DNA & Neuro Disorders Flashcards
2 kinds of neurodegen conditions?
inherited
acquired
subset of inherited neurodegen conditions caused by?
unstable repeat expansions
what is the most common type of repeat expansion?
trinucleotide
there is also tetranucleotide
below the threshold for number of repeat expansions?
stable in both sperm/egg and somatic
above the threshold for number of repeat expansions?
unstable and could become toxic
what is a characteristic of unstable repeat expansions?
dynamic mutations
what is it called when the expansion size increases across generations?
anticipation
anticipation of repeat expansions associated with?
greater severity of symptoms
what is a proposed mechanism for expansion?
slipped mispairing
what is anticipation in terms of unstable repeat expansions for neuro degen diseases?
the expansion size increases across generations
unstable repeat expansions are usually what kind of disorders generally?
neurological
3 kinds of unstable repeat expansion in terms of coding?
- non-coding = loss protein function
- non coding = novel RNA
- codon = novel toxic protein
Huntington’s mutation is where in terms of coding?
repeats in codon
Friedreich ataxia mutation happens in which coding area?
non-coding leads to loss of protein function
what do you see in late onset unstable repeat expansion?
loss of movement control
symptoms worsen
DNA testing
3 main features of Huntingtons:
- motor disorder
- cognitive disorder
- psychiatric/emo disorder
Huntington’s early or late onset?
late normally
small proportion can be <20 due to expansion
huntington’s inheritred how genetically?
autosomal dominant
What repeat in huntington’s?
CAG repeat in HTT gene
What is HTT?
protein called huntingtin
expanded CAG in huntingtin has toxic effect where in brain?
basal ganglia
esp. medium spiny neurons
what do you see in brain scans of huntington’s?
cerebral atrophy
PolyQ-huntingtin cleaved by capsases and make what toxic fragments?
N-terminal fragments
huntington’s you lose function of normal HTT and also?
mRNA
huntington’s 27-35 repeats is?
‘normal’ mutable
huntington’s >40 repeats?
full penetrance
huntington’s zone of reduced penetrance is how many?
36-39 repeats
huntington’s less than 26 repeats?
normal
CAG repeats mitigated by?
CCG interruptions
huntington’s classical testing uses?
radioactive nucleotide tagging and PCR
current huntington’s testing
fluorescent tagging and fragment analysis
spinocereballar ataxias: genetics? onset? features?
autosomal dominant
late onset
progressive cerebellum degen and spinocerebellar tracts
spinocereballar ataxias SCA6 causes?
Ca2+ channel protein malformation
spinocereballar ataxias SCA 3 called?
Machado-Joseph disease
what is Machado Joseph disease?
spinocereballar ataxias SCA3
Friedreich ataxia genetics and onset?
autosomal recessive
puberty onset
Friedreich ataxia features? 3
- limb/gait ataxia
- cardiomyopathy (65%)
- DM (30%)
Friedreich ataxia mutation occurs where in genome?
intron, causes formation of triple helix and inhibits transcription
Friedreich ataxia expansion letters?
GAA repeats expansion
Friedreich ataxia defect causes what cellularly?
mitochondrial iron accumulation = oxidative damage
Friedreich ataxia repeats normal range?
5-33
Friedreich ataxia repeats expansion can be?
66-1700!
Friedreich ataxia mutable range is?
34-65
problems with pre-symptomatic genetic testing?
ethical as there is not really much treatment
SCA results interpretations,
REVIEW!!
