Journal Article

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

Aileen Kenneson, Fuping Zhang, Curt H. Hagedorn and Stephen T. Warren

in Human Molecular Genetics

Volume 10, issue 14, pages 1449-1454
Published in print July 2001 | ISSN: 0964-6906
Published online July 2001 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/10.14.1449
Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers

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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.

Journal Article.  4886 words.  Illustrated.

Subjects: Genetics and Genomics

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