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Flashcards in Exam 5 Deck (92):
1

Describe Duschenne/Becker Muscular Dystrophies

- Both common x-linked recessive diseases - Affects 1/3000 - Defect in dystrophin leads to muscle damage. Gene is large target for new mutations. Large target - Pts are wheel-chair bound by age 12, death occurs before repro age

2

Explain why balanced chromosomal alteration often cause infertility of otherwise health carriers. Explain the inheritance of balanced alterations.

- Carriers of balanced alterations ~ 0.2% of live births are not aware of their condition as there is typically no impact on the carrier - Their genetic abnormality does; however, shows at reproduction when they lead to the production of aberrant gametes. See image below

 

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3

Explain how epigenetic changes play a role in the development of cancer

- Global hypomethylation of DNA outside of CpG islands is seen in most cancers- Hypomethylation causes genomic instability and therefore elevated transposon activity, resulting in chromosomal abnormalities. This causes cancer.- Hypermethylation of CpG islands in promoter can shut down tumor suppressor genes – sometimes seen in non-familial breast cancers

4

Name the five most frequent birth defects. Give frequencies

1.) Heart defects – 1/100-2002.) Pyloric stenosis – 1/3003.) Neural tube defects – 1/10004.) Orofacial clefts – 1/700-10005.) Clubfoot – 1/1000

5

List three axes and discuss the function of each, what gene/factor is responsible for formation of this axis?

1.) Anterior-posterior axis- First visible structure defined by primitive streak with groove. Node is at the anterior end. Nodal gene is responsible for formation of this axis2.) Dorsal-ventral axis- Secreted proteins noggin and chordin are secreted from cells in the node and induce dorsal development in a concentration-dependent manner3.) Left-right axis- Asymmetric expression of the gene for the signaling protein Shh: sonic hedgehog from the notochord causes left/right asymmetry. This leads to asymmetric expression of nodal on the left-side that initiates development of the heart tube.

6

What is the Pierre Robin Sequence?

- Collagen disorder, generalized growth retardation, neurogenic hypotonia, oligohydramnios leads to ….- Mandibular hypoplasia leads to ….- U-shaped cleft palate and micrognathia (small jaw/chin)

7

Give general prevalence figures for common multifactorial birth defects

- Risk for general population = 0.5% risk- If second degree relative affected = 0.7-2% risk- If first degree relative affected = 3-4% risk- If two first degree relatives affected = 5-8% risk- Three first degree relatives affected = 9-12% risk- Identical twin = 20-30% risk

8

Give examples of diseases that affect genetically isolated populations

1.) Ellis van Creveld Syndrome: Old Order Amish of Lancaster County2.) Tay-Sachs Disease (ganglioside storage disease): Ashkenazi Jews3.) Tyrosinema: French Canadians in Quebec

9

Describe chromosomal defects in Di George Syndrome

- Deletion in chromosome 22 q. Frequency = 1/4000. Usually a new mutation- Malformations include: congenital heart defect, immunodeficiency, hypoparathyroidism, mental retardation, cleft palate

10

Give epidemiology figures for congenital malformations

- 2-3% of children are born with a recognizable birth defect- 20% of total mortality, birth defects are most common cause of infant death in US- Another 20% of infant deaths are caused by prematurity, which also can be considered a failure of normal development

11

Describe the effects of 5-azacytidine on genome methylation

- Hypermethylation can be reversed by this drug, which is a DNMT inhibitor. Treatment serves to allow for re-activation of silenced tumor suppressor genes

12

Contrast de-novo and maintenance methylation

De-novo DNA methylation- Methylation is introduced into an unmethylated strand of DNA by DNA methyltransferases DNMT3a and bMaintenance- Pattern of DNA methylation is maintained through mitosis by DNA methyltransferase DNMT1- During S-phase, DNA pol synthesizes a non-methylated strand from the methylated template strand- New double-strand consists of a methylated and non-methylated strands transiently. DNMT1 methylates the non-methylated strand based on what is seen on the template

13

Identify the first visible axis in the developing embryo

- Anterior/posterior axis. This is defined by the primitive streak, which is defined by the position of the entry of the sperm into the egg. Node is the anterior end of the streak and the groove is the primitive streak and serves as the anterior/posterior axis.

