Exome Sequencing Reveals a Homozygous SYT14 Mutation in Adult-Onset, Autosomal-Recessive Spinocerebellar Ataxia with Psychomotor Retardation
Exome Sequencing Reveals a Homozygous SYT14 Mutation in Adult-Onset, Autosomal-Recessive Spinocerebellar Ataxia with Psychomotor Retardation
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DOI：
10.1016/j.ajhg.2011.07.012
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发表时间：
2011-08-12
影响因子：
9.8
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
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作者：
Doi, Hiroshi;Yoshida, Kunihiro;Matsumoto, Naomichi
常染色体隐性遗传性小脑共济失调(Arcas)是一种临床和遗传上的异质性疾病，其发病年龄在20岁以前，具有多种神经系统和非神经系统特征。目前，已发现20多个基因的突变，但大约一半的ARCA患者的遗传问题仍未解决。在这篇报道中，我们描述了一个日本家庭，其中两个兄弟姐妹有一种伴有精神运动发育迟缓的ARCA进展缓慢。利用全外显子测序和纯合性定位相结合的方法，我们在SYT14中发现了一个编码突触素XIV(SYT14)的纯合错义突变。用Taq Man方法对SYT14基因的表达进行分析，证实SYT14基因在人胎儿和成人脑组织以及小鼠脑(尤其是小脑)中高表达。在体外过表达系统中，突变体SYT14表现出与野生型不同的胞内定位。免疫组织化学分析清楚地表明，SYT14特异性地定位于人和小鼠小脑浦肯野细胞。Synaptoagmins与分泌小泡(包括突触小泡)的胞吐有关，这表明SYT14突变对膜运输机制的改变可能代表了与人类神经退行性疾病相关的一种独特的病理机制。
Autosomal-recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous disorders associated with diverse neurological and nonneurological features that occur before the age of 20. Currently, mutations in more than 20 genes have been identified, but approximately half of the ARCA patients remain genetically unresolved. In this report, we describe a Japanese family in which two siblings have slow progression of a type of ARCA with psychomotor retardation. Using whole-exome sequencing combined with homozygosity mapping, we identified a homozygous missense mutation in SYT14, encoding synaptotagmin XIV (SYT14). Expression analysis of the mRNA of SYT14 by a Taq Man assay confirmed that SYT14 mRNA was highly expressed in human fetal and adult brain tissue as well as in the mouse brain (especially in the cerebellum). In an in vitro overexpression system, the mutant SYT14 showed intracellular localization different from that of the wild-type. An immunohistochemical analysis clearly showed that SYT14 is specifically localized to Purkinje cells of the cerebellum in humans and mice. Synaptotagmins are associated with exocytosis of secretory vesicles (including synaptic vesicles), indicating that the alteration of the membrane-trafficking machinery by the SYT14 mutation may represent a distinct pathomechanism associated with human neurodegenerative disorders.