Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

BIOL312 Medical Genetics > Lecture 8: Repeat Expansion Disorders I > Flashcards

Lecture 8: Repeat Expansion Disorders I Flashcards

You may prefer our related Brainscape-certified flashcards:
Biology 101 flashcards USMLE® Step 1 flashcards
1
Q

What is genetic anticipation?

A

When a disease has earlier onset and increasing severity in later generations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the Sherman paradox?

A

An example of genetic anticipation where it was observed that there were increased number of individuals with symptoms of Fragile X Syndrome (FXS) in later generations.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is the molecular basis of genetic anticipation?

A

Expanded number of microsatellite repeats (Short tandem repeats of up to around 9-10 nucleotides)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What type of microsatellite repeat is most commonly expanded in REDs?

A

a triplicate repeat sequence

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the basic cause for Fragile X Syndrome?

A

Expanded number of CGG repeats in the 5’ untranslated region (UTR) of the FMR1 gene

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the full name of the gene lost in FXS?

A

Fragile X Messenger Ribonucleoprotein 1 (FMR1)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the product of the FMR1 gene?

A

FMRP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

True or false: expanded repeats are stable?

A

False: they are unstable

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is dynamic mutation?

A

Since expanded repeats are unstable, they can expand and contract on parental transmission and in somatic tissues (somatic instability) = this is called dynamic mutation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

True or false: Dynamic mutation can be inherited in a typical Mendelian fashion?

A

False

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

True or false: REDs can only occur in coding exons of genes to have an affect?

A

False: they can occur in:
- UTRs (E.g. FXS)
- Introns (E.g. Friedreich Ataxia)
- Exons (E.g. Huntington’s Disease)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How many human REDs have been identified?

A

over 50

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

How many different sequence repeats have been identified associated with REDs?

A

13 (so not all microsatellite repeats are associated with REDs)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How does the number of repeats correlate with (1) disease severity and (2) age of onset

A

(1) positively correlates with disease severity

(2) negatively correlates with age of onset

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the different modes of inheritance of REDs?
(there are 3)

A
  • autosomal dominant
  • autosomal recessive
  • X-linked
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the 4 mechanisms of disease for REDs?

A
  1. Expansion of non-coding repeats - leading to loss of function (lof) of gene containing the repeat
  2. Expansions of CAG coding repeats leading to gain of function and production of abnormal proteins containing expanded polyglutamine (PolyQ) fragments
  3. Expansions resulting in gain of function RNA containing an expanded repeat
  4. Expansions resulting in gain of function Repeat Associated Non-ATG (RAN) translation of repeat containing RNA to produce toxic peptides
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

REDs that involve a loss of function are inherited in which manner?

A

autosomal recessive
(or X-linked dominant if affecting sex chromosomes - such as FXS)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

REDs that involve a gain of function are inherited in which manner?

A

Dominant inheritance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

True or false: disease associated with each RED will only follow one of the four mechanisms?

A

False: the mechanisms are not mutually exclusive
(there are contributing factors from more than one mechanism in some REDs, E.g. HD)

20
Q

What does it mean that FXS is X-linked dominant?

A

Increased severity in males, females are always manifesting carriers that exhibit symptoms of the disease but typically more mildly due to random X-inactivation

21
Q

What is the commonest myogenetic cause of autism?

A

FXS

22
Q

Give 2 physical and 3 medical manifestations associated with FXS

A

Physical:
1. mild abnormal facial features (sucken eyes, large ears)
2. macroorchidism (increased testicular volume)

Medical:
1. Seizures
2. Mitral valve prolapse
3. GI problems
4. Otitis media (middle ear infections)

23
Q

What is the locus and cytogenetic nomenclature of the ‘fragile site’ associated with FXS?

A

Locus = Xq27.3
Cytogenetic nomenclature = FRAXA

24
Q

How many CGG repeats are present in the FMR1 gene associated with:
1) normal/stable repeat
2) intermediate repeat
3) Premutation repeat
4) Full FRAX mutation

A

1) normal /stable = 6-44 repeats (average 30 repeats)

2) Intermediate = 45-54 repeats (at this stage the repeat number is less stable and more susceptible to dynamic mutation but no disease associated yet)

3) Premutation = 55-200 repeats (may have symptoms related to fragile X associated disorders such as FXTAS and FXPOI)

4) Full FRAX mutation = 200 to more than 4000 repeats

25
Q

What term is used to describe females with premutation in FXS?

A

Carrier

26
Q

What is the difference between a premutation carrier and a manifesting carrier of X-linked disorders?

A

A premutation carrier does not have the full mutation that causes the disease

A manifesting carrier has the full disease causing mutation

27
Q

Why does severity of FXS vary more in females?

