Dynamic Mutation Diorders Flashcards
1
Q
What are static mutations
A
stably transmitted to offspring and retained in somatic tissues through development
2
Q
What are dynamic mutations
A
the mutations may continue to change during transmission to offspring and during tissue development (Creating mosaicssiM)
3
Q
All diseases with dynamic mutations have what kind of symptoms
A
neurological
4
Q
What sequences are dynamic
A
short tandem repeats
5
Q
What specifically is the location of the dynamic mutation disorders
A
trinucleotide/triplet repeats
6
Q
Where are trinucleotide repeats that are mutated found
A
eveywhere:exons, introns, 5’ UTR, 3’UTR
7
Q
Trinucleotide repeats loci have what
A
normal polymorphic variation in repeat length with no clincal significance
8
Q
backward slippage of trinucleotide repeat leads to what
A
expansion
9
Q
forward slippage of trinucleotide repeat leads to what
A
contraction
10
Q
what can happent o trinucleotide repeats during replciation that would lead to mutations
A
slippage
11
Q
Is expansions or contractions more likely
A
expansion
12
Q
why are expanions more likely
A
contractions do not cause phenotype (usually)
13
Q
What is MOI of fragile X syndrome
A
X linked Dominant
14
Q
What is genetic anticipation?
A
as a disease is transmitted from generation to generation it increases in severity
15
Q
How is anticipation explained
A
increase in repeat sizes occur in each generation
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
17
Q
When is anticipation observed
A
increasein clinical severity or decrease in age of onset
18
Q
The longer and more expansion, how does it affect severity
A
the more severe or earlier the age of onset
19
Q
define normal alleles
A
not associated w/ disease, stable upon transmission
20
Q
define mutable alleles
A
do not cause disease, show meiotic instability. their children at greater risk, person themself will not be affected
21
Q
define reduced penetrance alleles
A
if they show phenotype its late onset and show meiotic instability
22
Q
define disease alleles
A
associated w/ disease and full penetrance. show meitoic instability and for some other diseases also mitotic instability.
23
Q
where is trinucleotide repeat
A
can be anywhere within structure of a gene
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.
25
Expansions in coding regions generally have shorter ____ ____ and sharper _____ b/w normal and pathogenic repeat sizes
pathogenic repeats
| boundries
26
In Fragile X where is the repeat?
CGG
27
Where is repeat in Huntington?
CAG
28
Where is repeat in SCA?
CAG
29
Where is repeat in myotonic dystrophy
CTG
30
Where is repeat in Friedrich ataxia?
GAA
31
In huntington what is the bias
paternal - so it only expans when inherited from father
32
what is paternal expansion bias
genes only epand when in herited from father
33
Fragile X has what bias
CGG maternal expansion bias
34
Myotonic dystrophy has what bias?
CTG maternal expansino bias
35
cerebellar ataxias has what bias
CAG paternal expansion bias
36
How are repeat expansions measured?
PCR/gel electrophoresis
37
why would a pt only have one allele on PCR/gel?
if the repeat is too big PCR might not be able to detect
| they could also be homozygous
38
what is the limit of PCR in measuring repeats?
limited to repeats that are less than 1000 repeats
39
what is used to measure very large repeat expansions
southern blotting
40
what leads tot he phenotype in FRAXA?
loss of protein (null mutation)
41
what leads to the phenotype in FRDA
loss of protein (null mutation)
42
what is MOI of FRAXA?
X linked dominant
43
what is MOI of FRDA
AR
44
What does FRAXA stand for
Fragile X syndrome
45
what does FRDA stand for
Friedreich Ataxia
46
What causes phenotype for myotonic dystrophy
altered RNA, gain of function
47
what causes pathology of huntington?
altered protein - gain of function
48
what causes pathology of SCA?
altered protein - gain of function
49
what does SCA stand for
Spinocerebellar Ataxias
50
What is the most commonly inherited ataxia
FRDA
51
What codons are expanded in FRDA
GAA
52
what is the gene affected in FRDA?
Frataxin (FXN) - intron
53
what does FXN stand for
frataxin
54
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
FRDA
55
What has GAA repeats in Intron 1?
FRDA
56
what are the two theories for how repeat in intron causes FRDA
Repeat forms an unusual DNA structure that interferes with RNA polymerase
Repeat favors the formation of heterochromatin
57
If FRDA is not caused by GAA expansion, what is the other way it is mutated
point mutation
58
Describe how FRDA doesn't have anticipation
it's AR, is only observed in one generation
59
Fe-S centers are found where
in complexes of ETC in mitochondria
60
what organelle is affected if ataxin isn't working
mitochondria
61
below threshold how does diseae present
it will not present with phenotype
62
above threshold how does disease present
it depends on how many repeats
63
The size of which allele is important in FRDA
smaller allele
64
What is MOI in FRAXA
x-linked dominance
65
what codon has expansion in FRAXA
CGG
66
what gene has expansion in FRAA and by 5' or 3'?