14

Explain how cell migration is necessary for the development of the cerebral cortex

- Development of CNS begins from neural tube. Neuronal stem cells on ventricular side of neural tube divide and generate neuronal precursor cells- These precursor cells have to migrate outward from the ventricle along a scaffold of glial cells, which occurs in waves- Mutation / deletion of LIS1 gene interferes with orderly pattern of migration. Result = cerebral cortex is thickened and lacks defined cell layers. Lissencephaly = smooth brain. Individuals suffer from severe mental retardation.

15

Describe how the family history or the pts genotype influence the prediction of risk (relative risk ratio and relative risk)

- Incidence and prevalence data are different for ppl with different numbers of affected relatives.- In diseases with strong genetic component, prevalence for ppl with affected relatives is much higher than for general population- Therefore a measure known as relative risk ratio (lamda r where r indicates relationship) compares frequency of a dz in relatives of affected and unaffected probands.- Lambda r = prevalence of dz in relative r of affected person divided by prevalence in general population- Relative risk is a way to describe disease association of an allele: how much more likely a carrier of an allele is to develop the dz than a non-carrier. If RR for carrying allele Y is 3.5 then we tell pts: your risk is 3.5 times the risk of a non-carrier of allele Y

16

Fructose 1,6 bisphosphatase deficiency

- AR- Fasting hypoglycemia

17

What is genetic drift and how does it affect the gene pool of a population? Example

- Genetic drift is the change in allele frequency within a population due to random sampling/statistical variation. This occurs in small populations. - Example: 10 couples stranded on deserted island. One of males is heterozygous carrier of CFTR mutation. Allele frequency is 1/40 (2.5%). Time goes by and couples have average of 2 children. By chance, none of children have inherited mutation from father. By genetic drift, CFTR allele is now completely lost from this island’s population.

18

Explain genome-wide association studies

- GWAS refers to analysis of millions of SNPs to determine their connection with disease. Genetic polymorphisms underlie why certain individuals have a genetic susceptibility to certain disease or have different responsiveness to drugs.- From these studies, you get odds ratio that SNP is associated with disease state.- Note, SNPs are not necessarily disease-causing. SNPs often lie outside of coding regions, but show strong linkage with the mutation that causes the disease.

19

Describe the role of HLA haplotypes in the development of type 1 diabetes and other autoimmune disorders

- Think of haplotypes as blocks of genetic information that are inherited together. HLA haplotypes are expressed in a codominant manner. Each parent only transmits one haplotype to the child. Certain HLA haplotypes favor or protect against diseases.- T1D: Contribution of HLA haplotypes to risk for T1D is strong, but not exclusive – only accounting for ~40% of genetic risk. Genetic variation in DR-DQ haplotypes affects risk for T1D. Some DR-DQ haplotypes increases risk and are known as susceptibility alleles. Others decrease risk and are designated protective alleles- Other immune disorders: HLA-B haplotypes determine risk for spondyloarthropathy. HLA-C haplotypes predict risk for psoriatic arthritis.

20

What is heterozygote advantage? Describe in respect to mutation affecting CFTR, beta-globin and HFE.

- Heterozygote advantage refers to positive selection of heterozygotes as a result of their genotype conferring increased fitness in a particular environment.- CFTR: protects against typhoid fever (population that benefits = European)- Beta-globin/sickle cell: protects against malaria (population that benefits = Mediterranean and African)- Beta-globin/beta-thalassemia: protects against malaria (population that benefits = Meditteranean)- HFE/hemochromatosis: protects against plague (population that benefits = European)

21

Give figures for the genetic and environmental contributions of the burden of congenital malformations

- In over 50% of birth defects, no cause can be identified, remaining are:- Genetics: 50% have complex inheritance, 25% caused by chromosomal defects, 20% caused by single-gene mutations- Non-genetic factors such as maternal medication and infections = 5%

22

Name 5 processes by which cells participate in development

1.) Gene regulation by TFs and chromatin modification2.) Cell-cell signaling (direct contact or morphogens)3.) Development of specific cell shape and polarity4.) Movement and migration of cells5.) Programmed cell death

23

Achondroplasia. Inheritance, defect, frequency

- AD- Caused by defect in FGFR3, gain of function mutation where receptor is constitutively active, exhibits dominant negative effect. Most frequent form of dwarfirsm. Initiation of bone growth leads to short stature. New mutations occur frequently in this disease.- Mutation hotspot

24

CF. Inheritance, defect, frequency

- AR- Defect that impairs trafficking of CFTR chloride channel to cell surface causing pulmonary problems and pancreatic malfunction. CF pts have 2-5 times amount of NaCl in sweat. Severity varies (allele heterogeneity, modifier loci): pancreatic sufficient or insufficient- 1/2000

25

Neurofibromatosis type I. Inheritance, defect, frequency

- AD- Neurological defect in neurofibromin gene. Causes multiple benign tumors (neurofibromas) in skin, benign tumors on iris of eye called Lisch nodules, pigmented skin lesions (café-au-lait spots), tumors of CNS and mental retardation. New mutations, complete penetrance and variable expressivity- 1/3500

26

Contrast haploinsufficiency and dominant negative effect in the development of osteogenesis imperfecta subtypes

- Osteogenesis imperfecta-1 is caused by mutations in the collagen I genes.- OI-1 causes deformity of skeleton and predisposes bones to breakage. - Frequency = 1/10000, AD- There are 4 different classes of OI depending on the number of proalpha1 and 2 collagen chains and also if the chains are defective or not. Defect in one chain may disturb the larger structure. This is referred to as dominant negative effect.- Allele heterogeneity is also exhibited in this disease in that the severity depends on the AA exchanged. Type I have brittle bones and blue sclerae without bone deformities. Type II is perinatal lethal. Type III is progressively deforming. Type IV has bone deformities with predisposition to bone fractures.

27

Defect in Shh mutation

- Midline defects such as holoprosencephaly = failed or incomplete separation of forebrain early in gestation

28

Explain how to the Robertsonian translocations affect the health of a carrier

- Robertsonion translocation is movement of long and short arms of two chromosomes. Result = one chromosome composed of both the long arms the other composed of both of the short arms. The shorter derivative chromosome does not contain essential genetic information and is typically lost during cell division. Common Robertsonion translocation involves c/s 13 q and 14 q – happens at frequency of 1/1300.

29

Explain how masculinization of female babies (male pseudohermaphroditism) and feminization of male babies (female pseudohermaphroditism) occurs

1.) Masculinization of female babies: normal ovaries, but ambiguous or male genitalia- Congenital adrenal hyperplasia (most common, defect in 21-hydroxylase involved in cortisol biosynthesis results in block in cortisol synthesis with intermediates being shunted into androgen synthesis pathway). As result: females have high levels of androgens and develop ambiguous or male genitalia2.) Feminization of male babies: failure to develop unambiguous male genitalia- Defect in testes development during embryogenesis- Problem in androgen biosynthesis by testes (eg. Issue with steroid 5 alpha reductase) - Deficiency in androgren receptor production or signaling by target cells (androgen insensitivity)

30

Define loss-of-function.

- Loss-of-function: mutation reduces the protein’s activity

31

Describe chromosomal defects in cri-du-chat

- Deletion in chromosome 5 p. Usually a new mutation- Facial changes: microcephaly, hypertelorism (wide set eyes), micrognathia (undersized jaw). Brain/CNS changes: severe mental retardation. Cardiovascular: heart defects. Characteristic cat-like cry.

