14. Triplet repeat disorders - loss of function

Question 1

Which STR disorders are due to loss of function?

Answer 1

Friedreich ataxia (triplet)
Fragile X

Question 2

When do STRs expand and why?

Answer 2

During DNA replication due to slippage of the replisome

Question 3

What is meant by the term ‘anticipation’?

Answer 3

Increasing severity & early onset of symptoms in subsequent generation due to increasing expansion size

Question 4

What is somatic instability and what is its consequence?

Answer 4

Different repeat sizes in different cells

Causes phenotypic variability

Question 5

Describe the molecular pathogenesis of FRDA

Answer 5

Transcriptional silencing by:

1. Formation of abnormal DNA-RNA structures that block transcription machinery
2. R loops lead to increase in repressive chromatin marks –> recruitment of methyltransferase –> heterochromatin –> LoF

Question 6

What is the clinical phenotype of FRDA?

Answer 6

Progressive ataxia, dysarthia, muscle weakness, HCM, diabetes

Question 7

What genotype-phenotype correlation is seen in FRDA?

Answer 7

Patients with expansion + SNV (2%) have later onset and slower progression

Question 8

What treatments for FRDA are under investigation?

Answer 8

Histone deactylase inhibitors - bind to expanded RNA & block R loop formation - removes trigger for silencing

Question 9

What causes FRDA?

Answer 9

Biallelic GAA expansion in intron 1 of FXN

Or expansion + SNV