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MCB1 Block 4 > Dynamic Mutation Diorders > Flashcards

Dynamic Mutation Diorders Flashcards

1
Q

What are static mutations

A

stably transmitted to offspring and retained in somatic tissues through development

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2
Q

What are dynamic mutations

A

the mutations may continue to change during transmission to offspring and during tissue development (Creating mosaicssiM)

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3
Q

All diseases with dynamic mutations have what kind of symptoms

A

neurological

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4
Q

What sequences are dynamic

A

short tandem repeats

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5
Q

What specifically is the location of the dynamic mutation disorders

A

trinucleotide/triplet repeats

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6
Q

Where are trinucleotide repeats that are mutated found

A

eveywhere:exons, introns, 5’ UTR, 3’UTR

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7
Q

Trinucleotide repeats loci have what

A

normal polymorphic variation in repeat length with no clincal significance

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8
Q

backward slippage of trinucleotide repeat leads to what

A

expansion

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9
Q

forward slippage of trinucleotide repeat leads to what

A

contraction

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10
Q

what can happent o trinucleotide repeats during replciation that would lead to mutations

A

slippage

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11
Q

Is expansions or contractions more likely

A

expansion

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12
Q

why are expanions more likely

A

contractions do not cause phenotype (usually)

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13
Q

What is MOI of fragile X syndrome

A

X linked Dominant

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14
Q

What is genetic anticipation?

A

as a disease is transmitted from generation to generation it increases in severity

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15
Q

How is anticipation explained

A

increase in repeat sizes occur in each generation

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16
Q

for two alleles the top number and bottom number represent what in regards to dynamic mutations

A

top number is the number of repeats on normal allele

bottom number is number of repeats on disease allele

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17
Q

When is anticipation observed

A

increasein clinical severity or decrease in age of onset

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18
Q

The longer and more expansion, how does it affect severity

A

the more severe or earlier the age of onset

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19
Q

define normal alleles

A

not associated w/ disease, stable upon transmission

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20
Q

define mutable alleles

A

do not cause disease, show meiotic instability. their children at greater risk, person themself will not be affected

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21
Q

define reduced penetrance alleles

A

if they show phenotype its late onset and show meiotic instability

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22
Q

define disease alleles

A

associated w/ disease and full penetrance. show meitoic instability and for some other diseases also mitotic instability.

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23
Q

where is trinucleotide repeat

A

can be anywhere within structure of a gene

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24
Q

In exons what codon will mutation be in?

A

CAG - glutamine, always polyglutamine track and in diseaes it gets much longer which relates to pathology of disease.

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25
Q

Expansions in coding regions generally have shorter ____ ____ and sharper _____ b/w normal and pathogenic repeat sizes

A

pathogenic repeats

boundries

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26
Q

In Fragile X where is the repeat?

A

CGG

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27
Q

Where is repeat in Huntington?

A

CAG

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28
Q

Where is repeat in SCA?

A

CAG

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29
Q

Where is repeat in myotonic dystrophy

A

CTG

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30
Q

Where is repeat in Friedrich ataxia?

A

GAA

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31
Q

In huntington what is the bias

A

paternal - so it only expans when inherited from father

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32
Q

what is paternal expansion bias

A

genes only epand when in herited from father

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33
Q

Fragile X has what bias

A

CGG maternal expansion bias

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34
Q

Myotonic dystrophy has what bias?

A

CTG maternal expansino bias

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35
Q

cerebellar ataxias has what bias

A

CAG paternal expansion bias

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36
Q

How are repeat expansions measured?

A

PCR/gel electrophoresis

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37
Q

why would a pt only have one allele on PCR/gel?

A

if the repeat is too big PCR might not be able to detect

they could also be homozygous

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38
Q

what is the limit of PCR in measuring repeats?

A

limited to repeats that are less than 1000 repeats

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39
Q

what is used to measure very large repeat expansions

A

southern blotting

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40
Q

what leads tot he phenotype in FRAXA?

A

loss of protein (null mutation)

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41
Q

what leads to the phenotype in FRDA

A

loss of protein (null mutation)

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42
Q

what is MOI of FRAXA?

