the cleavage of noncollagen peptides In Arthrochalasia, the mutation is in one of the two types of Type 1 collagen ___ and as a result structurally abnormal ___ or ___ chains that resist cleavage of their N-terminal peptides and are formed and therefore no collagen can be formed In dermatosparaxis, the mutation is in the ___ gene and since this enzyme is defective, no cleavage occurs to produce collagens ^** Note that this is a defect in the enzyme, and thus this takes on an AR form of inheritance

Type 1 procollagen to collagen Genes (COL1A1 and COL1A2), Pro-alpha 1 and Pro-alpha 2 procollagen-N-peptidase

The classic type EDS contains mutations in the genes for type __ collagen Some other forms of Classic type EDS don't seem to be due to collagen gene abnormalities and instead can be from mutations in other genes like ____, which is a large protein that affects the synthesis and fibril formation of Type 4 and Type 1 collagens

Type 5 (COL5A1 and COL5A2) Tenascin-X

A receptor disease due to mutations in the gene encoding the LDL receptor involved in the transport and metabolism of cholesterol is called ___ This causes a loss of ___ control and subsequent increased levels of cholesterol that can lead to premature ____ and therefore a much higher risk for a ___ Remember, this is a autosomal ___ inheritance pattern so if a patient is heterozygous, they show a 2-3 times elevated plasma cholesterol levels leading to tendinous ___ and premature atherosclerosis in ___ life... If a patient is homozygous then they have a 5-6 times elevated plasma cholesterol level and can develop both xanthomas and atherosclerosis of the coronary, cerebral, and peripheral vasculature ___ in life (compared to later like in a heterzygote and therefore can have an MI before the age of 20) ** Also note that hypercholesterolemia is defined as being greater than 160 mg/dl

Familial hypercholesterolemia Feedback, atherosclerosis, MI Dominant, xanthomas (yellowing due to lipid deposits), atherosclerosis, Adult, Early

Cholesterol circulates in the plasma mainly in the form of ___ The synthesis of LDL occurs by first the liver cells secreting ___ into the blood stream. These contain the apoproteins ___ VLDLs are rich in ____ and contain less ___ When a VLDL reaches the capillaries of either an adipose tissue or muscle tissue, it is cleaved by ____ causing the TGs to be extracted and stored in the fat cells or used for energy in the muscle cells The resulting molecule is ___ and contains the apoproteins ___ with a lower ___ content than before and therefore and a higher ___ content than before After release from the capillary endothelium, IDL can either be taken back up into the liver to be recycled to VLDL via receptor mediated clearance of IDL via the ___ receptor or it can turn into ___ LDL has the apoproteins ___ and has NO ___ content, aka only CEs ^** So realize IDL is the immediate major source of LDLs Finally LDL is either recycled back into the liver as well via receptor mediated clearance of the LDL via the LDLR or it can undergo another type of clearance which is described on the next notecard

LDL VLDLs, B100/ApoC/ApoE Triglycerides (TG), Cholesteryl esters (CE) LPL (Lipoprotein lipase) IDL, B100/ApoE, TG, CE LDLR (LDL Receptor), LDL B100, TG

Various cells contain LDLRs, however the liver is the major mechanism of LDL clearance (70%) This type of receptor mediated clearance occurs as LDL binds to the cell surface LDLRs which are clustered in specialized regions of the plasma membrane called ___ After binding, the coated pits with LDLR and LDL are internalized and now the clathrin coated vesicle continues the receptor mediated endocytosis we talked about in chapter 1.... Clathrin coated vesicles -> Endosome -> Fuse with lysosome (LDL dissociates from receptor and receptor is recycled to the surface) In the lysosome, the enzymatic degradation of the apoprotein part (B100) is hydrolyzed to ___ and the CEs are broken down into ___ The free cholesterol crosses the lysosomal membrane via the action of two proteins ___ and ___, and enters the cytosol where it is used for membrane synthesis and cholesterol homeostasis (which is discussed more on the next card) ^** There is where Niemann-Pick Disease Type C comes from

Coated pits Amino acids, free cholesterol NPC1 and NPC2

Once free cholesterol enters the cytosol, it has 3 major actions 1) ____ cholesterol synthesis via inhibiting the enzyme ___ which is the rate limiting step needed for the synthesis of cholesterol 2) ___ esterification and storage of excess cholesterol due to the activation of the enzyme ___ 3) ___ the synthesis of LDL receptors in order to protect the cells from excessive accumulation of cholesterol

1) Suppresses, HMG CoA reductase (3-hydroxy-3-methyglutaryl) 2) Activates, Acyl-CoA (cholesterol acyltransferase) 3) Suppresses

So in familial hypercholesterolemia, one could have a defect in the ___ gene or a defect in the apoprotein ___ Since catabolism of LDL is impaired in FH, the plasma levels of LDL increase ^** Also, since IDL uses LDLRs for uptake back into the liver, since the uptake is defective you now get more IDLs moving into the precursor pool for plasma LDL so you get an even higher plasma LDL increase In addition to the defective clearance of LDL, there is also an ____ in synthesis of LDL since you loose feedback control and the cells think LDL is low so they produce more to compensate (but in reality, they just aren't being taken up into the cells)

LDLR, ApoB-100 Increased

LDL can also be taken up via ___ of the mononuclear phagocyte system via mainly ___ In FH, there is an increased scavenger receptor mediated trafficking of LDL cholesterol into mononuclear phagocytes which can cause the accumulation of cholesterol in the vascular walls leading to a "foam cell" and therefore this is why patients appear with ____ most commonly deposited along tendon sheaths and have premature atherosclerosis and coronary artery disease ^** Xanthomas (abnormally elevated cholesterol of lipids in the blood) is also referred to as ____

Scavanger receptors, macrophages/monocytes Xanthomas Dyslipidemia

There are 5 mutation classes of the LDLR... Name them 1) LDLR reach the cell surface, but their binding domains are defective and can not bind LDL properly 2) LDLRs are properly expressed on the cell surface, bind and even internalize the LDL, however the pH-dependent dissociation of the LDLR and the bound LDL does not occur and therefore these LDLRs are trapped in the endosome where they get degraded when the endosome meets up with the lysosome 3) Complete failure of synthesis of the LDLR (null allele) 4) Proteins for the LDLRs are synthesized and transported to the cell surface properly and the receptors are able to bind LDL, but it is unable to localize and internalize the LDL into clathrin coated pits 5) LDLRs accumulate in the ER due to folding defects that make it impossible for them to be transported to the golgi complex

1) Class 3 2) Class 5 3) Class 1 4) Class 4 5) Class 2

One way to treat FH is to inhibit the enzyme ____ using ___ This works because if you inhibit HMG CoA reductase, you decrease cholesterol synthesis and therefore decrease the inhibition on LDLR synthesis... Now you produce more LDLRs that can in turn lower plasma cholesterol

HMG CoA reductase, statins

Lysosomal enzymes (aka acidic hydrolases) are important for 2 main reasons 1) They contribute to the ___ environment of the lysosome 2) They can function as a special category of ___ proteins that are destined for intracellular organelles These lysosomal enzymes are synthesized in the ER and transported to the golgi just like all other proteins... However, in the golgi they undergo posttranslational modification via the attachment of a ____ group that becomes recognized by M6PRs on the inner surface of the golgi membrane that separates these enzymes from other secretory proteins Once bound, these transport vesicles pinch off from the golgi and merge with lysosomes and vesicles are recycled ^** Defects in this process is what gives rise to lysosomal storage diseases

