Human Molecular Genetics, 2001, Vol. 10, No. 14 1449-1454
© 2001 Oxford University Press
Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers
Howard Hughes Medical Institute and Department of Biochemistry, Department of Genetics and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA and 1Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
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.
+ To whom correspondence should be addressed at: Howard Hughes Medical Institute, Emory University School of Medicine, 1510 Clifton Road, Room 4035, Rollins Research Center, Atlanta, GA 30322, USA. Tel: +1 404 727 5979; Fax: +1 404 727 5408; Email: swarren@emory.edu
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