Repeat expansion disorders

Question 1

Repeat expansion diseases

Answer 1

50 REDs
Number of repeats positively correlates with disease severity and negatively correlates with age of onset
Can be autosomal recessive/dominant and x-linked

Question 2

Dynamic mutation

Answer 2

Threshold number of repeats
Below threshold, the repeats are stably inherited
Above threshold, repeats show intergenerational and somatic instability

Question 3

Fragile X syndrome

Answer 3

Expansion of non-coding repeat leads to loss of protein function
X-linked dominant
Mild abnormal facial features
Increased severity in males
Mild in females (X inactivation)
Maternal expansion

Question 4

FRAXA site

Answer 4

CGG repeat expansion in 5’ UTR of FMR1 gene on X chromosome
6-44 repeats is stable
45-54 is intermediate
55-200 is premutation (carrier)
200 to 4000 repeats is full FRAX mutation

Question 5

FMRP

Answer 5

Localised to postsynaptic spaces of dendritic spines
Phosphorylated FMRP represses translation of target dendritic mRNAs
Loss of FMRP in FXS, so excessive translation

Question 6

Huntington disease

Answer 6

Neuronal degeneration
Expansion of CAG trinucleotide repeat in HTT gene (encodes huntingtin htt).
Normal allele has 11-26 CAG repeats
Mutable normal allele has 27-35
HD allele with reduced penetrance has 36-39
HD allele has 39 to 250
Paternal expansion bias

Question 7

mutant htt protein

Answer 7

Wild type acts as a scaffold to coordinate protein complexes and as a transcriptional regulator
Mutant protein has abnormal conformation, post-translational modification and caspase cleavage to N-terminal fragments

Question 8

Effects of htt mutant

Answer 8

htt is cleaved to generate toxic fragments (inhibit chaperones, proteasomes and autophagy in the cytoplasm) leading to accumulation of abnormally folded proteins
NH2-terminal polyQ fragments accumulate in cytoplasm and cause mitochondrial dysfunction and impaired calcium signalling
Fragments translocate to nucleus and impair transcription
Mutant alters vesicular transport and recycling

Question 9

HD age of onset

Answer 9

Variability in age of onset is primarily caused by repeat length (50-70% of variants)
Variation may also be affected by environment and modifying genes