1) Acidic 2) Secretory M6P (Mannose-6-phosphate)

There are two consequences when a defect in the lysosomal enzyme synthesis pathway occurs 1) Deficiencies in degradative enzymes prevent the clearance of autophagic (intracellular) and heterophagic (extracellular) substrates causing a partially degraded, insoluble metabolite to exist inside the lysosome... So in other words, autolysosomes or endolysosomes will accumulate in the cells and these become large and interfere with the normal cell functions. This is called ____ 2) Secondary accumulation is due mainly to impaired ___ Lysosomal enzyme function remains intact, but there is impaired heterotypic fusion of autophagic and endocytic organelles with lysosomes, which results in the accumulation of autophagosomes and endosomes Since there is no degradation of autophagic substrates like polyubiquinated proteins or old mitochondria; the accumulation of old mitochondria can occur in the cells with poor buffering capacity and altered membrane potentials leading to ROS, apoptosis generation, and eventually tissue damage To recap, if you see excess autophagosomes and endosomes, it is ___ accumulation If you see excess autolysosomes and endolysosomes it is ___ accumulation

1) Primary accumulation 2) Autophagy Secondary Primary

Three general approaches to treatment 1) Enzyme replacement therapy 2) Reduce the substrate so that when the lysosome does pick it up, it might have the ability to degrade the reduced substrate amount 3) Give an exogenous ____ to the lysosomal enzymes in order to act as a "folding template" that assists in the proper folding of the enzyme and therefore allow it to fold properly and be processed in the ER properly ^** Referred to as a ____ therapy (This works because in many lysosomal storage disorders, mutant lysosomal protein enzyme precursors are degraded in the ER due to their miss folding) One diseased example that this would work for is ___ disease

Competitive inhibitor Molecular chaperone Gaucher

Lysosomal storage diseases can be separated into distinct conditions based on 1) The tissue where the material to be degraded is found 2) The location where the actual degradation occurs The ___ and ___ is often enlarged in lysosomal storage diseases due to the fact that these organs have lots of mononuclear phagocytotic cells that contain lots of lysosomes

Spleen and liver

GM2 gangliosidoses are a group of 3 lysosomal storage diseases due to the inability to catabolize GM2 gangliosides (a glycosphingolipid) ^** Degredation requires 3 polypeptides (enzymes) encoded by 3 distinct genes The most common diseases seen is Ashkenazic jews is ___ and is due to a defect in the ___ enzyme located on Ch 15 In this disease the enzyme is defective in all tissues leading to the accumulation of GM2 gangliosides in the heart, liver, spleen, nervous system, etc... However, the most involved tissues include neurons in the ___, ___, and ___ Many different mutations in the Hexosaminidase alpha-subunit enzyme have been described, but the most common problem is a defective protein ___, which triggers the ___ leading to apoptosis and therefore death

Tay-Sachs, Hexosaminidase Alpha-subunit CNS, ANS, and Retina Folding, UPR (unfolded protein response)

Morphology of Tay-Sachs disease includes ___ neurons with cytoplasmic vacuoles (represents accumulated gangliosides), ____ configurations seen under the electron microscope (represents onion-skin layers of membranes due to ____ which are stored nutrients, secretory products, or pigmented granules) There is also a noticible ____ in the retina, specifically it occurs in the ___

Ballooned, Whirled, Cytoplasmic inclusions Cherry red spot, macula

The clinical symptoms include For infantile TSD, manifestation of the disease around ___ months of age, loss of control of mental and physical abilities, deafness, blindness, and inability to swallow... The child will not live past the age of 4 If a child develops it around the age of 2-10 (juvenile) they also have loss of motor skills, speech disorders, difficulty swallowing, loss of coordination, and death by 15 If they develop it as an adult (30-40s) they lose congenitive thinking, speech disorders, and have difficulty swallowing but it is usually not fatal

Two other GM2 ganglioside diseases include Sandhoff disease due to a Hexosaminidase Beta subunit enzyme deficiency leading to excess GM2 gangliosides and globoside And GM2 gangliosidosis variant AB due to a Ganglioside activator protein enzyme deficiency leading to excess GM2 gangliosides Tay sachs and these two other diseases are classified as GM2 gangliosidosis which is classified as the larger group called ___ The other subgroup that isnt GM2 gangliosidosis disorders is the GM1 gangliosidosis which include Type 2 (juvenile) and Type 1 (Infantile or generalized) that both have the defective enzyme GM1 ganglioside Beta-Galactosidase, which leads to an excess GM1 ganglioside accumulation and galactose containing oligosaccharide accumulation

Sphingolipidoses

Neiman-Pick disease is due to the accumulation of ___ from a defective ____ enzyme There are two types Type ___ patients have severe organomegaly but NO CNS involvement and can survive into adulthood Type ___ patients are those with a sever infantile form leading to extensive neurologic involvment, marked visceral accumulations of sphingomyelin (hepatosplenomegaly), and progressive wasting and death before 3 years old Both are common is Ashkenazi Jews These mutations are mainly expressed from the maternal chromosome due to epigenetic silencing of the paternal chromosomes gene. This disease is ____ inherited, however if one is a heterozygote carrier but got their mutated gene from the mother, they can still develop the disease **So just to recap, if a patient shows neurological deficits and accumulation of sphingomyelin, it is type ___ NP since it affects the CNS

Sphingomyelin, Sphingomyelinase Type B Type A Autosomal Recessive Type A

Morphology NPA (Niemann-Pick type A occurs due to a ___ mutation that causes loss of the sphingomyelinase enzyme... This enzyme is needed for the breakdown of the lipid called sphingomyelin in the lysosomes and since this enzyme is now defective it results in the accumulation of sphingomyelin inside lysosomes (mostly in the cells of the mononuclear phagocyte system) and this causes cells to become enlarged (up to 90 um) due to the distention of the lysosomes with sphingomyelin and cholesterol Small vacuoles of uniform size are created in the cytoplasm giving a ___ appearance (since remember, sphingomyelin is a lipid) Electron microscopy reveals that the engorged vacuoles are secondary lysosomes that contain membranous cytoplasmic bodies resembling myelin figures (phospholipid masses from damaged plasma membranes) called ___ Hepatosplenomegaly is present (with the spleen being more enlarged than the liver) In the brain, the gyri are shrunken and the sulci widened and there is vacuolation and ballooning of neurons which can lead to cell death (apoptosis) and loss of brain substance; along with a retinal cherry spot ^** However, don't confuse these brain morphological features seen in NPA with that of Tay-sachs

Missense Foamy Zebra bodies

So just to recap the differences between Tay sachs and Niemann-Picks disease Type A Obviously, enzyme deficiencies are different Both occur in Jews and recessive inheritance Onset occurs in both around the age of 6 months Both involve loss of motor control, feeding difficulties, neurologic invovlement, and a cherry red macula However, in ___ there is areflexia (loss of reflexes) and Hepatosplenomegaly In ___ there is hyperreflexia

NPA Tay sachs

Niemann-Picks Type C Unlike other storage diseases, NPC is due to a primary defect in nonenzymatic lipid transport and is the most common Niemann-Picks disease It occurs due to defects in the ___ or ___ genes which are needed to transport free cholesterol across the lysosomal membrane into the cytoplasm This disease form is heterogenous (can present many different ways) including 1) Hydrops fetalis (abnormal accumulation of fluid) and stillbirth 2) Neonatal hepatitis (inflamed liver) 3) Most commonly, as childhood chronic neurological damage marked by ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, and psychomotor regression

NPC1 or NPC2 (NPC1 is most common)

