15. Triplet repeat disorders - gain of function

Question 1

What is the clinical phenotype of HD?

Answer 1

Motor (chorea, dystonia), progressive decline in cognitive ability, psychiatric disturbances,

Question 2

What causes HD?

Answer 2

CAG expansion in HTT exon 1

Question 3

When do expansions in HD usually occur? Why?

Answer 3

On paternal transmission

Due to increased number of meiotic divisions in spermatogenesis

Question 4

Which STRs in coding regions show a GoF mechanism of disease?

Answer 4

HD
SCAs
DRPLA
SBMA

Question 5

What proves a GoF mechanism of disease in STR disorders?

Answer 5

1. No other mutations in the gene- deletions including HTT do not cause HD
2. Expanded alleles are transcribed and transmitted
3. HD homozygotes are phenotypically identical to heterozygotes

Question 6

What theories could explain the molecular pathogenesis of GoF STRs?

Answer 6

1. Build up of toxic aggregates produces by expansion in neurones. Protein aggregates (inclusion bodies) observed in HD & SCA3 patients
2. Toxic fragments - abnormal HHT protein is substrate for proteolytic cleavage
3. Expanded proteins accumulate & interact with TFs –> disrupt transcription
4. Disruption of axonal transport

Question 7

What is the molecular pathogenesis of DM1 and DM2?

Answer 7

RNA-mediated GoF

Expansion of non-translated repeats - altered RNA function instead

Question 8

Describe the molecular pathogenesis of DM1

Answer 8

Coding region intact, CTG repeast transcribed into mRNA

mRNA folds into hairpins that accumulate - acquire toxic function by trapping MBNL1 protein

MBNL1 regulates splicing - reduction in its activity results in accumulation of embronic-specific transcripts/proteins in adult muscle

Question 9

What causes DM1?

Answer 9

CTG repeat in 3’ UTR of DMPK - expressed in heart and skeletal muscle

Question 10

When do DM1 alleles usually expand?

Answer 10

On maternal transmission

Question 11

What is the clinical phenotype of DM1?

Answer 11

Multisystem disorder

Continuum including mild, classic & congenital forms depending on expansion size

Myotonia, progressive muscle weakness & wasting, ptosis, cataracts, testicular atrophy, cardiac conduction defects

Question 12

What causes DM2?

Answer 12

Expansion of complex repeat unit in intron 1 of CNBP

No anticipation

Question 13

What is the clinical phenotype of SBMA & how is it inherited?

Answer 13

Degeneration of lower motor neurones - proximal muscle weakness & atrophy, gynecomastia

XLR

Question 14

What are the SCAs?

Answer 14

Neurodegenerative disease that affect the cerebellum

Incoordination of gait, speech, limb movements

Typically adult onset

Question 15

What therapies are under investigation for HD?

Answer 15

Antisense oligos - inhibit expanded mRNA –> reduce conc of mutant HTT

Adeno-associated vectors expressing short hairpin RNAs - reduce expression levels

Question 16

How would an allele in the intermediate range be reported?

Answer 16

Unaffected but at risk of expansion in subsequent generation, especially if patient is male