32

What do defects in Shh cause?

- Left/right asymmetrical defects – situs inversus

33

How are x-chromosomes inactivated?

- XIC (x-chromosome inactivating center) on x-chromosomes has a gene known as XIST (inactive x-specific transcript).- XIST is transcribed- XIST RNA associates closely with x-chromosome and mediate inactivation of most of the chromosome- DNA and histones on x-chromosome become methylated, transcription is inactivated and chromosome condenses

34

Sucrase-Isomaltase Deficiency

- AR- Sucrose/glucose polymer intolerance

35

How does methylation silence transcription?

- Methylation of DNA occurs on cytosine residues in CpG islands- After methylation occurs, methylcytosine binding proteins bind methylcytosine.- MBPs interact with repressors of transcription leading to transcriptional block and HDACs that lead to chromatin condensation

36

Contrast the effects of gain-of-function and loss-of-function mutations in the RET gene

- RET gene encodes tyrosine kinase receptor located in the plasma membrane. Both mutations below are autosomal dominant.- Loss of function mutation in RET gene causes Hirschprung disease. Receptor has inability to respond to stimulus. In this disease, there is impaired development of neurons that populate the colon giving rise to aganglionic colon.- Gain of function mutation in RET gene causes Multiple Endocrine Neoplasia (MEN). Receptor renders signaling molecule constitutively active. Proliferation of neuroendocrine cells occur.

37

What is locus heterogeneity?

- Mutations in different genes cause the same phenotype

38

Name two main sources for mutations affecting chromosome structure

1.) Nonhomologous End Joining during double-strand break repair2.) Unbalanced recombination between non-homologous sequences

39

Implication of epigenetic changes in T-Cells as implicated in SLE

- SLE is caused by epigenetic changes in T-cells- This is an autoimmune disease with incidence = 1/2000 affecting females 8-10 times more than males- In this condition, antibodies against nuclear components are produced.- Global hypomethylation of the T-cell genome is seen in these patients- DNMT inhibitor treatment on T-cells causes SLE-like phenotypes

40

Name two functions of the Shh morphogen

- Shh gradient secreted from notochord and floorplate of neural tube helps organizing the different cells in brain and spinal chord. Defects leads to midline defects- Shh also secreted from zone of developing limb to induce development of posterior limb elements.

41

LHON

- Most prevalent mitochondrial disorder. Rare at 1/50000- Caused by mutation by ND1 gene (oxphos)- LHON leads to a rapid deterioration of the optic nerve- Exhibits heteroplasmy as mitochondrial disorder

42

What is Beckwith-Wiedemann syndrome?

- Example of uniparental disomy disorder- Incidence = 1/13000- Some types arise when child inherits homologues of a portion of chromosome 11 from father.- S&S: overabundance of IGF2, leads to kidney, adrenal and liver problems, resulting in severe hypoglycemia. Characterized by microcephaly, macroglossia (large tongue) and umbilical hernia. Susceptible to childhood cancer.

43

Glycogen storage disorders

- AR- Hypoglycemia, accumulation of glycogen

44

What characteristics does an ideal population follow in terms of HW?

- Large population size- Equal fitness among offspring- Random mating- No influx of new alleles by migration or mutation

45

What is penetrance? What is expressivity?

- Penetrance: percentage of people with disease gene who develop symptoms- Expressivity is the severity of the symptoms

46

Explain how a cell changes shape and polarity. Provide example using developing kidney

- In development, cells must respond to environmental clues by changing their shape and polarity, which involves rearranging cytoskeleton and polarizing secretion of proteins to apical or basal surfaces of cell- Kidney: Epithelial cells need to sense fluid flow in kidney tubule. Detection of fluid stream leads to stopping of cell proliferation and correct polarization of cell. This occurs by relocating erb-b2/EGFR to basal surface. In polycystic ovary disease, mutations to two genes polycystin 1 and 2 render a cell incapable of sensing fluid flow. As a result, cell proliferation doesn’t stop, development of polarity doesn’t occur (erb-b2/EGFR) remains on the apical surface and kidney develop cysts.