Gaucher disease refers to a cluster of autosomal recessive disorders resulting from mutations in the gene encoding the enzyme ___ that is needed to cleave a glucose residue from ceremide leading to excess ___ in the cells of mainly phagocytes, RBCs and the sometimes the CNS ^** Glucocerebrosides are formed from the breakdown of glycolipids in the cell membranes of red and white blood cells This diseases manifests itself not only due to the accumulation of glucocerebrosides, but also due to the fact that ____ are activated leading to IL-1, Il-6, and TNF being secreted

Glucocerebrosidase, glucocerebroside Macrophages

There are three types of Gaucher disease Type 1 is the MOST common (99%) and limited to mononuclear phagocytes throughout the body (most notably the ___ and ___ tissues) however it does NOT involve the ___ (therefore it is called a chornic nonneuronopathic form) ^** This is found mainly in Europen jews and has some activity of the glucocerebrosidase enzyme Type 2 is classified as the ___ Gaucher disease and no enzyme activity at all if found and while hepatosplenomegaly is found, the major involvement is the ___ leading to death at an early age Type 3 has systemic involvements like type 1 and also some CNS involvements like type 2 and begins in adolescents or early adult hood

Spleen and skeletal, brain Acute Neuronopathic, CNS

Gaucher cells are found all over like the spleen, liver, bone marrow, lymph nodes, tonsils, thymus, lungs, peyers patches, etc and unlike other lipid storage diseases, they rarely appear ____ and instead have a fibrillary type of cytoplasm linked to ____ ^** Using electron microscopy, these fibrillary cytoplasm crumpled tissue paper looking cells are seen as elongated, distended lysosomes containing the stored lipids in stacks of bilayers They also have 1 or more dark ___ In Type __, the spleen is hugely enlarged, up to 10 kgs In type 1 disease, there is accumulation of Gaucher cells 70-100% of the time in the bone marrow leading to bone ___ that if large enough can give rise to pathological fractures ^**Further bone destruction can occur due to the activated macrophages and their cytokine release *** So to recap, in patients with Type 1 (chronic non neuronopathic type), one would see ___megaly, bone ___, and ___ (reduced blood cells can be pancytopenia aka all 3 blood cells lost, or thrombocytopenia aka just platelets lost) In patients with cerebral involvement (Type 2 or 3), Gaucher cells are seen in ___ spaces in the brain and the arterioles are surrounded by swollen adventital cells ^** Even though no lipids are stored in the neurons, the neurons are shriveled and destroyed due to the cytokines secreted by the activated macrophages So just to recap, in type 2 and 3 one would see ___ dysfunctions/Convulsions/Progressive mental deterioration as the main features...and some other organ systems affected as well

vacuolated, crumpled tissue paper Type 1 Erosion Splenomegaly, fractutes, cytopenias Virchow-Robin CNS

Niemann-Pick disease A and B, along with Gaucher disease is classified in a larger group called ___

Sulfatidoses

Mucopolysaccharidoses (MPS) is the major group name for syndromes that result from genetically determined deficiencies of enzymes involved in the degradation of ____ also called ___ These GAGs are long chains of complex carbohydrates that are linked to a protein core and hyaluronic acid to form ___, which is abundant in the ground substance of connective tissue Normally, enzymes cleave the terminal sugars from the GAG chains, however if they are absent no cleaving occurs and the chains accumulate in the lysosomes of various tissues The GAGs that accumulate in MPS include ____, ____, ____, and ____

Mucopolysaccharides, Glycosaminoglycans aka GAGs Proteoglycans Dermatan sulfate, Heparan sulfate, Keratan sulfate, and chondroitin sulfate

Like lysosomal storage diseases, ALL MPSs are inherited via ___ traits, except one which is called ____ syndrome, inherited by an ___ trait Hunter's syndrome is due to a defect in the enzyme ___ MPS 1 also called ___ syndrome is due to a defect in ___

AR, Hunter syndrome (MSP2), X-linked recessive L-iduronosulfate sulfatase (also called iduronate-2-sulfatase aka I2S) Hurler syndrome, Alpha-L-Iduronidase

MPS disorders are progressive and include general characteristics such as coarse facial features, ___ of the cornea, joint stiffness, and mental retardation Urinary excretion of the accumulated GAGs are also increased Accumulated GAGs are found in mononuclear phagocytic cells, endothelial cells, intimal smooth muscle cells, and fibroblasts Histologically, cells are distended and ___ shaped due to clearing of the cytoplasm (which electron microscopy shows as numerous small vacuoles containing GAGs) The MPSs with CNS involvement shows lysosomal changes in neurons where the lysosomes are replaced by ___ (similar to those found in NPA) Hepatosplenomegaly, skeletal deformities, valvular lesions, subendothelial arterial deposits (particularly in the coronary arteries), and brain lesion are the most common features seen in all MPSs ^** Subendothelial arterial deposits/lesion can lead to myocardial ischemia, and therefore MIs and cardiac decompensation leading to death

Clouding Ballon Zebra bodies

In order to tell the difference between Hunters syndrome and Hurlers syndrome not based on enzyme deficiency or mode of inheritance is that ___ syndrome is more severe and death occurs around the age of 6-10 due to cardiovascular complications ___ syndrome also has NO corneal clouding whereas ___ syndrome has corneal clouding like most other MPSs ^** So in other words, MPS II (hunters) is a milder form

Hurlers Hunters, Hurlers

The storage form of glucose is ___ and therefore glycogenesis is the synthesis of glycogen from glucose and glycogenolysis is the degradation of glycogen into glucose Glycogen storage diseases are also called Glycogenoses For the normal glycogen pathway, we start with the formation of glycogen from glucose 1) First, Glucose is converted to ___ via ___ 2) Then G6P is converted to ___ via ___ 3) Then G1P is converted to ___ and then it is further converted to glycogen via the enzyme ___ where it is built as a large polymer linked together by alpha 1-4 glucoside bonds 4) Then ___ enzyme converts it to the full Glycogen storage form For Glycogenolysis, we now start off with Glycogen 1) Glycogen in the liver and muscles can split G1P off of Glycogen via the enzyme ____ 2) The degradation continues until 4 residues remain on each branch and this oligosaccharide is called ____, which can only be further degraded to glucose via the enzyme ___ 3) In addition to these two pathways for glycogen breakdown, in the lysosomes, glycogen is degraded via ____ to glucose

Glycogen 1) G6P, Glucokinase 2) G1P, Phosphoglucomutase 3) UDP, Glycogen synthase 4) Branching Enzyme 1) Glycogen Phosphorylase 2) Limit dextrin, debranching enzyme 3) Lysosomal Acid Maltase

In hepatic forms of Glycogenoses (remember, this is glycogen storage diseases) if there are liver cells that are deficient in the necessary enzymes for glycogen degredation, two things will happen 1) ___ storage of glycogen in the liver 2) ___ blood glucose concentration (since the liver breaks down the glycogen and releases the now glucose into the blood) also called ___glycemia One common hepatic-hypoglycemic form of glycogen storage disease is ____ aka Type ___ glycogenosis due to a enzyme deficiency of ___ Other examples include Type 3 which is a defect in the ___ enzyme, Type 6 which is a defect in the ___ enzyme and Type 8 which is a defect in the ___ enzyme ***** So if you see hepatic enlargement (hepatomegaly) and hypoglycemia, it is a hepatic type glcogenosis... You might also see renomegaly Patients can also present with hyperlipidemia and hyperuricemia due to defective glucose metabolism and leads to gout and skin xanthamos

