6. AD - gain of function

Question 1

What is the result of gain of function variants?

Answer 1

Increase in gene expression
Increase in length of functional lifespan
Gene developing new function

Question 2

Give 2 examples of STRs that show an AD GoF mechanism of disease

Answer 2

1. HD
   - CAG repeat translated into polyQ tract, acquires novel deleterious function –> neurodegeneration
   - evidence for GoF: deletions including HTT show no phenotype, homozygotes clinically identical to hets.
2. DM1
   - toxic RNA GoF, expansions form stable structures that recruit RNA binding proteins - affects regulation of other genes

Question 3

Describe the mechanism of disease in achondroplasia

Answer 3

FGFR3 (fibroblast growth factor) negatively regulates bone growth

Mutations in transmembrane domain activate receptor –> severely limited bone growth

99% of cases caused by Gly308Arg - enhances dimerisation of protein that catalyses downstream signalling

Question 4

Give an example of GoF disease in cancer

How is it treated?

Answer 4

BCR::ABL t(9;22)(q34;q11) in CML and ALL

Fusion gene produces abnormal tyrosine kinase with increased activity –> promotes genomic instability

Treated with tyrosine kinase inhibitors (TKIs) - Imatinib. MRD testing by RT-PCR to determine response

Question 5

What is the significance of a PMP22 duplication?

What causes it?

Answer 5

Causes CMT1A1 (30% of CMT)

Peripheral myelin protein 22 present in myelin membranes of peripheral nerves - major role in arresting division of Schwann cells

Due to NAHR during male gametogenesis