Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers

TLDR

The fragile X mental retardation‑1 (FMR1) gene contains a CGG repeat whose expansion beyond 200 repeats causes fragile X syndrome, while intermediate and premutation alleles (≈40–200 repeats) are generally thought to be non‑penetrant despite occasional subtle cognitive or psychosocial effects. Using a sensitive assay, we found that carriers exhibit FMRP levels that decline with increasing repeat number, while FMR1 mRNA is overexpressed in a repeat‑dependent manner, suggesting that the phenotypic spectrum of fragile X syndrome may need to be reconsidered.

Abstract

The 5′ untranslated CGG repeat in the fragile X mental retardation-1 (FMR1) gene is expanded in families with fragile X syndrome, with more than 200 CGGs resulting in mental retardation due to the absence of the encoded fragile X mental retardation protein (FMRP). Intermediate and premutation alleles, containing between approximately 40 and 200 repeats, express grossly normal FMRP levels and such carriers are widely believed to be non-penetrant, despite continued reports of subtle cognitive/psychosocial impairment and other phenotypes. Using a highly sensitive quantification assay, we demonstrate significantly diminished FMRP levels in carriers, negatively correlated with repeat number. Despite reduced FMRP, these carrier alleles overexpress FMR1, resulting in a positive correlation between repeat number and FMR1 message level. These biochemical deviations associated with intermediate and premutation FMR1 alleles, found in ∼4% of the population, suggest that the phenotypic spectrum of fragile X syndrome may need to be revisited.