Mutations in ANO3 Cause Dominant Craniocervical Dystonia: Ion Channel Implicated in Pathogenesis

作者：Charlesworth Gavin; Plagnol Vincent; Holmstroem Kira M; Bras Jose; Sheerin Una Marie; Preza Elisavet; Rubio Agusti Ignacio; Ryten Mina; Schneider Susanne A; Stamelou Maria; Trabzuni Daniah; Abramov Andrey Y; Bhatia Kailash P^*; Wood Nicholas W

来源：American Journal of Human Genetics, 2012, 91(6): 1041-1050.

DOI：10.1016/j.ajhg.2012.10.024

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.

• 出版日期2012-12-7