Trinucleotide Repeat Diseases

Question 1

Name an example of a trinucleotide repeat disease

Answer 1

Huntington’s disease

Question 2

What is meant by the critical threshold?

Answer 2

There is a certain length beyond which you will have the disease

Question 3

What is meant by pre-mutation?

Answer 3

Parent has certain number of repeats. Becomes unstable when passed onto child. Parent wont have disease but child will

Question 4

What is meant by anticipation?

Answer 4

Longer the repeats, earlier the age of onset

Question 5

What is the mechanism of repeat expansion?

Answer 5

Formation of looped DNA intermediated, incorporation into DNA

Question 6

What are the variables to the mechanism of repeat expansion?

Answer 6

Coding vs non-coding repeats
Dividing vs non-dividing cells
Parent of origin

Question 7

What is a small expansion?

Answer 7

Replication-based
Very small : ~1-3 units, slippage of DNA polymerase
Small: ~55-200 units, backing up replication fork and restarting of DNA pol

Question 8

What is a large expansion?

Answer 8

Repair-based
~100-1000 unit gains
Non-diving cells

Question 9

What is the slippage model?

Answer 9

Uncoupling of Pol and Helicase as Pol slowed down by CAG repeats
“Stress” of separation causes looping out of repeats
Loop formed

Question 10

What is the model for generation of large expansions in non-dividing cells?

Answer 10

Repair of break leads to expansion

Loop arises from repair of single strand breaks during excision of damages DNA bases from nucleotide excision repair

Question 11

How do CAG expansion lead to disease?

Answer 11

Gain of toxic function

Protein misfolding and RNA toxicity