1) Increased 2) Decreased, hypoglycemia von Gierke disease, Type 1, Glucose-6-phosphatase debranching enzyme, liver phosphorylase, liver phosphorylase kinase

Myopathic forms of glycogen storage diseases are due to defective enzymes from glycogen to the ____ pathway that is needed to produce ATP in order for muscles to get energy So a defect in the muscle phosphorylase enzyme that breaks down Glycogen into G1P is called ___ disease aka Type ____ There could also be a defect in the ___ enzyme that is called Type (VII aka 7) Glycogen storage disease *********In all of these myopathic diseases, the patient presents with muscle cramps and no increase in lactate levels after exercise since remember, the glycolysis pathway is inhibited ^** Serum creatine kinase is also elevated and some patients (50%) will have myoglobinuria (excess myoglobin in urine) Finally, note that accumulations of glycogen are predominant in the ___ location

Glycolysis McArdle, Type 5 Phosphofructokinase Subsarcolemmal (cell membrane of striated muscle fiber cells)

Other Glycogen storage diseases that don't fit this category include defective Alpha-glucosidase (aka ___) which leads to ___ disease aka Type ___ The prominent feature for this disease although it occurs in all organs, is massive ___megaly which is shown to contain glycogen within the sarcoplasm (the cytoplasm of striated muscle cells), along with hypotonia and cardiorespiratory failure in 2 years The other glycogen synthesis disease associated with miscellaneous is Type ___ which is due to an ___ enzyme deficiency *** So just to recap, if you see glycogen accumulations in the subsarcolemmal location, it is a ___ type of glycogen storage disease whereas if you see sarcoplasm accumulation of glycogen it is a ___ type of glycogen storage diseases Don't confuse sarcoplasm (cytoplasm of a muscle fiber) vs sarcolemma (cell membrane of striated muscle fibers)

Lysosomal acid maltase, Pompe disease, Type 2 Cardiomegaly Type 4, Branching Myopathic (skeletal), Miscellaneous

A gene that has at LEAST 2 alleles which occurs at a frequency of at least 1% in the population is said to be ___ and therefore according to the common disease/common variant hypothesis, complex genetic disorders (aka multifactorial diseases) occur when many polymorphisms are co-inherited However, different inherited polymorphisms vary in significance Also, some polymorphisms are specific to a disease type while others are common to multiple diseases

Polymorphic

In order to karyotype, chromosomes are examined via arresting them in ____ with mitotic spindle inhibitors (like Colcemid) and then staining the chromosomes and plating a metaphase spread where the individual chromosomes then take on 2 chromatids Staining methods to identify individual chromosomes is accomplished most commonly by Giemsa staining called ___

metaphase G-banding

The short arm of a chromosome is designated the __ arm and the long arm is ___

P (for petite), Q (since it's the next letter in the alphabet)

In aneuploidy (aka an abnormal number of chromosomes) the cause is from either nondisjunction or anaphase lag If nondisjunction occurs in meiosis, you end up with either with either a ___zygote (2n+1) or ____ zygote (2n-1) In anaphase lag, one homologous chromosome in meiosis or one chromatid in mitosis lags behind and is left out of the cell and this results in one normal cell and one cell with a ___ Monosomy on an autosome (non sex chromosome) generally can't sustain life, but autosomal trisomy can sustain life

Trisomy, Monosomy Monosomy (2n-1)

Mitotic errors in the early development of life give rise to two or more populations of cells with different chromosomal complement and this is called ___ This can occur as somatic cells undergo mitosis or during cleavage of the ___ and often affects the sex chromosomes (since autosomal mosaicism is most often not viable) ^** Remember, cleavage takes the zygote from a single cell to a blastocyst For example, during cleavage a cell might get 3 sex chromosomes and the other only gets 1 resulting in 2 distinct cells (one being 45, X and the other being 47, XXX mosaic) and all cells derived from these have that composition of the original 45, X or 47, XXX cells

Mosaicism fertilized ovum (zygote)

Chromosomes can also have structural changes due to chromosome breakage and then rearrangement of the material Deletions can be ___ (two breaks in a chromosome arm -> loss of material -> fusion of broken ends) or ___ (Single break in chromosome arm -> One fragment is lost at next cell division and the other is a chromosome with a deletion) If a break occurs at both ends of the chromosome (both arms) and the damaged ends are fused, it is called a ___ chromosome which is a special type of deletion Two breaks within a single chromosome leading to the reincorporation of the inverted, intervening segment is called an ___ and if the break is only on one arm of the chromosome it is called a ____ inversion and if it is on both sides of the centromere (both arms) it is called a ___ inversion ___ are when one arm (either short or long) is lost and the remaining arm gets duplicated leaving two short or two long arms ^** The most common isochromosome is the long arm of the X chromosome designated i(Xq) and is associated with ___somy vs i(Xp) aka the short arm isochromosome, which is less common and associated with ___somy In a ___ a segment of one chromosome is transferred to another There are two types, ____ translocations is when single breaks in each of the two chromosomes exchange material and since no genetic info is lost, patients appear phenotypically normal but are at increased risk for producing abnormal gametes The other type of translocation is a ____ (give both names) in which two acocentric (chromosomes with their centromere located near the end of the chromosome) which breaks near the centromeres and leads to one large chromosome and one small chromosome ^** The small chromosome is normally lost however since it is small and carries mainly redundant genes, it is compatible with life and this type of translocation is seen in ___ syndrome although remember, the major cause of down syndrome is ___

Interstitial, terminal Ring Inversion, paracentric, pericentric Isochromosomes Trisomy, Monosomy Translocation Balanced reciprocal Centric fusion aka Robertsonian Down Meiotic nondisjunction

Down syndrome is most commonly called ____ and 95% of the time due to ___ ^**And is designated 47,XX,+21 4% of patients can have down syndrome due to ___ like we just talked about in the previous note card and most often this is familial (passed down) from a parent who is a carrier of a robertsonian translocation ^**And is designated 46,XX,der(14;21)(q10;q10),+21 1% of patients are ___ and therefore have a mixture of cells with 46 and 47 chromosomes due to ___ of chromosome 21 during early embryogenesis (like cleavage) ^**And is designated 46,XX/47,XX,+21 ^** Both translocation and mosaicism has no relation to maternal age ^** Centric fusion (Robertsonian) occurs from the ___ arm of chromosome 21 to another acrocentric chromosome most commonly 14, and sometimes 22 Since maternal age has a strong influence on the incidence of trisomy 21, that means that the meiotic nondisjunction most likely occurs in the ___ and therefore the extra chromosome in 95% of the cases is of maternal origin

Trisomy 21, meiotic nondisjuction, Robertsonian translocation Mosaic, mitotic nondisjunction Long Ovum

The diagnostic clinical features of a patient with down syndrome include a shortened opening between the eyelids called ___, skin folds of the upper eyelid covering the inner cornea called ___, a __ facial profile, mental retardation, a gap between the first and second toe, hypotonia 40% of patients have congenital __ disease most commonly due to defects of the ____ which is important in development of the heart valves and septa to form a proper 4 chambered heart ^**Endocardial cushion defects result in ostium primum, atrial septal defects, AV valve defects, and ventricular septal defects There is also a 10-20 fold increased risk of developing ___ with the most common being acute megakaryoblastic leukemia All patients older than 40 develop neuropathologic changes like Alzheimers disease Finally, patients have abnormal ___ responses that predisposes them to serious infections commonly in the lungs and thyroid autoimmunity

