Fragile X syndrome results from CGG trinucleotide repeat expansion in the FMR1 gene. The molecular mechanism by which expansion silences FMR1 expression is:
- A Frameshift mutation causing premature stop codon
- B Hypermethylation of the CpG island in the FMR1 promoter, silencing transcription ✓
- C Missense mutation in the RNA-binding domain of FMRP
- D Haploinsufficiency due to deletion of one FMR1 allele
Explanation
Normal FMR1 has 5-54 CGG repeats in the 5' UTR; full mutation (>200 repeats) causes hypermethylation of the adjacent CpG island in the promoter, converting it from a transcriptionally active to a silenced chromatin state, with resultant absence of FMRP (fragile X mental retardation protein). FMRP is an RNA-binding protein that regulates translation of mRNAs at synapses; its absence leads to unchecked synaptic mRNA translation and altered synaptic plasticity. Premutation alleles (55-200 repeats) do not cause methylation silencing but lead to FMR1-associated tremor/ataxia syndrome (FXTAS) in premutation males via RNA gain-of-function toxicity.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.