fragile X mental retardation
Image Gallery
Etiology
Fragile X syndrome (FXS) is almost always caused by silencing of the FMR1 gene.
- Expansion of a CGG repeat in the 5’ untranslated region of the fragile X mental retardation 1 gene (FMR1). This polymorphic CGG triplet repeat results in silencing of FMR1 expression. This expansion triggers methylation of FMR1’s CpG island, hypoacetylation of associated histones, and chromatin condensation, all characteristics of a transcriptionally inactive gene.
Pathogeny
In fragile-X syndrome, there are 250 to 4000 tandem repeats of the sequence CGG within a gene called FMR-1. In normal populations, the number of repeats is small, averaging 29.
Such expansions of the trinucleotide sequences prevent normal expression of the FMR-1 gene, thus giving rise to mental retardation. Another distinguishing feature of trinucleotide repeat mutations is that they are dynamic (i.e., the degree of amplification increases during gametogenesis).
References
Bagni C, Greenough WT. From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nat Rev Neurosci. 2005 May;6(5):376-87. PMID: 15861180
Jin P, Warren ST. Understanding the molecular basis of fragile X syndrome. Hum Mol Genet. 2000 Apr 12;9(6):901-8. PMID: 10767313