Oblique palpebral fissures, epicanthic folds, flat Heart, Endocardial cushion Acute lukemia Immune

Trisomy 18 is called ___ and Trisomy 13 is called ___ Trisomy 18 occurs mainly from ___ and has the karyotype 47,XX,+18 and can also come from mosaicism 46,XX/47,XX,+18 Trisomy 13 comes mainly from ___ and has the karyotype 47,XX,+13 and can also come from translocations 46,XX,+13,der(13;14)(q10;q10) or mosaic type 46,xx/47,xx,+13 Both trisomies have Rocker-bottom feet, heart defects, renal defects, mental retardation, a cleft palate can appear in both but is more common in trisomy 13, also babies have extra fingers (polydactylyl) commonly found in trisomy ___ Trisomy ___ has low seated ears, prominent occiput, small jaw and mouth called micrognathia

Edward's syndrome, Patau syndrome Meiotic nondisjunction Meiotic nondisjunction 13 18

Deletion syndrome consists of multiple disorders and has the karyotype ___ and therefore has a small deletion on the long arm (q band) of chromosome 22 at region 1, band 1, sub-band 2 CATCH22 aka ___ syndrome is one that has a micro-deletion on chromosome 22 and has 1) ____ hypoplasia (incomplete organ development), and as a result also T-cell immunodeficiency 2) ____ hypoplasia, leading to hyp__calcemia 3) Cardiac malformations affecting outflow tract 4) Mild facial anomalies (low-set ears, wide-set eyes, small jaw, and bowing up of upper lip) Another chromosome 22q11.2 deletion syndrome is ___ syndrome with the clinical features including 1) Facial anomalies (prominent nose, retrognathia aka abnormal positioning of the jaw) 2) Cleft palate 3) Cardiac malformations involving outflow tracts 4) Learning disabilities (aka developmental delay) ^** So realize that both of these and many other 22 deletions have similar clinical presentations including Immune defects, hypocalcemia, facial dimorphisms, developmental delay, palatal defects, and cardiac defects (however, DiGeorge syndrome patients more commonly have immunodeficiencies) ** Also, individuals with a 22q11.2 deletion syndrome are at high risk for developing ___ and ___ disorders and ADHD is also seen in 30-35% of these children While there isn't a direct known cause, the __ gene has shown to be associated with phenotypic features of these diseases and it targets the ___ gene which is a protein coding gene that controls the development of the palate, parathyroids, and thymus

22q11.2 DiGeorge syndrome, 1) Thymic 2) Parathryoid, hypocalcemia Velocardiofacial Schizophrenia and bipolar TBX-1 (a T-box transcription factor), PAX9

Sex chromosome disorders are better tolerated than autosomal disorders due to 1) ____ (AKA X inactivation) of all but one X chromosome 2) The Y chromosome only carries a modest amount of genetic material The Lyon hypothesis states that only 1 X chromosome is active and the other undergoes heteropyknosis to render it inactive. Also, inactivation occurs randomly during the ___ stage of embryonic life (around day 5.5) and all cells derived from that have the same inactive and active X representation In females, their inactive X can be seen in the interphase nucleus as a dark staining mass called a ___ The inactivation is due to the gene ___, whose product is a specialized RNA called a ___, that stays in the nucleus and coats the X chromosome that will be inactivated and initiates gene ___ via chromatin modification and DNA methylation (The XIST allele is switched off in the active X) However, it is important to note that some X genes on the inactive X chromosome escape X inactivation and are needed for proper growth and development and this is shown via ___ syndrome (45, X) which has patients with somatic and gonadal abnormalities but only one X... Lastly, note that the inactive X is reactivated in the Oogonia before the first meiotic division during embryogenesis

1) Lyonization Blastocyst Barr body (aka x-chromatin) XIST, lncRNA (long noncoding), silencing Turner syndrome

For the Y chromosome, no matter how many X's, a single Y determines the male sex due to the expression of the ___ gene that is important for testicular development (located on the short arm) There are many other gene families in the ___ region of the Y chromosome that encode for teste-specific proteins related to ____ Since all these proteins are involved in spermatogenesis, it makes sense that ALL Y chromosomal deletions are associated with ___

SRY MSY (Male specific Y), spermatogenesis Azoospermia (aka absence of sperm)

When there are two or more X chromosomes, and 1 or more Y chromosomes, the patient is said to have ___ syndrome which is associated with ____ (male or female?) ____ ^** Most common is 47,XXY karyotype This disease is not diagnoses before puberty due to the fact that the testicular abnormality does not develop before early puberty, the patient has a ___ body habitus (which means they are tall, slim, underweight, and have long arms and legs) The patients will also have reduced spermatogenesis due to small atrophic testes They will also have a lack of secondary male characteristics (no deep voice, pubic hair, etc) and a lowering of the IQ Man boobs also called ____ may be present Patients also have an increased risk for Type 2 diabetes and a metabolic syndrome that gives rise to insulin resistance and 50% of patients have a mitral valve prolapse ^** So realize there are many different clinical features but the only one that is consistent is ____ ****Patient's plasma gonadotropin levels have ___ FSH (and LH) and ___ Testosterone**** Leydig cells (cells that produce testosterone) due to atrophy and crowding of the tubules and elevated LH levels Patients have a 20 times higher risk for ___ cancer, ____ cell tumors (germ cells that were suppose to develop into sperm within the gonads aka testicles instead develop into germ cells and then tumors in other parts of the body), and ___ diseases like systemic lupus erythematosus (immune system attacks healthy tissues)

Klinefelters, male hypogonadism eunuchoid Gynecomastia Hypogonadism Increased, Decreased Breast, extragonadal germ, autoimmune

Klinefelter syndrome occurs from mainly ____ in the germ cells of one of the parents 15% of patients can also have a form of mosaic Klinefelter syndrome like 46,Xy/47,XXY or 47,XXY/48,XXXY ^** Note that like we said, only 2 X or more and at least 1 Y is needed for the classification of this syndrome Now remember, all Xs except for one undergoes X inactivation, however also remember than some genes on each inactive X are able to escape X inactivation... This is one of the mechanisms that leads to the features associated with Klinefeters syndrome (aka the over-expression of some of the X genes leading to hypogonadism) The other reason why this syndrome occurs is due a defect in the gene encoding the ___ receptor which is needed for ___ to produce its effect ^** The androgen receptor is located on the X chromosome, and contains highly polymorphic ___ trinucleotide repeats and the functional response of the receptor to any androgen (aka like testosterone) depends on how many of these repeats it has... The more repeats, the ___ sensitive the receptors are to androgens and the less repeats, the ___ sensitive the receptors are to androgens... So what happens in Klinefelters syndrome is that the X chromosome with the androgen receptor gene that has the ___ amount of CAG repeats is inactivated (aka the long CAG repeats are left active) and therefore the X chromosome that has the most sensitive receptors to androgens no longer works and therefore in patients with already low testosterone levels like in XXY males, the fact that the androgen receptors are not very sensitive to the little amount of androgens present in the first place (testosterone) exacerbates the hypogonadism and results in small penis size

Meiotic nondisjunction Androgen receptor, testosterone CAG Less, more, least

Complete or partial monosomy of the X chromosome characterized by hypogonadism in females in called ___ syndrome ^** Most common (57%) karyotype is 45,X (Complete absence of an X chromosome) and 29% are mosaics that ALL have a 45,X cell population and then some other normal or abnormal population (Ex: 45,X/46,XX or 45,X/46,XY) and 14% have only structural abnormalities of the X chromosome (46,X,i(Xq) or 46,X,del(Xq) or 46,X,r(X), etc....) ^** I wold make sure you can recognize the disorder based off of if they give you just a straight up karyotype ^** Also take note that one of the mosaic examples was 45,X/46,XY and this type of mosacism with a Y chromosome occurs in 5-10% of patients and puts patients at an increased risk to develop a ___ tumor

