Elevated Fmr1 mRNA levels and reduced protein expression in a mouse model with an unmethylated Fragile X full mutation
Elevated Fmr1 mRNA levels and reduced protein expression in a mouse model with an unmethylated Fragile X full mutation
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DOI：
10.1016/j.yexcr.2006.10.002
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发表时间：
2007-01-15
影响因子：
3.7
通讯作者：
Willemsen, R.
中科院分区：
文献类型：
--
作者：
Brouwer, J. R.;Mientjes, E. J.;Willemsen, R.
人FMR 1基因在其5'非翻译区含有CGG重复序列。正常群体中的重复长度是多态的（5-55个CGG重复）。超过200个CGG的突变（完全突变）通过异常甲基化和基因沉默导致FMR 1基因产物FMRP的缺失。这会导致脆性X综合征，这是最常见的遗传性精神发育迟滞。前突变的老年携带者，定义为重复长度在55和200 CGG之间，可以发展为进行性神经退行性综合征：脆性X相关震颤/共济失调综合征（FXTAS）。在FXTAS中，FMR 1 mRNA水平升高，并且已经假设FXTAS是由致病性RNA功能获得机制引起的。我们已经开发了一种携带扩展CGG重复序列（98个重复序列）的敲入小鼠模型，该模型显示重复序列不稳定性，并显示FXTAS的生化、表型和神经病理学特征。在这里，我们报告了进一步的重复不稳定性，高达230个CGG。观察到扩增偏倚，最大扩增为43个CGG单位，最大收缩为80个CGG重复。在人类中，这个长度将被认为是一个完整的突变，预计将导致基因沉默。携带长重复序列（类似于230 CGG）的小鼠显示mRNA水平升高和FMRP水平降低，但不存在异常甲基化，这表明在小鼠中模拟脆性X完全突变需要额外的重复序列或其他遗传操作。(c)2006年爱思唯尔公司All rights reserved.
The human FMR1 gene contains a CGG repeat in its 5' untranslated region. The repeat length in the normal population is polymorphic (5-55 CGG repeats). Lengths beyond 200 CGGs (full mutation) result in the absence of the FMR1 gene product, FMRP, through abnormal methylation and gene silencing. This causes Fragile X syndrome, the most common inherited form of mental retardation. Elderly carriers of the premutation, defined as a repeat length between 55 and 200 CGGs, can develop a progressive neuro degenerative syndrome: Fragile X-associated tremor/ataxia syndrome (FXTAS). In FXTAS, FMR1 mRNA levels are elevated and it has been hypothesised that FXTAS is caused by a pathogenic RNA gain-of-function mechanism. We have developed a knock in mouse model carrying an expanded CGG repeat (98 repeats), which shows repeat instability and displays biochemical, phenotypic and neuropathological characteristics of FXTAS. Here, we report further repeat instability, up to 230 CGGs. An expansion bias was observed, with the largest expansion being 43 CGG units and the largest contraction 80 CGG repeats. In humans, this length would be considered a full mutation and would be expected to result in gene silencing. Mice carrying long repeats (similar to 230 CGGs) display elevated mRNA levels and decreased FMRP levels, but absence of abnormal methylation, suggesting that modelling the Fragile X full mutation in mice requires additional repeats or other genetic manipulation. (c) 2006 Elsevier Inc. All rights reserved.