Dixon-Salazar Tracy, Silhavy Jennifer L, Marsh Sarah E, Louie Carrie M, Scott Lesley C, Gururaj Aithala, Al-Gazali Lihadh, Al-Tawari Asma A, Kayserili Hulya, Sztriha László, Gleeson Joseph G
Laboratory for Neurogenetics, Department of Neurosciences, University of California-San Diego, La Jolla, CA 92093-0691, USA.
Am J Hum Genet. 2004 Dec;75(6):979-87. doi: 10.1086/425985. Epub 2004 Oct 4.
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.
乔布综合征（JS）是一种常染色体隐性疾病，其特征为小脑蚓部发育不全、共济失调、肌张力减退、眼球运动失用、新生儿呼吸异常和智力发育迟缓。尽管这种病症在30多年前就已被描述，但分子基础仍了解甚少。在此，我们在三个患有JS的近亲家庭中鉴定出AHI1基因的两个移码突变和一个错义突变，其中一些家庭还伴有皮质多小脑回。AHI1编码Jouberin蛋白，是一种选择性剪接的信号分子，包含七个色氨酸-天冬氨酸（WD）重复序列、一个SH3结构域和众多SH3结合位点。该基因在胚胎后脑和前脑强烈表达，我们的数据表明AHI1对人类小脑和皮质发育均是必需的。最近在一部分患有JS加肾单位肾痨的患者中描述的NPHP1突变，该基因编码一种含有SH3结构域的蛋白，提示存在一条共同途径。