Turners Gonadal tumor (aka gonadoblastoma)

The severity of Turner syndrome clinical manifestations can vary. If patients have a high cell population of 45,X they will have more severe phenotypic changes whereas a patient who is strongly mosaic may present normal and only have ____ (abnormal absence of menstruation) The most severe patients have ___ stasis which results in edema of the hand and foot (peripheral lymphedema) and swelling of the nape (back) of the neck called ____ (fluid filled sacks caused by blockage of the lymphatic system) at birth... and over time the swelling goes down but leads to a webbed neck and loose skin on back of the neck The most common cause of increased mortality in children with this disease is due to ____ abnormalities, specifically dual ____ of the aorta (narrowing of the large blood vessels aka the aorta that leads from the heart) In children, they fail to develop secondary sex characteristics (inadequate breast development, no pubic hair, etc...) but usually have a normal IQ *******Adult patients are easily diagnosed due to their ___ body stature via haploinsufficiency of the ____ gene and ___ (failure of the menses to occur by the age of 16)....This is due to the fact that the fetal ovaries develop normally at first during embryogenesis, but by the age of 2 the absent X chromosome in patients with Turner syndrome causes a huge loss of oocytes and in that sense its as if menopause occurred before menarche (the first menstrual cycle) and therefore the ovaries atrophy and become fibrotic which is called ___ ovaries and lead to infertility******** ^** So if you get a question talking about how the patient hasn't had her menses yet and is 16 or older, start thinking Turner syndrome Some patients also have hypothyroidism, insulin resistance, glucose intolerance, and obesity

Primary amenorrhea Lymph, Cystic hygroma Cardiovascular, coarctation Short, SHOX, primary amenorrhea, streak

In a ___ there is presence of ovarian and testicular tissue In a ____ there is a disagreement between the phenotypic and gonadal sex (such as a female pseudo-hermaphrodite has ovary tissue, but a penis and a male psuedo-hermaphrodite has testicular tissue but a vagina) ^** So a Pseudo has the oppsoite external genitalia as their sex and the same tissue as their sex

True hermaphrodite Pseudo hermaphrodite

Single-Gene disorders with nonclassical inheritance include 1) Trinucleotide repeats - which are important in ____ disorders 2) Mitochondrial mutations 3) Genomic imprinting 4) Gonadal mosaicism

1) Neurodegenerative

Trinucleotide repeats seem to all be insertion mutations, but not all insertion mutations are trinucleotide repeats The trinucleotide mutations are due to expansions of trinucleotide stretches that usually contain the nucleotides ___ and ___ and expansion above a certain threshold causes 1) LOSS of gene function (typically via ____ like in ___ syndrome) and these regions are generally in the ___ (coding or non-coding?) part of the gene 2) A toxic GAIN of function due to alterations in protein structure like in ____ disease or spinocerebellar ataxis and this occurs in the ___ (coding or noncoding?) regions of the genes 3) A toxic GAIN of function mediated by mRNA like in _____ syndrome that occurs in the ___ regions of the gene The tendency for expansion to occur depends on the sex of the transmitting parent so in Fragile X syndrome, the expansion occurs during ___ whereas Huntington's syndrome the expansion occurs during ___

G and C 1) Transcription silencing, fragile X, noncoding 2) Huntingtons, coding 3) X tremor-ataxia syndrome, noncoding Oogenesis, Spermatogenesis

Like we just said, toxic gain of functions occur in ___ regions of the gene In the case of Huntington's disease, the trinucleotide repeat ___, which is associated with the coding regions of the ___ gene, becomes expanded (normally CAG repeats 6-35 times but now it repeats 36-121 times) The HTT gene codes for the ____ protein, however the expanded CAG repeats leads to production of the huntingtin protein with abnormally long ____ expansions These polyglutamine expansions cause a toxic ___ of function, which leads to ____ protein and then aggregation of the proteins, interfering with the function of the normal proteins (dominant negative activity) and therefore causes "polyglutamine diseases" that characterized by progressive neurodegeneration ^** The aggregated proteins cause transcription suppression, mitochdonrial dysfunction, or the UPR leading to apoptosis ********* Therefore, if you see a large accumulation of aggregated mutant misfolded proteins in large ___, think polyglutamine expansion due to CAG triplets in the coding region of HTT gene leading to a gain of function mutation and therefore huntingtin protein misfolding and aggregation

Coding (exons) CAG, HTT Huntingtin, Polyglutamine Gain, misfolded Intranuclear inclusions (aggregates of stainable proteins)

Like we just said, loss of functions occur in ___ regions of the gene In the case of Fragile X, the trinucleotide repeat ___, which is associated with the noncoding regions of the ___ gene becomes expanded (normally CGG repeats 6-55 times but now it repeats 50-200 for pre or more than 230 for full) The FMR1 gene codes for the ____ protein, and in this syndrome there are inducible cytogenic abnormalities in the X chromosome where this gene and its protein is mapped ^** This abnormality shows up as a discontinuity of staining of constriction in the long arm of the X chromosome when cultured in a folate-deficient medium The molecular mechanism of how this happens is when there becomes an excess of CGG repeats (230ish or more) the DNA of the FMR1 gene becomes abnormally ____, which remember causes gene transcription ____ and the methylation extends up to the promoter region and therefore no FMRP is produced FMRP is a cytoplasmic protein found mostly in the ___ and ___ and therefore these two organs are most affected

Noncoding CGG, FMR1 (FRAXA) FMR-1 (FMRP) Methylated, inactivation Brain and testes

In fragile X, the males are ____ (IQ 20-60) and physical phenotype includes ___ face with large mandible, large everted ears, and *** THE MOST COMMON FEATURE IS ___ aka large testicles Fragile X is a ____ inherited disorder, however unlike most types of these inheritance patterns, there are some special patterns of transmission not normally associated with X-linked recessive transmission 1) Normally a male who has an X-linked recessive chromosome disorder is affected, however in 20% of the cases for Fragile X, the male can be clinically and cytogenetically normal and is therefore labeled as a carrier male... When the male has a child with a normal female, he passes his mutated X onto all his daughters (who now have one copy of the X and are still labeled carrier daughters since they need both Xs to be mutated in order to show this RECESSIVE disease). However, when the carrier daughter mates with a normal male, if there child is a male the gene might fully mutated and now the male expresses the fragile x syndrome..) ^** So in other words, the carrier male (father) transmits the trait to phenotypically normal daughters but affected grandchildren and is therefore called a normal transmitting male 2) Normally, carrier females don't have any signs of disease for a RECESSIVE mutation, however in fragile X 30-50% of heterozygous females are affected ^** Both normal transmitting males (aka carrier males) and carrier females has the CGG repeat 55 - 200 which is called ___mutations*************** 3) Risk depends on the position of the individual in the pedigree (aka grandsons of normal transmitting males are much higher risk than brothers of normal transmitting male due to amplification) 4) The fact that clinical features worsen in each generation, which is called anticipation ******Affected individuals have the CGG repeats more than 230 times so like 200-4000 is common and this is called ___mutations When a carrier male (normal transmitting male) passes on his X there isn't much change in repeat size (55-200 still); however, when his carrier daughters pass on her X to either a male or female, there is a huge amplification of the CGG repeats and this is what leads to that daughters males being affected and 50% of the girls being affected even if they only have one copy of the mutated X repeats and this is the reasoning behind where premutations become converted to full mutations, which must be during ____ and not spermatogenesis

