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

被引:361
作者
Kenneson, A
Zhang, FP
Hagedorn, CH
Warren, ST
机构
[1] Emory Univ, Sch Med, Howard Hughes Med Inst, Rollins Res Ctr, Atlanta, GA 30322 USA
[2] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA
[3] Emory Univ, Sch Med, Dept Genet, Atlanta, GA 30322 USA
[4] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA
[5] Emory Univ, Sch Med, Dept Med, Atlanta, GA 30322 USA
关键词
D O I
10.1093/hmg/10.14.1449
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 similar to4% of the population, suggest that the phenotypic spectrum of fragile X syndrome may need to be revisited.
引用
收藏
页码:1449 / 1454
页数:6
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