Charlesworth, G;
Plagnol, V;
Holmström, KM;
Bras, J;
Sheerin, UM;
Preza, E;
Rubio-Agusti, I;
... Wood, NW; + view all
(2012)
Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis.
The American Journal of Human Genetics
, 91
(6)
1041 - 1050.
10.1016/j.ajhg.2012.10.024.
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Abstract
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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