Mental retardation, long, Macro-orchidism X-linked recessive Premutations Full mutations Oogenesis

We already talked about how FMR1 becomes inactivated (gene silencing) leading to no production of FMRP... But what does FRMP even do? FMRP selectively binds ____s associated with polysomes (aka polyribosomes) and regulates their intracellular transport into ___ So in other words, FMRP translocates to the nucleus of a neuron where it forms and FMRP-mRNA complex. This complex is exported into the cytoplasm where it gets trafficked to dendrites near neuronal synapses At the synaptic junctions, signaling from ___ receptors stimulates FMRP, which acts as a ___ regulator, to suppresses protein synthesis from the bound mRNAs Therefore, if there is a decreased FMRP due to transcription silencing of the FMR1 gene, then no protein suppression at the synaptic junctions will occur and instead, the bound mRNAs will be translated and activated, which leads to synaptic plasticity and mental retardation

mRNAs, dendrites mGLU-R (Group 1 metabotropic glutamate receptors), Translation

Toxic gain of functions mediated by mRNA occurs in the ___ region Fragile X Tremor/Ataxia is one example of this noncoding toxic gain of function via mRNA mutation and involves CGG ____ in the ___ gene ^** Remember, permutation patients are female carriers (one copy of mutated X) or normal transmitting males (one copy of the mutated X but since it's premutated and not full-mutated they don't express Fragile X syndrome) However, even those these premutation patients don't present with Fragile X syndrome, 20% of carrier females have premature ____ failure and 50% of normal transmitting males (carrier males) have progressive ____ syndrome and therefore that is where this syndrome differs from fragile X syndrome So patients with Fragile X tremor/ataxia have intention tremors (trembling of a part of the body when attempting a precise movement) and cerebellar ataxia (inflammation or damage to the cerebellum which often presents with dysarthria aka speech problems and many other problems) ^** So premutation CGG expansion of the FMR1 gene = Fragile X tremor/ataxia

Noncoding Premutations, FMR1 ovarian, neurodegenerative

Unlike fragile X syndrome where the FMR1 gene is silenced due to methylation, and therefore transcription is silenced.... In Fragile X tremor/ataxia the FMR1 gene has transcription ____ so in other words, the CGG-containing FMR1 undergo transcription to form mRNAs, but the formed mRNAs are toxic The mRNAs accumulate in the nucleus and form intranuclear inclusions and the aggregated mRNAs recruit ___ that most likely are the cause of toxicity since they are recruited to abnormal locations

Dysregulation RNA-binding proteins

Mitochondrial DNA (mtDNA) is entirely ___ inherited since the ova contains lots of mitochondria and the sperm does not mtDNA has 37 genes that codes for tRNAs, rRNAs, and most importantly subunits of the respiratory chain enzymes involved in oxidative phosphorylation (OP) and therefore mtDNA defects involve organs that depend on OP like CNS, skeletal muscles, cardiac muscles, liver, and kidneys (many affect the neuromuscular systems) Each mitochondria has many copies of mtDNA and sometimes only some of the copies are affected (leading to mtDNA with some mutant and some normal copies of the same genes) and this is called____ however a threshold effect must be reached for the number of mutant mtDNA before any damage is done Also, mtDNA is randomly distributed to daughter cells during cell division so expression of disorders is extremly variable The classic case of an mtDNA disease, where progressive bilateral loss of central vision occurs, is called ___ ** So if you see a pedigree with an affected male but no male or female progeny affected, or an affected female and all male and female progeny are affected, it is an mtDNA disease

Maternally Heteroplasmy LHON (Leber's hereditary optic neuropathy)

So just to recap, hypogonadism in genetic males is ___ syndrome and hypogonadism in genetic females is ___ syndrome

Klinefelter, Turner

We inherit two copies of each autosomal gene (one from a maternal chromatid and one from a paternal chromatid) One would assume that a specific allele coming from the mother and father is identical, however that is not the case due to genomic ___ which is the act of selectively inactivating either the maternal or paternal allele So maternal imprinting is the transcriptional silencing of the maternal allele and paternal imprinting is the transcriptional silencing of the paternal allele and they occur in both the sperm and ovum, before fertilization so it is passed to all cells as somatic cells go through mitosis The inactivation of transcription occurs via DNA ___ at ___ nucleotides or H4DACs (which remember are histone deactylases that cause chromatin condensation leading to inactivation) and histone methylation These imprinted genes are found commonly in groups regulated by cis-acting elements called imprinting control regions

Imprinting Methylation, CG

Prader-Willi syndrome is a good example of genomic imprinting Characteristics include mental retardation, short stature, hypotnia, small hands and feet, hypogonadism, obesity, and a strong distinguishing characteristic of ____ In 70% of ALL CASES, there is a ___ on chromosome ___ that is ____ derived There is another disease called ____ syndrome that presents with a deletion on the EXACT same spot of the chromosome, however this chromosome is ___ derived ^** Angelman syndrome presents with mental retardation, ataxic gait, seizures, and referred to as ____ laughter

Profound hyperphagia (Excessive hunger and abnormally large intake of solids by mouth) Deletion, 15, paternally ^**15,del(15)(q11.2q13) Angelman, maternally Happy Puppet (inappropriate laughter)

For prader-Willi syndrome to occur, there is the mother and fathers chromosome... There are three ways for the diseases to occur 1) Like we mentioned before, 70% of cases are due to a deletion At the 15q12 area, the maternal chromatid has an ____ Prader-Willi gene whereas the paternal chromatid has an ____ Prader-Willi gene Therefore, if there is a deletion of the paternal Prader-Willi gene, the child ends up with NO active genes at all (since it lost its paternal gene, and the maternal one was already silenced aka imprinted) The opposite goes for Angelmans syndrome where at the 15q12 area, the maternal chromatid has an ____ Angelman gene whereas the paternal chromatid has an ____ Angelman gene 2) Another cause (20-25%) of these syndromes can be due to ____ which is simply the patient has 2 copies of either the maternal or paternal chromosome If a patient has 2 copies of the maternal chromosome 15, then they have ___ syndrome due to the fact that both copies have imprinted PW genes and no active PW genes If the patient has 2 copies of the paternal chromosome 15, they have ___ syndrome for the same reasons as above ^ 3) In 1-4% of cases there can be an imprinting defect where in ___ syndrome the maternal chromosome carries the paternal imprint and in ___ syndrome the paternal chromosome carries the maternal imprint ^** Note that UBE3A (a ubiquitin ligase) is the name for the ___s gene and SNORP family of genes (snRNAs involved in rRNA modification) is associated with the ___s gene

Imprinted (aka silenced), active Active, Imprinted (silenced) Uniparental disomy Prader-Willi Angelman Angelman, Prader-Willi Angelman, Prader-Willi

In an autosomal dominant disorder, an affected child would have to have one affected parent. However, sometimes this is not the case and instead two phenotypical normal parents can give birth to a child, where there was a mutation in the egg or sperm that leads to the autosomal dominant disorder ^** In this case, the affected child's sibling obviously wouldn't be affected or at an increased risk for disease... However, in ____ phenotypical normal parents actually have more than one affected child and therefore is a result of ____ So in other words, the parents are phenotypically normal due to the fact that their somatic cells have no mutations, but their gonadal cells sometime during early embryonic development (postzygotically) acquired a mutation and therefore they have a mosaic pattern of mutated gonadal cells and normal somatic cells so when they give birth to a child, that child can acquire the mutated gonadal cells and therefore osteogensis imperfect