A

Dependent on the number of repeats as well as X-inactivation bias

28
Q

FMR1 mutation has maternal ___(1)___ bias and some paternal ___(2)___ bias

A

(1) expansion
(2) contraction

29
Q

Explain how normal CGG repeat number allows protein FMRP to be produced

A

normal mRNA produced that is translated to FMRP in embryonic stem cells and differentiated cells
- the DNA is in active euchromatin form characterised by unmethylated DNA and H3K9Ac (acetylation of Lys9 on histone 3) and H3K4Me (Methylation of Lys4 on histone 3)

30
Q

Explain how >200 CGG repeats in FXS prevent protein FMRP production

A

In embryonic stem cells, FMR1 is initially transcribed (mRNA has expanded repeats) and translated but during differentiation the expanded mRNA initiates silencing.

During differentiation of neurons, the expanded mRNA interacts back with the DNA, resulting in methylation of DNA (MeCpG) and histones (H3K9Me2) to sequester DNA into heterochromatin and prevent FMRP expression

31
Q

How does loss of FMRP function in a normal neuron?

A

FMRP normally localises to postsynaptic spaces of dendritic spines and transports target mRNAs in and out of the nucleus.
When phosphorylated = FMRP binds to and represses translation of target dendritic mRNAs.
Synaptic signals result in de-phosphorylation of FMRP to remove repression and allow synthesis of key synaptic plasticity proteins that play important roles in memory and learning.

32
Q

How does loss of FMRP lead to the FXS disorder?

A

No FMRP means there is no repression of translation of transcripts normally targeted by FMRP so proteins are abnormally and excessively expressed leading to the symptoms associated with Fragile X

33
Q

How many distinct disorders are due to CAG repeat expansion in protein-coding regions?

A

nine

34
Q

What type of disorders result from expansions in coding repeats (CAG)?

A

Dominant, gain of function disorders

35
Q

Give an example of a disorder that results from expansions in coding repeats (CAG)?

A

Huntington disease

36
Q

What is Huntington disease characterised by?

A

Neuronal degeneration

37
Q

Give 3 clinical features of huntington disease

A
  1. progressive, selective neural cell death
  2. Choreic movements
  3. Dementia
38
Q

What is the genetic basis for HD?

A

Expansion of CAG trinucleotide microsatellite repeat within the HTT gene beginning at codon 18 in exon 1 resulting in polyQ residues in the htt protein

39
Q

What is the name of the gene affected in Huntingon Disease?

A

HTT on chromosome 4

40
Q

What is the product of the HTT gene?

A

htt (hungtintin protein)

41
Q

How many CAG repeats are present in the HTT gene associated with:
1) normal allele
2) mutable normal allele (intermediate)
3) HD mutated allele with reduced penetrance
4) HD allele

A

1) normal allele = 11-26 CAG repeats

2) mutable normal allele =27-35 repeats (prone to dynamic mutation)

3) HD allele with reduced penetrance = 36-39 repeats (some people will have disease depending on other genetic factors)

4) HD allele = >39- around 250 repeats (lower number of repeats = later onset, less severe symptoms)

42
Q

Describe the expansion bias in HD?

A

Paternal expansion bias of more than 7 CAG repeats as goes down paternal line

43
Q

What can be used to estimate the repeat numbers in HD?

A

A PCR assay
- PCR primers flank repeat containing region to amplify repeat
- products separated and size of band corresponds to number of CAG repeats (i.e. bigger band = more repeats)

44
Q

What is the structure and function of wild type huntingtin protein?

A

Huntingtin mainly consists of HEAT repeats (Huntingtin, Elongation factor 3, a protein subunit of protein phosphatase 2A, and TOR1)
- it is widely expressed but has highest levels in neurons of CNS

It acts as a scaffold protein to coordinate other protein complexes
Also acts as a transcriptional regulator

45
Q

Describe the pathogenic cellular mechanisms in Huntington disease

A

N-terminal polyQ-containing fragments oligomerise, aggregate and form cytoplasmic inclusions
–> these oligomers, aggregates and inclusions impair proteostasis network, synaptic function, axonal transport and mitochondria.
- N-terminal polyQ fragments also translocate to the nucleus where they form intranuclear inclusions that impair gene transcription

46
Q

can HD be only caused by gain of function of Htt protein associated with toxicity of expanded polyQ tract?

A

No, model systems where CAG repeats are interrupted by CAA repeats (which also encode glutamine) decreased cellular toxicity even though the number of glutamines were the same
–> this means age of onset is better predicted by the length of uninterrupted CAG repeats rather than number of Qs in huntingtin protein

BIOL312 Medical Genetics (10 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions