Mutations in ANO3 Cause Dominant Craniocervical Dystonia: Ion Channel Implicated in Pathogenesis
Mutations in ANO3 Cause Dominant Craniocervical Dystonia: Ion Channel Implicated in Pathogenesis
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DOI：
10.1016/j.ajhg.2012.10.024
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发表时间：
2012-12-07
影响因子：
9.8
通讯作者：
Wood, Nicholas W.
中科院分区：
文献类型：
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作者：
Charlesworth, Gavin;Plagnol, Vincent;Wood, Nicholas W.
在这项研究中，我们结合了连锁分析与两个人的全外显子组测序，以确定候选的因果变异在一个中等规模的英国亲属表现出常染色体显性遗传的颅颈肌张力障碍。随后在大量的家族性和散发性宫颈肌张力障碍病例中筛选这些候选致病变异体，导致在ANO3中鉴定出总共6个脓毒症致病突变，ANO3是一种编码预测的Ca2+门控氯离子通道的基因，我们显示其在纹状体中高度表达。在病例和对照成纤维细胞中使用Ca2+成像的功能研究表明，内质网依赖性Ca2+信号传导明显异常。我们的结论是ANO3突变是常染色体显性颅颈肌张力障碍的原因。DYT23基因座被保留为该基因的同义词。离子通道在肌张力障碍发病机制中的意义为进一步研究开辟了新的途径。
In this study, we combined linkage analysis with whole-exome sequencing of two individuals to identify candidate causal variants in a moderately-sized UK kindred exhibiting autosomal-dominant inheritance of craniocervical dystonia. Subsequent screening of these candidate causal variants in a large number of familial and sporadic cases of cervical dystonia led to the identification of a total of six putatively pathogenic mutations in ANO3, a gene encoding a predicted Ca2+-gated chloride channel that we show to be highly expressed in the striatum. Functional studies using Ca2+ imaging in case and control fibroblasts demonstrated clear abnormalities in endoplasmic-reticulum-dependent Ca2+ signaling. We conclude that mutations in ANO3 are a cause of autosomal-dominant craniocervical dystonia. The locus DYT23 has been reserved as a synonym for this gene. The implication of an ion channel in the pathogenesis of dystonia provides insights into an alternative mechanism that opens fresh avenues for further research.