47

What is Smith-Lemli-Opitz Syndrome?

- Impairment of Shh signaling secondly to defect in cholesterol biosynthesis. - This is an autosomal recessive disorder affecting 1/20-50K- Leads to multiple severe congenital malformations

48

Explain the significance of CpG islands for gene expression

- Methylation of DNA occurs on cytosine residues in areas rich in CG known as CpG islands- CpG islands are found upstream of genes close to the 5’ region- Methylation acts to silence part of the genome

49

What are population bottlenecks and founder effect and how does it affect the gene pool of a population? Example

- If a large part of a population is wiped out by a catastrophic event, population has to recover from a small founder population of survivors. This bottleneck leads to amplification of rare alleles in the founder’s genotype. - Example: Samuel King immigrated to Eastern PA and founded a large family. He carried a rare recessive mutation in EVC, which cause Ellis Van Creveld syndrome (skeletal dysplasia disorder). This was propagated through founder effect. Consanguineous matings were inevitable in this genetically isolated community and children homozygous for EVC mutation were born. Carrier frequency for EVC is 12.3% in Old Order Amish community in PA, which is only 0.8% in general population

50

Define dominant negative effect

- Dominant negative effect: If the mutation produces an abnormal protein, the mutant protein may compete with the wildtype form. If the protein in question is part of a large complex, the presence of a few deformed mutant proteins may destabilize the structure. A dominant negative effect affects mostly structural proteins

51

Explain the function of boundary elements

- Boundary elements aka chromatin barriers serve to separate active and inactive genomic regions

52

Explain the function of the HOX transcription factors in development

- Following specification of axes, patterning takes place. Patterning defines which end of undevelopmed mass of cells is head, which is tail. It segments cells to define which parts become head, thorax, abdomen etc.- Patterning along ant/post axis is determined by homeobox (HOX) genes, which are a family of transcription factors containing a special DNA binding domain called homeodomain. There are 4 HOX clusters on 4 chromosomes- Expression of each of the genes belonging to a cluster correlates with position of respective cell in embryo and with timing of expression. Each cell along axis experiences a different ratio of expression of different HOX genes. Ultimately, the pattern of HOX gene expression determines fate of a cell in segment.

53

What influences cause deviations from HW equilibrium?

- Genetic drift (non-small populations)- Selection (fitness is unequal in offspring)- Assortative mating (mating is non-random)- Population bottlenecks/founder effect

54

Compare the impact of problems during the first 4 weeks, weeks 5 to 8 and in later stages of development

1.) 1-4 weeks (blastogenesis): abnormalities during this period produces multiple major abnormaities in entire embryonic regions. Example = VACTERL2.) 5-8 weeks (organogenesis): abnormalities during this period affects specific organs and produces single major anomalies. Example = congenital heart defects3.) 9+ weeks: major organs have formed, abnormalities here will have mild effects on the individual. Example = single palmar crease

55

Explain how the genetic and the environmental influences on complex disease can be estimated

- Twin and adoption studies (MZ vs DZ twins)- Concordant trait = trait shared by both twins- Discordant trait = trait not shared by both twins- Diseases with significant genetic component will show higher concordance rate in MZ twins than in DZ twins using crude measure known as heritability H2- H2 = (concordance MZ – concordance DZ) x 2- High heritability = trait is determined predominantly by genetic factors

56

What is Rett Syndrome?