A

X linked dominant

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43
Q

what is MOI of FRDA

A

AR

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44
Q

What does FRAXA stand for

A

Fragile X syndrome

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45
Q

what does FRDA stand for

A

Friedreich Ataxia

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46
Q

What causes phenotype for myotonic dystrophy

A

altered RNA, gain of function

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47
Q

what causes pathology of huntington?

A

altered protein - gain of function

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48
Q

what causes pathology of SCA?

A

altered protein - gain of function

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49
Q

what does SCA stand for

A

Spinocerebellar Ataxias

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50
Q

What is the most commonly inherited ataxia

A

FRDA

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51
Q

What codons are expanded in FRDA

A

GAA

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52
Q

what is the gene affected in FRDA?

A

Frataxin (FXN) - intron

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53
Q

what does FXN stand for

A

frataxin

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54
Q

Neurodegeneration, Vision, hearing, speech problems, Muscle weakness, Spine Curvature, Diabetes, Progressive heart condition, Diagnosis: aged 5-15
Require a wheelchair by 20s is what disease

A

FRDA

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55
Q

What has GAA repeats in Intron 1?

A

FRDA

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56
Q

what are the two theories for how repeat in intron causes FRDA

A

Repeat forms an unusual DNA structure that interferes with RNA polymerase
Repeat favors the formation of heterochromatin

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57
Q

If FRDA is not caused by GAA expansion, what is the other way it is mutated

A

point mutation

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58
Q

Describe how FRDA doesn’t have anticipation

A

it’s AR, is only observed in one generation

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59
Q

Fe-S centers are found where

A

in complexes of ETC in mitochondria

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60
Q

what organelle is affected if ataxin isn’t working

A

mitochondria

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61
Q

below threshold how does diseae present

A

it will not present with phenotype

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62
Q

above threshold how does disease present

A

it depends on how many repeats

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63
Q

The size of which allele is important in FRDA

A

smaller allele

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64
Q

What is MOI in FRAXA

A

x-linked dominance

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65
Q

what codon has expansion in FRAXA

A

CGG

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66
Q

what gene has expansion in FRAA and by 5’ or 3’?

A

5’ UTR of FMR1

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67
Q

what does FMR1 stand for

A

fragile x mental retardation 1

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68
Q

describe how x chromosomes look in FRAXA

A

there’s little bits on the end that look like they could break off, considered fragile sites

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69
Q

what disease is the 2nd leading cause of mental retardation?

A

fraxa

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70
Q

prepubertal, neurological/behavir - mental retardation, hyperacitivyt, autism spectrum, tantrums, large testes post pubertiy, flat foot smooth skin is what disease?

A

FRAXA

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71
Q

can females be affected by FRAXS

A

yes

72
Q

describe how females are affected by FRAXA phenotypically

A

less severey, same physical and behavior features as maales, lower frequency & milder involvement

73
Q

what is observed as a discontinuity of staining

A

the fragile site of x chromosme in fragile x

74
Q

what part of cgg can be methylated

A

c in cgg can be methylated causing hypermethylation

75
Q

are chromosmes in fragile x broken

A

no (but they CAN break)

76
Q

where is the fragile x site in the chromosoems in fragile x?

A

near the telomere of q arm

77
Q

what is the sherman paradox?

A

risk of having affected offspring increases in each generation. clinical severity increases with each generation

78
Q

what is the sherman paradox now referred to as?

A

anticipation

79
Q

how is anticipation explained?

A

repeat expansions

80
Q

What is the chance a daughter of a non transmitting male will be affected?

A

0% - the daughter will not be affected

81
Q

what is the chance grandson of non-transmitting male will be affected

A

40%

82
Q

what is the affect a grandaughter of non-transmitting male will be affected

A

16%

83
Q

exansions are only in which germline

A

female

84
Q

how big can repeats get in fragile x?

A

huge -over 2000 repeats

85
Q

what would you use to detect FRAXA expansion

A

southern blotting

86
Q

where would you design probe in southern blotting for FRAXA?

A

probe outside of repeat region in a stable part, but still where it is inside of region that will be cut

87
Q

what are the symptoms of non-transmitting males (premutation alleles)?

A

many do have phenotype later in life - tremor/ataxia

88
Q

if females have premutation alleles what will their phenotype be

A

premature ovarian failure

89
Q

what will have tremor/ataxia?

