Unstable Repeats Flashcards
mechanism of unstable repeats?
slipped mispairing of DNAP
what is the consequence of mitotic instability?
phenotypic variability
what diseases is mitotic instability most severe?
fragile X
myotonic dystrophy
friedrich ataxia
how is HD inherited?
autosomal dominant
does HD manifest differently with age?
age-related penetrance.
more repeats –> younger age
is there variable expressivity in HD?
yes
what are the symptoms of HD?
chorea dystonia personality changes gradual loss of cognition death
normal, premutation, borderline, affected repeat #
normal = 40
when does anticipation occur?
when father is carrier
pathology behind HD?
expansion in exon 1 of huntington gene
confers novel property in protein that causes it to accumulate in neurons –> death
how frequent is fragile X
most common form of inherited MR
how is fragile X inherited?
X linked
loss of function
phenotype of X linked/
mental retardation hyperactivity and autism speech delay long narrow face/large ears/big jaw macroorchidism
normal, premutation, affected repeat numbers
normal = 200
what if you have a premutation?
males get FXTAS
females get POI
clinical features of FXTAS
late onset cerebral ataxia w/ parkinsonism
dementia
executive fxn deficits
when does anticipation occur?
PSYCH! anticipation doesn’t technically occur because can’t be passed on by father. BUT
if mother is carrier of premutation will see expansion
are heterozygous females affected?
50% have MR
less severe than in males
no risk of POI
skewed X inactivation in brain makes it worse
how do you diagnose repeat disorders?
PCR and southern blot
how is myotonic dystrophy inherited?
autosomal dominant
gain of function
what is the phenotype of myotonic dystrophy
myotonia cataracts hypogonadism diabetes frontal balding
what is the genotype of myotonic dystrophy
triplet in 3’ UTR of DMPK
what is the range of phenotypes?
normal premutation mildly affected classically affected severely affected
does anticipation occur?
when passed on from mother can get MASSIVE expansions
how is friedreich ataxia inherited?
autosomal recessive
loss of function
what is the phenotype of friedreich ataxia?
incoordination of limb movements speech difficulty impairment of position and vibratory sense cardiomyopathy scoliosis manifests prior to adolescence
genotype of freidrich ataxia?
triplet in intron of frataxin (Fe metabolism)
rarely see compound heterozygote w/ expansion + point mutation
anticipation in freidrich ataxia?
NO!
autosomal recessive
