Triple Repeat Disorders

Question 1

close to or over the threshold mean

Answer 1

close to threshold - premutation

over the threshold - disease

Question 2

______ slippage on the ______ strand results in the insertion mutation called ______

Answer 2

backwards, offspring, expansion

Question 3

______ slippage on the ________ strand results in the deletion mutation called ______

Answer 3

forward, parental, shrinkage

Question 4

mechanism for triple repeat expansion

Answer 4

unequal crossing over during meiosis because strands/sister chromatids did not properly overlap each other —> 2 germ cells where one has shortened and other has expanded repetitive region

Question 5

where can triple repeats occur

Answer 5

exons, intron, UTRs, non coding RNA region

Question 6

definition: with triple nucleotide repeats, age of onset becomes early and the severity of disease increased with every generation

Answer 6

anticipation

Question 7

if TNR is in protein coding region, possibilities of what could be the consequences

Answer 7

toxic protein or gain of function

Question 8

if TNR is in RNA coding region, possibilities of what could be the consequences

Answer 8

mRNA instability, translational effects

Question 9

if TNR is in non RNA coding region, possibilities of what could be the consequences

Answer 9

transcriptional effects or interference with regulation of nearby genes

Question 10

name the syndrome: TNR repeat in the 5’ UTR, intron, exon, 3’ UTR

Answer 10

5’ UTR - fragile X (CGG)
intron - Friedreich Ataxia (GAA)
exon - Huntingtons and spinocerebellar ataxias (CAG)
3’ UTR - myotonic dystrophy (CTG)

Question 11

which one of TNR are gain or loss of function

Answer 11

gain of function - Huntingtons and spinocerebellar ataxias and myotonic dystrophy

loss of function - fragile X, Friedreich ataxia

Question 12

progressive dementia and involuntary movements

Answer 12

huntingtons

Question 13

Chorea (involuntary movements) in huntingtons is caused by

Answer 13

degeneration of basal ganglia

PS: in huntingtons there is a loss of neurons in the basal ganglia and cortex

Question 14

this polyglutamine disease has paternal anticipation

Answer 14

huntingtons

Question 15

first group to use positional cloning to identify the gene causing huntingtons

Answer 15

1983 US and Maraicabo, Venezuela researchers

Question 16

molecular diagnostic method used to identify huntingtons gene

Answer 16

RFLP and Southern blotting

found A haplotype in US and C haplotype in Venezuelan family

Question 17

why is late onset huntingtons hard to identify

Answer 17

because of age related dementia but during autopsy this can all be cleared up

Question 18

phenomenon whereby germ cells or gametes that contain expanded repeats have a selective advantage

Answer 18

meiotic drive

Question 19

huntingtons, spinocerebellar ataxia and myotonic dystrophy have what type of anticipation

Answer 19

huntingtons and spinocerebellar ataxia - paternal (male gametogenesis)
myotonic - maternal (female gametogenesis)

Question 20

range of CAG repeats that can lead to huntingtons

Answer 20

40 - >100

Question 21

proposed mechanisms that lead to huntingtons disease

Answer 21

increase in polyglutamine tract length causes huntingtons proteins to aggregate, form inclusion bodies, and behave as a toxin

abnormal huntingtons protein interact with diff transcription factor proteins hence causing disregulation of gene expression

Question 22

martin bell syndrome

Answer 22

fragile X

Question 23

most common inherited form of intellectual disability

Answer 23

fragile X

Question 24

full mutation in fragile X results in

Answer 24

methylation of FMR1 gene hence transcriptionally silencing it so FMR1 protein is absent

Question 25

number of repeats required to be normal, premutation, and diseased for fragile X

Answer 25

normal: 5 - 50
premutation: 50 - 200
disease: >200

Question 26

fragile X is more severe in what population and why

Answer 26

more severe in males because they only have one X

Question 27

expansion in CGG is through which parent

Answer 27

exclusively through mother

Question 28

triple nucleotide repeat that has insulin resistance

Answer 28

myotonic dystrophy

Question 29

autosomal recessive TNR

Answer 29

friedreich ataxia

Question 30

difference in DM1 and DM2

Answer 30

DM1 - myotonic dystrophy with triple nucleotide repeat (most common)

DM2 - myotonic dystrophy with four nucleotide repeat

Question 31

expanded repeat found in DMPK gene is thought to cause what problem

Answer 31

sequesters and cause abnormal expression of various RNA binding proteins —> global splicing alterations

Question 32

neuro degenerative disease that causes lack of muscle coordination during voluntary movements

Answer 32

Friedreich ataxia

Question 33

symptoms of friedreich ataxia

Answer 33

• ataxia and muscle weakness
• vision and hearing impairment
• scoliosis of the spine
• diabetes
• heart disorders

Question 34

common cause of death in friedreich ataxia

Answer 34

heart disease

Question 35

what is the early and late onset of friedreich ataxia

Answer 35

early - 5 to 15

late - 20 to 35

Question 36

what happens 10 to 20 years after onset of friedrich ataxia

Answer 36

persons becomes confined to a wheelchair

Question 37

mechanism of friedreich ataxia

Answer 37

formation of triplex DNA and DNA methylation of bases and histone methylation which results in formation of heterochromatin of frataxin gene

Question 38

TNR that is a muscle degenerative disease

Answer 38

spinocerebellar ataxia

Question 39

lack of coordination of hand, eyes, and speech

Answer 39

spinocerebellar ataxia

Question 40

type of inheritance is spinocerebellar ataxia

Answer 40

autosomal dominant, autosomal recessive, X linked hence has locus heterogenity

Question 41

what is so unique about spinocerebellar ataxia 8

Answer 41

CTG expansion repeat in 3’ terminal exon of a non-protein coding RNA from the SCA8gene

Question 42

what do large polyglutamine tracts affect

Answer 42

protein function, protein interaction, protein aggregation, and make cytotoxic proteins

Question 43

normal and abnormal range for myotonic dystrophy and friedreich ataxia

Answer 43

DM: 5 to 37 —> 100 to 1000

friedreich ataxia: 7 to 22 —> 200 to 900