Fragile X syndrome Flashcards
What is fragile X syndrome (FXS) - phenotype
- inherited intellectual disability in males & females: autism & ASD (mental impairement, learning disabilities, development delays)
- dysmorphic features: large ears, narrow face
molecular abnormality in Fragile X syndrome (FXS)
- expansion mutation in FMR1 gene (> FX mental retardation protein)
- 99% CGGn repeat in 5’ UTR of FMR1 promoter (& before FMR1 gene)
- CGG repeat either pure or interspersed w/ 9 or 10 AGGs (more stable = risk of full expansion)
What happens if the CGG expansion has >200 repeats (full mutation)
- Hypermethylation of cystosine residues of CGG repeats
= deactivation of MFR1 gene= no FMRP produced => FXS
What happens if the CGG expansion has
a) <55 repeats
b) 55-200 repeats (pre-mutation)
a) normal phenotype
b) RNA cytotoxicity = Premutation => FX primary ovarian insufficiency (FXPOI) & FX tremor axtaxia syndrome (FXTAS) & Fragile-X Neuropsychiatric Disorders (FXAND)
How can a) expansion mosiacism & b) methylation mosiacsim cause c) FXS
a) Cell pop. A has full mutation + B has pre-mutation
b) Cell pop. A has full mutation + B >200 repeats but not methylated
a) + b) = c) Low FMRP expression = FXS
Reporting & classifying no. of CGG repeats of FXS
<=44
45-54
55-200
>200
<=44: normal
45-54: Intermediate or gray zone (low risk of disease but still chance)
55-200: Premutation = FXTAS, FXPOI
>200: full mutation = FXS
*NOTE: 1 mutated X means = full effect/severe for males, heterogen. for females
What lab tests are there for detecting CGGn expansions
- PCR
- southern blot (gold std)
- Real time PCR
- repeated- prime PCR & capillary separation - ASuragen assay
FMRP functions
repressor of target mRNA translation at neural synapses = inhibit mRNA translation (for regulation)
- shuttles target mRNA through dendrites
- important in generation of synapse (during development)
Inheritance type
autosomal recessive