- X-linked dominant disorder mapped to mutations in the gene for methyl-cytosine binding protein MECP2- Mutation leads to loss of transcriptional silencing- Symptoms: autism-like symptoms, repetitive teeth grinding and hand-wringing, motor problems and characteristic gait. Onset age 6-18 months

57

Describe the function of HP1 in transcriptional control

- De-acetylated histones are methylated and bind HP1 proteins- HP1 proteins bind histone methylase- This binding results in methylation of histones spreadings along chromosomes until boundary elements are reached.

58

Contrast malformation, deformation and disruption. Examples

- Malformation: intrinsic abnormality in developmental process. Eg. Polydactyly- Deformation: extrinsic influence on development of the affected tissue. Eg. Oligohydramnios- Disruption: destruction of developing tissue. Eg. Amniotic bands

59

What is Treacher-Collins Syndrome?

- Pts present with cleft palate, micrognathia (small jaw), down slanting palpebral fissures and malar hypoplasia (underdeveloped zygoma). - This is an AD disorder. Individuals have high risk for complications relating to this disorder – eg. Cardiovascular.

60

Explain patterning. Discuss role of signaling molecules that are necessary for this to occur

- Following specification of axes, patterning takes place. Patterning defines which end of undevelopmed mass of cells is head, which is tail. It segments cells to define which parts become head, thorax, abdomen etc.- Patterning along ant/post axis is determined by homeobox (HOX) genes, which are a family of transcription factors containing a special DNA binding domain called homeodomain. There are 4 HOX clusters on 4 chromosomes- Expression of each of the genes belonging to a cluster correlates with position of respective cell in embryo and with timing of expression. Each cell along axis experiences a different ratio of expression of different HOX genes. Ultimately, the pattern of HOX gene expression determines fate of a cell in segment.

61

What are modifier genes?

- The individual genetic background modifies the phenotype

62

What is assortative mating and how does it affect the gene pool of a population?

- Assortative mating is the selection of partners based on specific genetic traits.- It disturbs the equilibrium distribution of alleles, specifically, the mating of genetically similar individuals increases the degree of homozygosity in a population. The allele frequencies in the gene pool don’t change, only change is increase in homozygote frequency.

63

Li-Fraumeni

- XR- Defects in p53 causes brain tumors and leukemias- Two-hit model

64

PKU. Inheritance, defect, frequency

- AR- IEM, Defect in Phe hydroxylase, Phe accumulates and damages the CNS. With many other IEM, screened for at birth- 1/2900

65

In a recessive disease with an incidence of 1/10000, how high is the allele frequency in the gene pool? How high is the carrier frequency?

- f(a)^2 = 1/10000, then f(a) = 1/100 = 0.01- f(A) = 1-f(a) = 99/100 = 0.99- Since the disease is so rare, assume f(A) = 1, then frequency of heterozygote = 2f(a)f(A) = 0.02

66

Sickle Cell Anemia

- AR- Hemolysis

67

Retinoblastoma

- Autosomal dominant inheritance, expression at cellular level is autosomal recessive- Defects in Rb protein, leads to predisposition and / or development of cancer- Two-hit model

68

Explain the meiotic problems arising from an inversion

- Inversion results when a c/s suffers two breaks and the broken off fragment is re-inserted in the wrong orientation.- As this is a type of balanced alteration, carriers are asymptomatic- Problems arise in offspring as chromosome with inverted region forms inversion loop during pairing with normal homolog. If crossing over occurs, material is translocated and some gametes are inviable.

69

Describe the gene therapy trial for ADA-SCID

- This was the first successful gene therapy trial in 1990. Cured SCID pt caused by absence of ADA: adenosine deaminase.- ADA gene was inserted into modified retro-virus- T-cells were isolated from pt. - Retrovirus was cultured with T-cells and inserted ADA into cells.- Cells that incorporated ADA gene into their genome were selected and grown in culture. - Cells were re-implanted into pt.

70

What is situs inversus and situs ambiguous, what causes it?

