School of Psychological Science, La Trobe University, Melbourne, VIC 3086, Australia.
Clin Genet. 2012 Jul;82(1):88-92. doi: 10.1111/j.1399-0004.2011.01675.x. Epub 2011 Apr 28.
The Fragile X syndrome is caused by a CGG repeat expansion >200 in the promoter of the Fragile X mental retardation 1 (FMR1) gene termed full mutation (FM). These alleles are silenced through methylation of the FMR1 promoter, leading to deficit of the FMR1 protein (FMRP), and neurodevelopmental changes. However, occasional FM individuals have a complete lack of methylation, and those typically have only minor deficit of FMRP levels compared with normal controls and their intelligence may be in the normal range. FM alleles are generated through expansion of the CGG repeat from the premutation (PM) range of 55-200 repeats, linked to the late onset Fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder has been attributed to a 'toxicity' of the FMR1 mRNA, which is significantly elevated in male carriers of PM alleles and of unmethylated FM alleles. This is the first report of a 65-year-old male with an unmethylated FM allele and history of alcohol abuse, who developed symptoms of FXTAS. We postulate that, although the elevation of FMR1 transcripts associated with unmethylated FM alleles have a potential to cause FXTAS, in some cases this disorder may occur through an additional effect of exposure to neurotoxicants including alcohol.
脆性 X 综合征是由脆性 X 智力低下 1 基因（FMR1）启动子中的 CGG 重复扩展>200 引起的，称为完全突变（FM）。这些等位基因通过 FMR1 启动子的甲基化沉默，导致 FMR1 蛋白（FMRP）的缺乏，并导致神经发育变化。然而，偶尔 FM 个体完全没有甲基化，与正常对照相比，这些个体的 FMRP 水平通常只有轻微的缺乏，并且他们的智力可能在正常范围内。FM 等位基因是通过 CGG 重复从 55-200 重复的前突变（PM）范围扩展产生的，与脆性 X 相关震颤/共济失调综合征（FXTAS）的迟发性相关。这种疾病归因于 FMR1 mRNA 的“毒性”，在 PM 等位基因和未甲基化的 FM 等位基因的男性携带者中，FMR1 mRNA 的水平显著升高。这是首例报道一位 65 岁的男性，他携带未甲基化的 FM 等位基因和酗酒史，出现了 FXTAS 的症状。我们推测，尽管与未甲基化的 FM 等位基因相关的 FMR1 转录本升高可能导致 FXTAS，但在某些情况下，这种疾病可能通过接触包括酒精在内的神经毒素的额外作用而发生。
