Exam 5 Flashcards
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
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
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
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
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.
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)
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
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
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
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
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
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
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.
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.
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
Fructose 1,6 bisphosphatase deficiency
- AR- Fasting hypoglycemia
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.
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.
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.
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)
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%
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
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
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
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
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.
Defect in Shh mutation
- Midline defects such as holoprosencephaly = failed or incomplete separation of forebrain early in gestation
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.
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)
Define loss-of-function.
- Loss-of-function: mutation reduces the protein’s activity
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.
What do defects in Shh cause?
- Left/right asymmetrical defects – situs inversus
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
Sucrase-Isomaltase Deficiency
- AR- Sucrose/glucose polymer intolerance
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
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.
