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

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 frag ile X mental retardation protein (FMRP). Intermediate and premutation allel es, containing between approximately 40 and 200 repeats, express grossly no rmal 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 demonst rate significantly diminished FMRP levels in carriers, negatively correlate d with repeat number. Despite reduced FMRP, these carrier alleles overexpre ss FMR1, resulting in a positive correlation between repeat number and FMR1 message level. These biochemical deviations associated with intermediate a nd premutation FMR1 alleles, found in similar to4% of the population, sugge st that the phenotypic spectrum of fragile X syndrome may need to be revisi ted.