A

male with premutation alleles of fragile x

90
Q

what will have premature ovarian failure

A

female with premuatation alleles of fragile x

91
Q

what can happen to each c site in CGG?

A

it can be mehtylated

92
Q

if there a lot of methylations what happens in cgg?

A

hypermethylation will travel to promotoer and stop gene expression

93
Q

What is MeCP2?

A

it binds to hypermethylated DNA and is involved in silencing

94
Q

what does MeCP2 stand for

A

methyl-bnding domain protein

95
Q

what does Sin3 do?

A

corepressor complex

96
Q

what is histone deactylase ?

A

it’s recruited with Sin3

97
Q

99% of FRAXA is caused by CGG expansion, if it’s cuased by something else what could it be

A

anything that causes loss of function - like nonsesnse, missense, frameshift, whole gene deletion

98
Q

FXTAS stands for?

A

fragile x associated tremor/ataxia syndrome

99
Q

describe FXTAS

A

late onset

inclusions in neurons and astrocytes throughout the brain

100
Q

what causes FXTAS

A

gain of function @ RNA, increase in FMR1 mRNA

101
Q

what is increased in FXTAS

A

FMR1 mRNA

102
Q

What does FMR1 gene encode

A

FMRP (protein)

103
Q

What does FMRP do

A

RNA-binding protein

104
Q

FMRP binds mRNA tanscripts of multiple and genes and limits ____

A

translation

105
Q

the translation of genes that FMRP that are limited b/c of it all have what in common

A

they are all involved in regulating the brain

106
Q

In the absence of FMRP what happens to the proteins it limits?

A

increased synthesis of the proteins, disruption of cell signaling in mulctiple cell types

107
Q

DM1 stands for what

A

myotonic dystophy

108
Q

what is MOI of DM1?

A

AD

109
Q

what codon has expansion in DM1?

A

CTG

110
Q

What gene is affected in DM1?

A

3’ UTR region of DMPK gene

111
Q

where is expansion in DM1?

A

CTG in female germline

112
Q 
Myotonia, muscle wasting, weakness
Lower legs, hands, neck, face
Abnormalities on electromyography
Cataract
Hypogonadism
Frontal balding
Insulin resistance
what disease?
A

DM1

113
Q

does DM1 display pleiotrophy?

A

yes

114
Q

If CUGBP1 are upregulated what happens

A

things are spliced incorrectly

115
Q

Does Friedrich Ataxia have anticipation?

A

none

116
Q

98% of disease alleles with friedrich ataxia have what expansion?

A

GAA

117
Q

2% of disease alleles with friedrich ataxia have what mutation?

A

point

118
Q

What accumulates in mitochondria in friedrich ataxia?

A

iron

119
Q

the repeat length of which allele is correlated with higher severity in friedrich ataxia

A

smaller allele

120
Q

what is frataxin involved in?

A

heme synthesis & formation of Fe-S centers

121
Q

In friedrich ataxia, why is the ETC and aconitase function reduced?

A

the frataxin gene which doesn’t function correctly in friedrich ataxia is involved in heme and Fe-S centers which are both important for ETC

122
Q

In southern blot of FXN if the smaller allele is not that small, what does that mean?

A

pt is more severly affected, the smaller allele is correlated to the higher severity in friedrich ataxia

123
Q

Expanded CGG repeat creates a large what in 5’ UTR

A

CpG island

124
Q

What is significant beyond the CGG repeats in pts who have fragile x

A

the region is also methylated

125
Q

What binds hypermethylated DNA?

A

methyl-binding domain protein (MeCP2)

126
Q

What does MeCP2 stand for?

A

methyl-binding domain protein

127
Q

What is the corepressor complex?

A

Sin3 complex w/ histone deacetylases (HDACs)

128
Q

HDACs and other chromatin remodeling factors promote what

A

chromatin condensation & transcriptional repression

129
Q

What is MBNL?

A

RNA-binding protein

130
Q

MBNL & CUGBP1 have a role in what function

A

alternative splicing

131
Q

The expanded RNA CUG repeats sequester what

A

MBNL (RNA-binding protein)

132
Q

Does MBNL have loss or gain of function in Dm1?

A

loss

133
Q

Does CUGBP1 have loss or gain of function in Dm1?

