title: Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers.
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 approximately 4% of the population, suggest that the phenotypic spectrum of fragile X syndrome may need to be revisited.
authors.affiliation: Howard Hughes Medical Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kenneson
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: C H
authors.initials: CH
authors.lastname: Hagedorn
authors.forename: S T
authors.initials: ST
authors.lastname: Warren
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D001681:Biological Assay / Q000379:methods; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics*; D008040:Genetic Linkage; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics*; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013223:Statistics as Topic; D014158:Transcription, Genetic; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human