Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis

Am J Hum Genet. 2012 Dec 7;91(6):1041-50. doi: 10.1016/j.ajhg.2012.10.024. Epub 2012 Nov 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anoctamins
  • Base Sequence
  • Calcium Signaling
  • Chloride Channels / genetics*
  • Chloride Channels / metabolism
  • Corpus Striatum / metabolism
  • Dystonia
  • Endoplasmic Reticulum / metabolism
  • Exome
  • Female
  • Fibroblasts
  • Gene Expression Regulation
  • Genes, Dominant*
  • Genetic Linkage
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Ion Channels / genetics
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Phenotype
  • Sequence Alignment
  • Torticollis / genetics*
  • Torticollis / metabolism


  • ANO3 protein, human
  • Anoctamins
  • Chloride Channels
  • Ion Channels