Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria
Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria
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DOI：
10.1086/425985
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发表时间：
2004-12-01
影响因子：
9.8
通讯作者：
Gleeson, JG
中科院分区：
文献类型：
--
作者：
Dixon-Salazar, T;Silhavy, JL;Gleeson, JG
Joubert综合征（JS）是一种常染色体隐性遗传病，以小脑蚓发育不全、共济失调、张力低下、动眼肌失用症、新生儿呼吸异常和智力低下为特征。尽管这种情况在30年前就被描述出来了，但其分子基础仍然知之甚少。在这里，我们在JS的三个近亲家族中发现了两个移码突变和一个错义突变，其中一些患有皮质多小回症。AHI1编码Jouberin蛋白，是一个选择性剪接的信号分子，包含7个Trp-Asp （WD）重复序列，一个SH3结构域和许多SH3结合位点。该基因在胚胎后脑和前脑中表达强烈，我们的数据表明AHI1是人类小脑和皮质发育所必需的。最近描述的NPHP1突变，编码一种含有SH3结构域的蛋白，在JS合并肾病患者的一个亚群中，提示了一个共享的途径。
Joubert syndrome (JS) is an autosomal recessive disorder marked by agenesis of the cerebellar vermis, ataxia, hypotonia, oculomotor apraxia, neonatal breathing abnormalities, and mental retardation. Despite the fact that this condition was described >30 years ago, the molecular basis has remained poorly understood. Here, we identify two frameshift mutations and one missense mutation in the AHI1 gene in three consanguineous families with JS, some with cortical polymicrogyria. AHI1, encoding the Jouberin protein, is an alternatively spliced signaling molecule that contains seven Trp-Asp (WD) repeats, an SH3 domain, and numerous SH3-binding sites. The gene is expressed strongly in embryonic hindbrain and forebrain, and our data suggest that AHI1 is required for both cerebellar and cortical development in humans. The recently described mutations in NPHP1, encoding a protein containing an SH3 domain, in a subset of patients with JS plus nephronophthisis, suggest a shared pathway.