A. Kenneson et al., Reduced FMRP and increased FMR1 transcription is proportionally associatedwith CGG repeat number in intermediate-length and premutation carriers, HUM MOL GEN, 10(14), 2001, pp. 1449-1454
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.