9. Fragile X and FMR1 related disorders

Question 1

What does FMR1 encode? What is its role?

Answer 1

FMRP (RNA binding protein) - present in brain, testes, ovaries

Regulates translation of proteins involved in the maintenance and regulation of synapses

Question 2

What causes FMR1-related disorders?
What are the disease repeat ranges?

Answer 2

CGG expansion in 5’ UTR

Fragile X:
>200 repeats

FXTAS and POI:
Premutations (55-200 repeats)

Question 3

Describe the Fragile X phenotype

Answer 3

Most common single gene cause of LD

Males - moderate/severe ID, macro-orchidism, characteristic appearance

Females - Variable phenotype, normal to mild/mod ID due to skewed X-inactivation

Question 4

Describe the POI phenotype and the cause

Answer 4

Caused by FMR1 premutations, low penetrance

Hypergonadotropic hypogonadism before age 40

Cessation of menses before 40, earlier menopause

Question 5

Describe the FXTAS phenotype and the cause

Answer 5

Occurs in some patients with premutation

Low penetrance

More common in males

Late onset cerebellar ataxia and tremor, onset and severity correlated with repeat length

Question 6

What FMR1 repeat sizes are unstable on transmission? What else effects stability?

Answer 6

Premutations (55-200) and some intermediate alleles (45-54)

Increasing size = less stable
More AGG interruptions = more stable

Question 7

What is the mechanism of disease in Fragile X?

Answer 7

> 200 repeats causes gene silencing due to hypermethylation of FRM1 promoter

Question 8

What is the mechanism of disease in FXTAS & FXPOI?

Answer 8

Premutations (55-200 repeats) = not due to lack of FMRP caused by full expansion - instead, excess FMR1 mRNA - toxic GoF

Question 9

How are FMR1 related disorders tested for?

Answer 9

Amplidex - TP-PCR + methylation

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Question 10

What is somatic instability and what is the consequence of it?

Answer 10

Different repeat sizes in different cells

Causes phenotypic variability