Osteogenesis imperfecta (fragile bones that break easily) Gonadal mosaicism

Human genetic markers can be either ____ aka present in each and every cell of the affected person (like CFTR mutations) or ___ aka restricted to specific tissue types or lesions Genetic testing is performed most commonly prenatal or postnatally, although sometimes older patients have it as well Prenatal testing occurs when there is... Advanced maternal age, parent known to carry balanced chromosomal rearrangement, fetal anomalies on ultrasound, blood screening indicating trisomy (like down syndrome) Postnatal testing occurs when there is... Multiple congenital anomalies, metabolic syndrome, unexplained mental retardation, suspected aneuploid or other syndromic chromosomal abnormality, suspected monogenic disease Older patients testing occurs when there is... Inherited cancer syndromes, atypical mild monogenic disease, neurodegerneative disorders

Constitutional, somatic

There are a variety of PCR techniques used to detect DNA sequence alterations and include 1) The "gold standard" of DNA sequencing called ___ sequencing which uses a mixture of the DNA template to be amplified, a DNA ___, a DNA ____ (to elongate the primer strand), a normal dNTP and a modified ddNTP (which terminates the DNA strand and is labeled with a dye) 2) ___ is used when testing for particular sequence variants and therefore more sensitive the Sanger sequencing... ^So in other words, if a patient has cancer in which the tumor cells are "contaminated" and therefore have large amounts of admixed stromal cells, you could use this method which occurs by incorporating individual nucleotides into the reaction and once a nucleotide is incorporated into the growing strand, it releases pyrophosphate that reacts with luciferase to produce light 3) ____ is used to identify mutations at a specific nucleotide position and is extremely sensitive, but only produces one base pair of sequence data ^So if you have a point mutation of codon 600 of the BRAF gene you could use this to determine the mutation 4) ___ is used by restriction enzymes recognizing and cutting DNA at specific sequences ^This is rarely used anymore, but can be used when a casual mutation always occurs at an invariant nucleotide position ***5) ___ can be used to detect mutations that affect the length of DNAs like deletions or expansions such as those seen in fragile X syndrome, etc...**** ^** However, realize that if the expansion is to large, then this will not work... So for example in fragile X syndrome, the premutation is only 55-200 repeats so it will show up on gel electrophoresis as a larger PCR product, but if there is a Full mutation with more than 230 repeats, the technique will fail due to the fact that it can't be amplified since it's so large and instead, ____ must be used 6) ___ is used to monitor the frequency of cancer cells bearing characteristic genetic mutations/lesions in the blood or tissues or infectious load of certain viruses

1) Sanger, primer, polymerase 2) Pyurosequencing 3) Single-based primer extension 4) RFLP (Restriction fragment length analysis) 5) Amplicon length analysis Souther blotting 6) Real time PCR

___ uses DNA probes to recognize sequences specific to particular chromosomal regions It is useful when a rapid diagnosis is warranted (like in acute myeloid leukemia) and can be performed on prenatal samples, peripheral blood, cytology materials (touch preparations from cancer biopsies), and fixed archival tissue sections *********Can be used to detect numeric abnormalities of chromosomes aka aneuploidy, subtle micro deletions (like in Digeorge syndrome or Velocardiofacial), or complex translocations not demonstrable by routine karyotyping and gene amplification (like HER2 in breast cancer or NMYC in neuroblastomas)******* ^** One of the disadvantages of FISH is that there must be prior knowledge of the few specific chromosomal regions suspected of being altered by the test sample (because you would need to know how to engineer the probe that will hybridize to the specific homologous genomic sequence), however genomic abnormalities with NO prior knowledge of the specific location can be determined via microarray technology via performing a global genomic survey (discussed more on another notecard)

FISH (Fluorescence In Situ Hybridization)

____ uses DNA hybridization, DNA ligation, and PCR amplification to detect deletions and duplications of any size including those that might be to large for PCR and to small for FISH Southern blotting can be used for detecting changes in structure of specific loci via EcoR I recognition sites cleaving the repeats and then hybridization of a radio labeled sequence specific probe

MLPA (Multiple ligation dependent probe amplification)

Examples of microarray technology used to identify genomic abnormalities with no prior knowledge of specific altered chromosomal regions include 1) Array-____ uses a red test DNA and green normal DNA and hybridizes them, then spots them with DNA probes that span all 22 autosomes and the sex chromosomes and looks for changes of color... If yellow, then mixture is equal and no mutations are present... However if there is a change in color such as red (means more test DNA is present and therefore excess of mutated DNA present) or green (means lack of test DNA) can show if there are deletions of inseetions 2) Array-___ can be used to make copy number variants and provide zygosity data ^** In the clinical setting, SNP-arrays are routinely used to uncover copy number abnormalities in pediatric populations when the karyotype is normal, but a structural chromosomal abnormality is still suspected ^** Use ___ arrays for detecting uniparental disomy (like Prader-Wili syndrome/Anngelman syndrome) ************* and also Loss of Heterozygosity (LOH) *** So lets say a patient comes in with a tumor, the doc will take a biopsy and send it in for a micro-array analysis to determine the expression pattern and create a drug cocktail formulated for that specific tumor type based on the individuals expression pattern

1) Array-CGH (aka Array-based comparative genomic hybridization) 2) Array-SNP SNP

In the event of a challenging or unknown pathogenic allele, a lab can instead examine nearby marker loci in the context of a family pedigree due to the fact that ___ occurs and the two types of genetic polymorphisms most useful for this linkage analysis is ___ and ___ polymorphisms like minisatellite and microsatellite repeats These genetic polymorphism linkage techniques are important for determination of relatedness, identity in transplantation, cancer genetics, paternity testing, and forensic medicine

Linkage, SNPs, Repeat-length

___ is done in large cohorts of patients with and without a disease (rather than families) and examine the entire genome of the patients for common genetic variants or polymorphisms that are overrepresented in patients with the disease ^** This is done via SNP genotyping array technology to perform large scale linkage studies of complex diseases like type 2 diabetes or hypertension

GWAS (Genome-Wide association studies)

The study of heritable chemical modifications of DNA or chromatin that does not alter the DNA itself is called ___ alterations Remember, genomic imprinting is due to DNA methylation and therefore if one were to treat genomic DNA with sodium bisulfite to uncover chemical modifications it can help determine Prader-Willi or Angelman syndromes Also, remember Fragixe X syndrome is due to promoter methylation and sodium bisulfite can also be used for determining unmethylated DNA vs methylated DNA Note RNA analysis can also be used for various detection like for RNA viruses such as HIV or Hep C

epigenetic

Sanger sequencing techniques requires a single, simple, homogenous template DNA, however, ____ can use DNA from almost any source and is therefore well suited for heterogeneous DNA samples 3 common ways to do NGS 1) ___ sequencing which is used for common genetic diseases (like cardiomyopathy and congenital deafness) or cancers used for detailed tumor profiling ^**Most common 2) ___ sequencing is a type of targeted sequencing that targets the 1.5% of the genome that codes for proteins 3) ___ sequencing is used in cancers and the only type of NGS that can detect novel structural rearrangements like insertions, deletions, translocations, etc.

NGS (Next generation sequencing) 1) Target sequencing 2) Whole exome sequencing (WES) 3) Whole genome sequencing (WGS)

Chapter 5 Flashcards

(103 cards)