Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation
Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation
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DOI：
10.1002/ajmg.b.30241
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发表时间：
2005-11-05
影响因子：
2.8
通讯作者：
Hagerman, RJ
中科院分区：
文献类型：
--
作者：
Hessl, D;Tassone, F;Hagerman, RJ
直到最近，脆性X智力低下1（FMR 1）基因的前突变等位基因（55-200 CGG重复）的个体被认为在心理上不受影响。然而，最近的文件FMR 1 mRNA的异常升高，脆性X相关震颤/共济失调综合征（FXTAS）的发现，并在儿童和成人的精神疾病与前突变的报告提出了致病基因-脑-行为机制。在一项大型合作研究中，68名男性和144名女性FMR 1前突变完成了心理症状检查表和FMR 1基因检测，包括测定CGG重复序列大小，FMR 1蛋白（FMRP）阳性淋巴细胞的百分比和FMR 1 mRNA水平。相对于已发表的规范，男性和女性FXTAS症状报告了几种类型的心理症状水平较高。此外，具有前突变且没有明显FXTAS证据的男性和女性报告了更高水平的强迫症症状。FMR 1 mRNA升高，而不是CGG重复序列大小或FMRP减少（通过免疫细胞化学测定），与有和无FXTAS症状的突变前男性的心理症状增加显著相关，主要是强迫症状和精神病。CGG重复序列大小、FMR 1 mRNA或FMRP与前突变妇女的心理症状之间没有关系，除非样本仅限于那些X激活率偏向>50%的活性前突变等位基因的妇女。本研究的结果支持这一假设，即FMR 1功能与前突变个体的心理困难有关，并提供了与神经精神表型中RNA毒性功能获得模型一致的证据。(c)2005 Wiley-Liss，Inc.
Until recently, individuals with premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene were believed to be psychologically unaffected. However, the recent documentation of abnormal elevation of FMR1 mRNA, discovery of fragile X-associated tremor/ataxia syndrome (FXTAS), and reports of psychiatric disorders in children and adults with the premutation have suggested a pathogenic gene-brain-behavior mechanism. In a large collaborative study, 68 men and 144 women with the FMR1 premutation completed a psychological symptoms checklist and FMR1 genetic testing, including determination of CGG repeat size, percentage of FMR1 protein (FMRP)-positive lymphocytes, and FMR1 mRNA levels. Relative to published norms, men and women with FXTAS symptoms reported higher levels of several types of psychological symptoms. In addition, men and women with the premutation and no overt evidence of FXTAS reported higher levels of obsessive-compulsive symptoms. Elevated FMR1 mRNA, but not CGG repeat size or reduced FMRP (as measured by immunocytochemistry), was significantly associated with increased psychological symptoms, predominantly obsessive-compulsive symptoms and psychoticism, in premutation men with and without FXTAS symptoms. There was no relationship between CGG repeat size, FMR1 mRNA or FMRP and psychological symptoms in premutation women unless the sample was restricted to those with skewed X-activation ratio toward >50% active premutation alleles. The results of this study support the hypothesis that FMR1 function is associated with psychological difficulties in individuals with the premutation, and provide evidence concordant with an RNA toxic gain-of-function model in a neuropsychiatric phenotype. (c) 2005 Wiley-Liss, Inc.