L11 - dynamic mutations

Question 1

what are dynamic mutations

Answer 1

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

Question 2

why are they considered dynamic

Answer 2

as products continue to mut within tissues and across gen

Question 3

what diseases cause y dynamic mut

Answer 3

fragile x
huntingtons
myotonic dystrophy

Question 4

what are polyglutamine disease

Answer 4

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

Question 5

what the mol mech behind huntingtons

Answer 5

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

Question 6

what is the polyq thresholds for huntingtons

Answer 6

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

Question 7

what is the toxic aggregate hypo

Answer 7

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

Question 8

what diseases have toxic aggregates been found

Answer 8

alzheimer/parkinson

Question 9

what evidence is there for the toxic aggregate hypothesis

Answer 9

incr aggregate more severe disease ptype
block htt primer = improve symptoms in hd
number of aggreg correlate with length polq

Question 10

what evidence i there against the toxic aggregate hypo

Answer 10

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

Question 11

what therpeutic mech can pot be used based on toxi aggreg

Answer 11

rnai dec toxic synth

incr autophagy

Question 12

what mech pot cause polyglutamine diseases

Answer 12

mitochondrial dysfunction

toxic aggregate

Question 13

what evidence is there for mitochondrial dysfunction in HD

Answer 13

ca defect in hd mito

more cyto c rel form mito

Question 14

eg of nonpolyglutamine diseases

Answer 14

fragile x
myotonic dystrophy
fragile x ataxia

Question 15

what are nonpolyglutamine diseases

Answer 15

non CAG repeat dynamic mut

Question 16

what cause fragile x

Answer 16

in the FMR1 gene CGG repeats
fmr1 encodes fmrp1 a rna binding pr
the cgg full expansion results in methy of dna - off gene

Question 17

what the role of fmrp

Answer 17

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

Question 18

what cause fragile x assoc ataxia syndrome

Answer 18

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

Question 19

what disease cause mytonic dystrohpy

Answer 19

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

Question 20

difference between fragile x and fragile x ataxia

Answer 20

ataxia - neurondegen with later onset

Question 21

what common ptype of tri nuc expansion diseases

Answer 21

rna gof

Question 22

what is anticipation

Answer 22

property of dynamic mut

symptoms of gen disorder with an early age onset

Question 23

what is the mech of dynamic mut

Answer 23

slippage of okazaki fragments