+ Molecular Mechanisms of Repeat-mediated genome instability Flashcards
1
Q
+ Are all repeat expansions responsible for a disorder?
A
- In some REDs, a mutation other than the repeat expansion can cause the disease
2
Q
What mode of inheritance do REDs display?
A
- AR
- AD
- X-linked
3
Q
+ 2 examples of REDs where the pathology is a LOF of the carrier gene due to transcriptional defect
A
- FXXS
- Congenital insensitivity to pain
4
Q
+ What is the molecular mechanism for DM2 pathology?
A
- Toxic GOF in the RNA transcript of CNBP gene
- The toxicity is likely associated with the ability to form unusual RNA secondary structures -> they generally remain in the nucleus and sequester RNA BPs
- In the case of DM1 and DM2, these repeats sequester Muscleblind (Mbn1) proteins
5
Q
+ How are expanded poly(A) tracts pathogenic?
A
- They undergo a conformational change as length increases (short: alpha helices, long = polymeric beta sheets and coiled coils)
- This introduces novel types of protein interactions
- Commonly, proteins with poly(A) expansions co-aggregate with their WT versions, leading to ineffective haploinsufficiency -> dominant inheritance pattern
