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Publication Detail
Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Charlesworth G, Plagnol V, Holmström KM, Bras J, Sheerin U-M, Preza E, Rubio-Agusti I, Ryten M, Schneider SA, Stamelou M, Trabzuni D, Abramov AY, Bhatia KP, Wood NW
  • Publication date:
    07/12/2012
  • Pagination:
    1041, 1050
  • Journal:
    Am J Hum Genet
  • Volume:
    91
  • Issue:
    6
  • Status:
    Published
  • Country:
    United States
  • PII:
    S0002-9297(12)00586-1
  • Language:
    eng
  • Keywords:
    Amino Acid Sequence, Anoctamins, Base Sequence, Calcium Signaling, Chloride Channels, Corpus Striatum, Dystonia, Endoplasmic Reticulum, Exome, Female, Fibroblasts, Gene Expression Regulation, Genes, Dominant, Genetic Linkage, High-Throughput Nucleotide Sequencing, Humans, Ion Channels, Male, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Sequence Alignment, Torticollis
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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