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. © 2012 The American Society of Human Genetics.
Charlesworth, G., Plagnol, V., Holmström, K. M., Bras, J., Sheerin, U. M., Preza, E., … Wood, N. W. (2012). Mutations in ANO3 cause dominant craniocervical dystonia: Ion channel implicated in pathogenesis. American Journal of Human Genetics, 91(6), 1041–1050. https://doi.org/10.1016/j.ajhg.2012.10.024