L11 - dynamic mutations Flashcards Preview

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Flashcards in L11 - dynamic mutations Deck (23):
1

what are dynamic mutations

muts caused by expansion of existing polymorphic dna repeat seq beyond a copy number threshold
norm trinucleotide repeats

2

why are they considered dynamic

as products continue to mut within tissues and across gen

3

what diseases cause y dynamic mut

fragile x
huntingtons
myotonic dystrophy

4

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

5

what the mol mech behind huntingtons

hd gene
in chr 4
codes pr HTT, with n termial polyQs
htt function unknow but ko lethal

6

what is the polyq thresholds for huntingtons

8-29 norm
29-35 pre mut unstabel norm becomes mut
>37 pathological
>60 juvenile HD

7

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

8

what diseases have toxic aggregates been found

alzheimer/parkinson

9

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

10

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

11

what therpeutic mech can pot be used based on toxi aggreg

rnai dec toxic synth
incr autophagy

12

what mech pot cause polyglutamine diseases

mitochondrial dysfunction
toxic aggregate

13

what evidence is there for mitochondrial dysfunction in HD

ca defect in hd mito
more cyto c rel form mito

14

eg of nonpolyglutamine diseases

fragile x
myotonic dystrophy
fragile x ataxia

15

what are nonpolyglutamine diseases

non CAG repeat dynamic mut

16

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

17

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

18

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

19

what disease cause mytonic dystrohpy

mut in DMPK CTG in 3'UTR
gof
incr rna incr splicing

20

difference between fragile x and fragile x ataxia

ataxia - neurondegen with later onset

21

what common ptype of tri nuc expansion diseases

rna gof

22

what is anticipation

property of dynamic mut
symptoms of gen disorder with an early age onset

23

what is the mech of dynamic mut

slippage of okazaki fragments