- Both are defects in left/right axis formation- Situs inversus: all organs are complete mirror images in what is normally found (known a situs solitus). Usually asymptomatic- Situs ambiguous describes a more serious condition in which orientation of organs is randomized. This is usually accompanied by heart defects.

71

Glucose 6-phosphate dehydrogenase deficiency

- XR- Sensitivity to H2o2 generating agents and fava beans

72

Contrast isolated anomalies, sequences and syndromes

- Isolated anomalies: single problem that can be sporadic or multifactorial in order that just affects a single body region. Ex: cleft palate. Major anomalies = anomalies requiring surgical or cosmetic consequences. Minor anomalies = little impact on well-being of pt – can give diagnostic clues about presence of a syndrome.- Sequences: cascade of events, starting from isolated anomaly and leading to multiple malformations- Syndromes: affect several body regions and often display chromosomal or Mendelian inheritance.

73

What is selection and how does it affect the gene pool of a population?

- Selection works against or in favor of certain genotypes. Over time, selection will reduce number of detrimental mutant alleles in a population. However, frequency of mutant alleles will stabilize at a low level. In this state of equilibrium, loss of mutant alleles by negative selection will be equal to spontaneous occurrence of new mutant alleles

74

Discuss concept of reduced fitness and new mutations in context of autosomal dominant disorders

- In some autosomal dominant disease, an allele carriers has a reduced chance of reproduction, ie. reduced fitness- Therefore, reduced fitness of the carriers would lead to disappearance of the mutant alleles in populations- However, allele frequencies stay constant as new mutations appear constantly and compensate for the loss of mutant alleles- Low fitness of carriers means high percentage of new mutations- If parents are not affected by dominant disease, affected children could have inherited a new mutation- New mutations are seen in DMD, NF and achondroplasia. Genes implicated in these disorders are large, complex or contain mutation hotspots.

75

Explain the parent-of-origin effect observed in Prader-Willi and Angelman syndromes

- Prader-Willi: deletion exists from paternal chromosome 15, mothers is imprinted and therefore silenced. Incidence = 1/10-50K. Characterized by obesity, excessive food seeking behavior, hypogonadism, mental retardation, small hands and feet- Angelman: deletion exists on maternal chromosome 15, fathers is imprinted and therefore silenced. Incidence = 1/15K. Characterized by unusual facial features – large mandible and open mouth, seizures, movement and gait disorders, mental retardation, excessive laughter and absence of speech.

76

Ehlers-Danlos Syndrome

- AR and AD collagen disorder- Dominant forms of EDS are caused by mutations in the collage genes. Misfolded collagen molecules exert a dominant negative effect- Other forms of EDS are caused by mutations in enzymes required or the processing of collage molecules. As typical for enzyme defects, these mutations show a recessive mode of inheritance.

77

Explain the dominant inheritance of familial hypercholesterolemia

- FH is frequent 1/500 person disease, AD- Heterozygotes have 2-fold elevation in LDL levels as there are insufficient receptors to clear LDL from serum. Homozygotes have 4-fold evelated in LDL levels. This is an example of haploinsufficiency, allele heterogeneity- Symptoms: xanthomas

78

Characteristics of dominant and recessive inheritance patterns

1.) Recessive inheritance: one normal allele prevents disease, recessive inheritance is mostly observed in defects of enzymes/proteins involved in transport and storage, loss of one functional allele can be compromised2.) Dominant inheritance: mostly observed in defects of structural proteins, proteins involved in growth, differentiation and development and receptor/signaling proteins

79

What is uniparental disomy? What are the effects of this?

- Zygote with only maternally or paternally imprinted homologues of a chromosome- This leads to problems with gene dosage (overabundance of one gene, lack of another for example).

