Mutations in Ano3 Cause Dominant Craniocervical Dystonia: Ion Channel Implicated in Pathogenesis.

December
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Mutations in Ano3 Cause Dominant Craniocervical Dystonia: Ion Channel Implicated in Pathogenesis.

Am J Hum Genet. 2012 Nov 27. pii: S0002-9297(12)00586-1. 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 Ca(2+)-gated chloride channel that we show to be highly expressed in the striatum. Functional studies using Ca(2+) imaging in case and control fibroblasts demonstrated clear abnormalities in endoplasmic-reticulum-dependent Ca(2+) 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.

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http://www.cell.com/AJHG/retrieve/pii/S0002929712005861