Single Gene Disorders Flashcards
1
Q
AD diseases
A
- familial hypercholesterolemia (LDL receptor deficiency)
- Huntington’s
- Neurofibromatosis Type 1
- Marfan
- Acute intermittent porphyria
2
Q
X-linked recessive diseases
A
- Duchenne muscular dystrophy
- lesch-nyhan syndrome (HGPRT deficiency)
- Glucose 6PDH deficiency
- Hemophilia A and B
- red-green color-blindness
- menke’s disease
- OTC deficiency
- SCID (IL-receptor gamma chain deficiency)
3
Q
How to calculate recurrence risk in X-linked recessive diseases when the sex of the fetus is unknown
A
- if the sex of the fetus is not known, then the recurrence rate is multiplied by 1/2, the probability that the fetus is male vs a female
- ex) if, for a couple the recurrence rate for a daughter is 0, and the recurrence rate for a son is 50%, then the recurrence risk for the unsexed fetus is 25%
4
Q
X-inactivation
A
- occurs in the blastocyst
- when inactivated, its DNA is not transcribed into mRNA.
- seen microscopically as a Barr body
1. it is random: in some cells of the female embryo the X-chromosome from dad is inactivated, in others the x-chromosome from mom is inactivated - most women have their paternal X chromosomes active in approx 50% of cells; mom’s X is active in 50%
= women are mosaics wrt the active X chromosome
2. it is fixed. once inactivation occurs, the same x chromosome is inactivated in all descendants of the cell
3. it is incomplete: there are regions throughout the X chromosome (including the tips of both the long and short arms) that are not inactivated
4. all X chromosomes are inactivated except 1. if a woman has 3, 2 will be inactivated
5
Q
X-inactivation is mediated by
A
- XIST = primary gene that causes x-inactivation
- XIST produces an RNA product that coats the chromosome, helping product inactivation - Condensation into heterochromatin
- methylation of gene regions on the X chromosome
6
Q
genetic mosaicism
A
a condition in which cells w different genotypes or chromosome constitutions are present in the same individual
7
Q
x-linked dominant
A
- males and females may be affected differently (have different degrees of penetrance)
- seen about 2x as often in females as in males
- phenotype seen in multiple generations of pedigree (like AD); skipped generations relatively unusual
- An affected male’s children: none of sons will be affected, but all daughters will have disease
- Ex) Fragile X Syndrome
- Ex) hypophosphatemic rickets
8
Q
Fragile X Syndrome
A
- Males = 100% penetrance
- mental retardation
- large ears
- prominent jaw
- macro-orchidism (usually post pubertal)
2. females = 60% penetrance (causes mental retardation
9
Q
Examples of mitochondrial diseases
A
- leber hereditary optic neuropathy
- MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)
- myoclonic epilepsy with ragged red muscle fibers
- only passed from a female to her children
- diseases are typically neuropathies/myopathies
10
Q
pleiotrophy
A
- single mutation affects multiple organ systems
- ex) marfans (AD)
11
Q
affect of allelic heterogeneity
A
- different mutations in the disease-causing locus may cause more/less severe expression
- usually results in phenotypic variation BETWEEN families, not WITHIN one family
- ex) missense mutations in factor VIII gene produce less severe hemophilia than nonsense mutations (which truncate the protein, so it produces very little (or no) factor VIII)
12
Q
heteroplasmy
A
- bc a typical cell contains hundreds of mito in the cytoplasm,
- sometimes a specific mutation is seen in only some of the mitochondria
= heteroplasmy - variations can result in substantial variation in the severity of expression of mitochondrial diseases
13
Q
incomplete penetrance
A
= when some people who have the disease GENOTYPE do not display the disease PHENOTYPE
- these are diseases where a secondary event is required to cause expression of the disease
- differs from variable expression in that the nonpenetrant gene has NO PHENOTYPIC EXPRESSION AT ALL
- ex) an unaffected male has an affected father and two affected sons; he must have the disease-causing mutation
- both dominant and recessive diseases can show incomplete penetrance
- Rb (AD) is an example of incomplete penetrance in familial cancer
- hereditary hemochromatosis is an example of incomplete penetrance AND variable expression
- among individuals with at least some phenotypic expression, the symptoms can be more or less severe (variable expression)
- however, 85% of ppl homozygous for the mutation never have any sx (nonpenetrance)
14
Q
locus heterogeneity
A
when the same disease phenotype can be caused by mutations in different loci
15
Q
Locus heterogeneity in osteogenesis imperfecta Type 2
A
- the severe perinatal form of OI (T2) is the result of a defect in type 1 collagen; 100% result from new mutations
- T1 collagen = trimeric molecule that has a triple helix structure
- 2 members of the trimer are encoded on Chromosome 17
- 3rd is encoded on chromosome 7
- pts with chromosome 17 mutations are often clinically indistinguishable from pts with mutations on chromosome 7
= locus heterogeneity