5' UTR of FMR1
67
what does FMR1 stand for
fragile x mental retardation 1
68
describe how x chromosomes look in FRAXA
there's little bits on the end that look like they could break off, considered fragile sites
69
what disease is the 2nd leading cause of mental retardation?
fraxa
70
prepubertal, neurological/behavir - mental retardation, hyperacitivyt, autism spectrum, tantrums, large testes post pubertiy, flat foot smooth skin is what disease?
FRAXA
71
can females be affected by FRAXS
yes
72
describe how females are affected by FRAXA phenotypically
less severey, same physical and behavior features as maales, lower frequency & milder involvement
73
what is observed as a discontinuity of staining
the fragile site of x chromosme in fragile x
74
what part of cgg can be methylated
c in cgg can be methylated causing hypermethylation
75
are chromosmes in fragile x broken
no (but they CAN break)
76
where is the fragile x site in the chromosoems in fragile x?
near the telomere of q arm
77
what is the sherman paradox?
risk of having affected offspring increases in each generation. clinical severity increases with each generation
78
what is the sherman paradox now referred to as?
anticipation
79
how is anticipation explained?
repeat expansions
80
What is the chance a daughter of a non transmitting male will be affected?
0% - the daughter will not be affected
81
what is the chance grandson of non-transmitting male will be affected
40%
82
what is the affect a grandaughter of non-transmitting male will be affected
16%
83
exansions are only in which germline
female
84
how big can repeats get in fragile x?
huge -over 2000 repeats
85
what would you use to detect FRAXA expansion
southern blotting
86
where would you design probe in southern blotting for FRAXA?
probe outside of repeat region in a stable part, but still where it is inside of region that will be cut
87
what are the symptoms of non-transmitting males (premutation alleles)?
many do have phenotype later in life - tremor/ataxia
88
if females have premutation alleles what will their phenotype be
premature ovarian failure
89
what will have tremor/ataxia?
male with premutation alleles of fragile x
90
what will have premature ovarian failure
female with premuatation alleles of fragile x
91
what can happen to each c site in CGG?
it can be mehtylated
92
if there a lot of methylations what happens in cgg?
hypermethylation will travel to promotoer and stop gene expression
93
What is MeCP2?
it binds to hypermethylated DNA and is involved in silencing
94
what does MeCP2 stand for
methyl-bnding domain protein
95
what does Sin3 do?
corepressor complex
96
what is histone deactylase ?
it's recruited with Sin3
97
99% of FRAXA is caused by CGG expansion, if it's cuased by something else what could it be
anything that causes loss of function - like nonsesnse, missense, frameshift, whole gene deletion
98
FXTAS stands for?
fragile x associated tremor/ataxia syndrome
99
describe FXTAS
late onset
| inclusions in neurons and astrocytes throughout the brain
100
what causes FXTAS
gain of function @ RNA, increase in FMR1 mRNA
101
what is increased in FXTAS
FMR1 mRNA
102
What does FMR1 gene encode
FMRP (protein)
103
What does FMRP do
RNA-binding protein
104
FMRP binds mRNA tanscripts of multiple and genes and limits ____
translation
105
the translation of genes that FMRP that are limited b/c of it all have what in common
they are all involved in regulating the brain
106
In the absence of FMRP what happens to the proteins it limits?
increased synthesis of the proteins, disruption of cell signaling in mulctiple cell types
107
DM1 stands for what
myotonic dystophy
108
what is MOI of DM1?
AD
109
what codon has expansion in DM1?
CTG
110
What gene is affected in DM1?
3' UTR region of DMPK gene
111
where is expansion in DM1?
CTG in female germline
112
```
Myotonia, muscle wasting, weakness
Lower legs, hands, neck, face
Abnormalities on electromyography
Cataract
Hypogonadism
Frontal balding
Insulin resistance
what disease?
```
DM1
113
does DM1 display pleiotrophy?
yes
114
If CUGBP1 are upregulated what happens
things are spliced incorrectly
115
Does Friedrich Ataxia have anticipation?
none
116
98% of disease alleles with friedrich ataxia have what expansion?
