L11 - dynamic mutations Flashcards
what are dynamic mutations
muts caused by expansion of existing polymorphic dna repeat seq beyond a copy number threshold
norm trinucleotide repeats
why are they considered dynamic
as products continue to mut within tissues and across gen
what diseases cause y dynamic mut
fragile x
huntingtons
myotonic dystrophy
what are polyglutamine disease
norm progressive neuromusc/degen disease caused by expansion of CAAG repeats (from 35-200) pat bias at more mitotic div in sperm encode a polyglutamine tract pr dom gof
what the mol mech behind huntingtons
hd gene
in chr 4
codes pr HTT, with n termial polyQs
htt function unknow but ko lethal
what is the polyq thresholds for huntingtons
8-29 norm
29-35 pre mut unstabel norm becomes mut
>37 pathological
>60 juvenile HD
what is the toxic aggregate hypo
hypo for how glutamine repeat cause disease
polyq form aggregates - neuronal intranuclear inclusion
toxic gof
sequester pr in the aggregate/block cell vesicle traffic/inh proteasome formation/titrate chaperones away in the cell
what diseases have toxic aggregates been found
alzheimer/parkinson
what evidence is there for the toxic aggregate hypothesis
incr aggregate more severe disease ptype
block htt primer = improve symptoms in hd
number of aggreg correlate with length polq
what evidence i there against the toxic aggregate hypo
mouse odel with hd = no neuronal intranuclear inclusion seen in early disease
single neuron image revealed the larger the aggreg the incr survival
the toxic polyq aare the insoluble form, the soluble form make up the aggregates
what therpeutic mech can pot be used based on toxi aggreg
rnai dec toxic synth
incr autophagy
what mech pot cause polyglutamine diseases
mitochondrial dysfunction
toxic aggregate
what evidence is there for mitochondrial dysfunction in HD
ca defect in hd mito
more cyto c rel form mito
eg of nonpolyglutamine diseases
fragile x
myotonic dystrophy
fragile x ataxia
what are nonpolyglutamine diseases
non CAG repeat dynamic mut
what cause fragile x
in the FMR1 gene CGG repeats
fmr1 encodes fmrp1 a rna binding pr
the cgg full expansion results in methy of dna - off gene
what the role of fmrp
represses the translocation of some dendritically localised mRNA eg mGluR
mGluR imp role in dendritic pr synth and synaptic plasticity
norm mGlur R act when fmrp active - and allows translation allows AMPR internalisation
what cause fragile x assoc ataxia syndrome
fmr1 repeats in 5'UTR results in RNA gof intranuc inclusion of FMR1 mRNA sequesters 20 pr inc lamins and rna bip = disruption of nuc architecture
what disease cause mytonic dystrohpy
mut in DMPK CTG in 3’UTR
gof
incr rna incr splicing
difference between fragile x and fragile x ataxia
ataxia - neurondegen with later onset
what common ptype of tri nuc expansion diseases
rna gof
what is anticipation
property of dynamic mut
symptoms of gen disorder with an early age onset
what is the mech of dynamic mut
slippage of okazaki fragments
