Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation
Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation
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DOI：
10.1038/31940
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发表时间：
1998-04-30
期刊：
影响因子：
64.8
通讯作者：
Chelly, J
中科院分区：
文献类型：
--
作者：
Billuart, P;Bienvenu, T;Chelly, J
原发性或非特异性X连锁精神发育迟滞（MRX）是一种异质性疾病，其中受影响的患者除认知障碍外，没有任何共同的独特临床或生化特征（1）。虽然它存在于大约0.15-0.3%的男性中（2），但与MRX相关的大多数遗传缺陷（可能涉及十多个不同的基因）仍然未知（3）。在这里，我们报告了X染色体长臂（位置Xq 12）上一个新基因的特征，并在不相关个体中识别出预计会导致功能丧失的不同突变。该基因在胎儿脑中高度表达，编码相对分子质量为91 K的蛋白质，命名为寡聚蛋白-1，其含有Rho-GTdR激活蛋白（rhoGAP）的典型结构域（4，5）。GAP蛋白通过增强其GT3的活性而取代小的Rho和Pas蛋白，因此rhoGAP蛋白的失活可能导致其GT3靶的组成性激活。已知这种激活影响体内细胞迁移和轴突和树突的生长（6-8）。我们的研究结果表明认知障碍和依赖于Ras样GTdR的信号通路缺陷之间存在关联。
Primary or nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which affected patients do not have any distinctive clinical or biochemical features in common apart from cognitive impairment(1). Although it is present in approximately 0.15-0.3% of males(2), most of the genetic defects associated with MRX, which may involve more than ten different genes, remain unknown(3). Here we report the characterization of a new gene on the long arm of the X-chromosome (position Xq12) and the identification in unrelated individuals of different mutations that are predicted to cause a loss of function. This gene is highly expressed in fetal brain and encodes a protein of relative molecular mass 91K, named oligophrenin-1, which contains a domain typical of a Rho-GTPase-activating protein (rhoGAP)(4,5). By enhancing their GTPase activity, GAP proteins inactivate small Rho and Pas proteins, so inactivation of rhoGAP proteins might cause constitutive activation of their GTPase targets. Such activation is known to affect cell migration and outgrowth of axons and dendrites in vivo(6-8). Our results demonstrate an association between cognitive impairment and a defect in a signalling pathway that depends on a Ras-like GTPase.