Kenneson A, Zhang F, Hagedorn C H, Warren S T
Howard Hughes Medical Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Hum Mol Genet. 2001 Jul 1;10(14):1449-54. doi: 10.1093/hmg/10.14.1449.
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.
脆性X智力低下1（FMR1）基因5'非翻译区的CGG重复序列在脆性X综合征家族中发生扩增，超过200个CGG会因编码的脆性X智力低下蛋白（FMRP）缺失而导致智力低下。中间型和前突变等位基因含有约40至200个重复序列，其FMRP水平总体正常表达，尽管不断有报道称存在轻微认知/心理社会损害及其他表型，但人们普遍认为这些携带者没有外显症状。通过一种高度灵敏的定量检测方法，我们发现携带者体内FMRP水平显著降低，且与重复序列数量呈负相关。尽管FMRP减少，但这些携带者等位基因会使FMR1过表达，导致重复序列数量与FMR1信使水平呈正相关。在约4%的人群中发现的这些与中间型和前突变FMR1等位基因相关的生化偏差，提示可能需要重新审视脆性X综合征的表型谱。