80

Explain the tumor progenitor cell model

- Tumor progenitor cells arise during development due to epigenetic changes and the action of tumor progenitor genes (TPG)- Then follows a Gatekeeper Mutation (GKM) in a tumor suppressor gene (TSM) or oncogene (ONC) to generate a benign tumor- Finally, epigenetic and genetic plasticity help evolve the benign growth into a metastatic, invasive and drug resistant tumor- Crux of matter: errors in epigenetic programming of stem cells in development lays seed(s) for cancer later in life

81

Give the frequency of chromosomal aberrations, both at conception and at birth

- Structural chromosomal abnormalities (rearrangements, loss and duplications) occur in approximately 0.5 % of pregnancies and 0.2 % of live births

82

Huntingtin Disease. Inheritance, defect, frequency

- AD- Neurodegerative disorder causes by gain of function mutation. Triplet expansion in gene causes protein instability. Neurodegenerative disorder with late age onset, age dependent on number of CAG repeats. Premutation = reduced penetrance = 35-40 repeats. 40+ = fully penetrant. New mutations occur frequently in this disease.- 5/100000

83

Explain the effect of hypomethylation on genome stability

- Hypomethylation reactivates transposable elements (jumping genes) that lead to somatic recombination and genomic instability.

84

Define haploinsufficiency

- Haploinsufficiency: half of gene dosage might not be sufficient for a cell to carry out its function. Many structural proteins are needed in quantities too large to be supplied by just one allele

85

Explain the gender-specific differences in recurrence risk for multifactorial disorders such as pyloric stenosis

- Pyloric stenosis is more common in male birth 1/200 than in female birth 1/1000. Accordingly, in pyloric stenosis, there is a lower threshold for males (males need few contributing alleles) and a higher threshold for females (females need more contributing alleles).- When assessing recurrence risk then: affected female proband has more contributing alleles than affected male proband and therefore has higher risk of having an affected sibling than does a male proband. Also her risk of having an affected brother is higher than her having an affected sister because a brother would only need fewer contributing alleles to develop a disease.- Affected male proband has higher recurrence risk for having a brother than a sister with pyloric stenosis.

86

What is VACTERL association? What is an association?

- vertebral defects, anal atresia, cardiac abnormalities, tracheo-esophageal fistula, renal and limb abnormalities- defects are through to occur in blastogenesis phase of development- risk factor: maternal diabetes- association = group of birth defects that for unknown reasons often occur together

87

Explain how the Philadelphia chromosome affect the health of a carrier

- Philadelphia chromosome = translocation bw c/s 9 & 22- ABL tyrosine kinase is moved from 9 to BCR region on 22.- BCR-ABL protein functions as dominant oncogene causing CML

88

Explain why a defect in cholesterol biosynthesis affects development

- For correct functioning of Shh, the protein must interact with cholesterol. - Disturbances in cholesterol biosynthesis will therefore also have broad impact on development.- Defect = Smith-Lemli-Opitz syndrome, IEM in cholesterol synthesis

89

Define gain of function.

- Gain of function: Mutated protein may have functions different from its wildtype variant. In this case, the few proteins with novel functions will have an effect no matter how many wildtype versions are present. This mechanism is frequently observed in signal transduction proteins.

90

Incontinentia pigmenti.

- X-linked dominant. Result from a defect in NEMO (NFkappaB essential modulator) that results in rash in early infancy, mental retardation, microcephaly and defects in tooth development. - It is lethal in male embryos

91

What is imprinting? Explain the time and effects of imprinting

- Imprinting is a form of DNA silencing that marks a chromosome as having come from the paternal or maternal parent. Why care? Transcriptional activities of paternal and maternal chromosomes are different.- Imprinting takes place during gametogenesis. Chromosomal regions are silenced by DNA methylation and histone deacetylation. This persists throughout the life of the individual.- Parent-of-origin imprint is erased and rewritten during gametogenesis. Female will reprogram both her chromosomes to make them look like maternal chromosomes. Male reprograms both his chromosomes to make them look like paternal chromosomes

92

What is allele heterogeneity?

- Different mutations in the same gene cause different phenotypes. Mutations can be gain of function or loss of function