UC Davis MIND Institute, UC Davis Health, Sacramento, California, United States of America.
Department of Public Health Sciences, University of California, Davis, School of Medicine, Davis, California, United States of America.
PLoS One. 2019 Dec 31;14(12):e0226811. doi: 10.1371/journal.pone.0226811. eCollection 2019.
Fragile X syndrome, the leading heritable form of intellectual disability, is caused by hypermethylation and transcriptional silencing of large (CGG) repeat expansions (> 200 repeats) in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. As a consequence of FMR1 gene silencing, there is little or no production of FMR1 protein (FMRP), an important element in normal synaptic function. Although the absence of FMRP has long been known to be responsible for the cognitive impairment in fragile X syndrome, the relationship between FMRP level and cognitive ability (IQ) is only imprecisely understood. To address this issue, a high-throughput, fluorescence resonance energy transfer (FRET) assay has been used to quantify FMRP levels in dermal fibroblasts, and the relationship between FMRP and IQ measures was assessed by statistical analysis in a cohort of 184 individuals with CGG-repeat lengths spanning normal (< 45 CGGs) to full mutation (> 200 CGGs) repeat ranges in fibroblasts. The principal findings of the current study are twofold: i) For those with normal CGG repeats, IQ is no longer sensitive to further increases in FMRP above an FMRP threshold of ~70% of the mean FMRP level; below this threshold, IQ decreases steeply with further decreases in FMRP; and ii) For the current cohort, a mean IQ of 85 (lower bound for the normal IQ range) is attained for FMRP levels that are only ~35% of the mean FMRP level among normal CGG-repeat controls. The current results should help guide expectations for efforts to induce FMR1 gene activity and for the levels of cognitive function expected for a given range of FMRP levels.
脆性 X 综合征是遗传性智力障碍的主要形式，由脆性 X 智力低下 1 基因（FMR1）5'非翻译区中（CGG）重复扩增（> 200 个重复）的超甲基化和转录沉默引起。由于 FMR1 基因沉默，几乎没有或没有产生 FMR1 蛋白（FMRP），FMRP 是正常突触功能的重要组成部分。尽管长期以来人们一直认为 FMRP 的缺失是脆性 X 综合征认知障碍的原因，但 FMRP 水平与认知能力（智商）之间的关系仅被粗略理解。为了解决这个问题，已经使用高通量荧光共振能量转移（FRET）测定法来量化皮肤成纤维细胞中的 FMRP 水平，并通过对跨越正常（< 45 CGGs）至完全突变（> 200 CGGs）重复范围的 184 名个体的成纤维细胞中的 FMRP 与智商测量值之间的关系进行统计分析来评估该问题。当前研究的主要发现有两点：i）对于具有正常 CGG 重复的个体，智商不再对 FMRP 超过约 70％的平均 FMRP 水平的阈值进一步增加敏感；低于该阈值，智商随 FMRP 的进一步降低而急剧下降；ii）对于当前队列，FMRP 水平仅为正常 CGG 重复对照的平均 FMRP 水平的约 35％时，智商达到 85（正常智商范围的下限）。当前的结果应有助于指导人们对诱导 FMR1 基因活性的努力以及对给定范围的 FMRP 水平所期望的认知功能水平的期望。