A

gain

134
Q

In Dm1 RNA missplicing of multiple genes leads to what

A

the multisystematic presentation of the disease

135
Q

Explain trans-dominant RNA in DM1

A

trans-dominant RNA

I believe it’s like a dominant affect b/c mutation in one RNA affects a bunch of different genes - pleiotropy

136
Q

What is gene that is mutated in SCA1?

A

attaxin

137
Q

WHat is MOI of huntington disease

A

AD

138
Q

what does HD stand for

A

Huntington disesase

139
Q

Where is repeat in HD

A

CAG

140
Q

What gene is CAG repeating in Huntington disease

A

Huntingtin (HTT)

141
Q

What does HTT stand for

A

Huntgintin

142
Q

degeneration of neurons in striatum and cerebral cortex, depression, chorea, difficulty walking speaking, swallowing, late onset, death about 15 years after diagnosis, cognitive decline is what disease?

A

HD

143
Q

What is treatment for HD?

A

supportive, pallative, tranquilizers, antidepressers

144
Q

How do you test for HD?

A

PCR/gel electrophoresis

145
Q

Why can you use PCR/gel electrophoresis to test for HD

A

repeats are fairly small

146
Q

Any allele size above 36 for CAG repeats will have what?

A

HD

If it’s below 36 they will not be affected

147
Q

What is MOI for SCA

A

AD

148
Q

What is onset for SCA

A

late onset

149
Q

what is degenerating in SCA

A

cerebellum

150
Q

All SCA exhibit what

A

ataxia

151
Q

wheelchair bound w/in 20 years of diagnosis, age dependent penetrance, ataxia, slowly progressive, is what disease?

A

SCA

152
Q

How many loci are involved in SCA

A

27

153
Q

SCA genes with exonic CAG expansions have what structural and functional similarity

A

none (at least it’s not obvious)

154
Q

CAG expansion leads to what that causes pathology in SCA

A

gain of function

155
Q

what is normal range of CAG repeats in the exon that would cause SCA

A

4-42

156
Q

Does CAG repeats cause loss of function or gain of function of ataxin?

A

gain of function

157
Q

CAG expands what tract

A

polyglutamine

158
Q

when there are polyglutamine diseases the extra CAG repeats cause what?

A

insoluble aggregates and inclusions

159
Q

B/w aggregates and inclusions which are the damaging ones that cause pathology?

A

inclusions are protective - the ones without aggregates are the neurons that have issues. soluble protein is what causes issues

160
Q

How is Huntington protein modified

A

Sumo modification

161
Q

what is sumolyation

A

sumo modification

162
Q

neurons in striatum and cerebral cortex exhibit what

A

Rhes

163
Q

What does Rhes promote

A

mHtt sumoylation preferentially over wt Htt

164
Q

Sumo modifcation favors what

A

soluble form (which kills neurons)

165
Q

Describe the potential novel therapy for HD

A

targets mRNA using antisense oligos ASOs which bind CAG expanded allele and trigger degradation by RNaseH

166
Q

what disease is caused by altered mRNA function

A

myotonic dystrophy

167
Q

which two have loss of function mutations?

A

FRDA and Fragile X

168
Q

which two have loss of function mutations?

A

FRDA and Fragile X

169
Q

In FRDA the expanded repeat interferes with what?

A

transcriptional elongation

170
Q

What kind of expansions causes fragile site

A

CGG expansion

171
Q

How many loci are involved in SCA?

A

27

172
Q

Out of the 27 loci involved in SCA how many are involved in a CAG expansion in an exon?

A

7 loci

173
Q

What is the normal range of CAG repeats in SCA?

A

4-42

174
Q

What are the 6 mechanisms that might cause polyQ disease?

A 
Proteolytic cleavage with toxic fragments
Proteasome impairment
Aggregate formation
Mitochondrial Dysfunction
Transcription dysregulation
RNA toxicity?
175
Q

What does mutant Htt do in cells?

A

aggregates

176
Q

Is the aggregate that accumulates with mutant Htt harmful to the cells?

A

it’s not harmful in and of itself, it’s actually protective

177
Q

Explain the pathology behind how Htt causes HD

A

mutant Htt promotes sumo modification which favors the soluble form - the soluble form is what is actually harmful

MCB1 Block 4 (17 decks)

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