GAA
117
2% of disease alleles with friedrich ataxia have what mutation?
point
118
What accumulates in mitochondria in friedrich ataxia?
iron
119
the repeat length of which allele is correlated with higher severity in friedrich ataxia
smaller allele
120
what is frataxin involved in?
heme synthesis & formation of Fe-S centers
121
In friedrich ataxia, why is the ETC and aconitase function reduced?
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
In southern blot of FXN if the smaller allele is not that small, what does that mean?
pt is more severly affected, the smaller allele is correlated to the higher severity in friedrich ataxia
123
Expanded CGG repeat creates a large what in 5' UTR
CpG island
124
What is significant beyond the CGG repeats in pts who have fragile x
the region is also methylated
125
What binds hypermethylated DNA?
methyl-binding domain protein (MeCP2)
126
What does MeCP2 stand for?
methyl-binding domain protein
127
What is the corepressor complex?
Sin3 complex w/ histone deacetylases (HDACs)
128
HDACs and other chromatin remodeling factors promote what
chromatin condensation & transcriptional repression
129
What is MBNL?
RNA-binding protein
130
MBNL & CUGBP1 have a role in what function
alternative splicing
131
The expanded RNA CUG repeats sequester what
MBNL (RNA-binding protein)
132
Does MBNL have loss or gain of function in Dm1?
loss
133
Does CUGBP1 have loss or gain of function in Dm1?
gain
134
In Dm1 RNA missplicing of multiple genes leads to what
the multisystematic presentation of the disease
135
Explain trans-dominant RNA in DM1
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
What is gene that is mutated in SCA1?
attaxin
137
WHat is MOI of huntington disease
AD
138
what does HD stand for
Huntington disesase
139
Where is repeat in HD
CAG
140
What gene is CAG repeating in Huntington disease
Huntingtin (HTT)
141
What does HTT stand for
Huntgintin
142
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?
HD
143
What is treatment for HD?
supportive, pallative, tranquilizers, antidepressers
144
How do you test for HD?
PCR/gel electrophoresis
145
Why can you use PCR/gel electrophoresis to test for HD
repeats are fairly small
146
Any allele size above 36 for CAG repeats will have what?
HD
| If it's below 36 they will not be affected
147
What is MOI for SCA
AD
148
What is onset for SCA
late onset
149
what is degenerating in SCA
cerebellum
150
All SCA exhibit what
ataxia
151
wheelchair bound w/in 20 years of diagnosis, age dependent penetrance, ataxia, slowly progressive, is what disease?
SCA
152
How many loci are involved in SCA
27
153
SCA genes with exonic CAG expansions have what structural and functional similarity
none (at least it's not obvious)
154
CAG expansion leads to what that causes pathology in SCA
gain of function
155
what is normal range of CAG repeats in the exon that would cause SCA
4-42
156
Does CAG repeats cause loss of function or gain of function of ataxin?
gain of function
157
CAG expands what tract
polyglutamine
158
when there are polyglutamine diseases the extra CAG repeats cause what?
insoluble aggregates and inclusions
159
B/w aggregates and inclusions which are the damaging ones that cause pathology?
inclusions are protective - the ones without aggregates are the neurons that have issues. soluble protein is what causes issues
160
How is Huntington protein modified
Sumo modification
161
what is sumolyation
sumo modification
162
neurons in striatum and cerebral cortex exhibit what
Rhes
163
What does Rhes promote
mHtt sumoylation preferentially over wt Htt
164
Sumo modifcation favors what
soluble form (which kills neurons)
165
Describe the potential novel therapy for HD
targets mRNA using antisense oligos ASOs which bind CAG expanded allele and trigger degradation by RNaseH
166
what disease is caused by altered mRNA function
myotonic dystrophy
167
which two have loss of function mutations?
FRDA and Fragile X
168
which two have loss of function mutations?
FRDA and Fragile X
169
In FRDA the expanded repeat interferes with what?
transcriptional elongation
170
What kind of expansions causes fragile site
CGG expansion
171
How many loci are involved in SCA?
27
172
Out of the 27 loci involved in SCA how many are involved in a CAG expansion in an exon?
7 loci
173
What is the normal range of CAG repeats in SCA?
4-42
174
What are the 6 mechanisms that might cause polyQ disease?
```
Proteolytic cleavage with toxic fragments
Proteasome impairment
Aggregate formation
Mitochondrial Dysfunction
Transcription dysregulation
RNA toxicity?
```
175
What does mutant Htt do in cells?
aggregates
176
Is the aggregate that accumulates with mutant Htt harmful to the cells?
it's not harmful in and of itself, it's actually protective
177
Explain the pathology behind how Htt causes HD
mutant Htt promotes sumo modification which favors the soluble form - the soluble form is what is actually harmful
