title: Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis.
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.
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Charlesworth
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Kira M
authors.initials: KM
authors.lastname: Holmström
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.forename: Una-Marie
authors.initials: UM
authors.lastname: Sheerin
authors.forename: Elisavet
authors.initials: E
authors.lastname: Preza
authors.forename: Ignacio
authors.initials: I
authors.lastname: Rubio-Agusti
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Schneider
authors.forename: Maria
authors.initials: M
authors.lastname: Stamelou
authors.forename: Daniah
authors.initials: D
authors.lastname: Trabzuni
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
mesh_terms: D000595:Amino Acid Sequence; D000075368:Anoctamins; D001483:Base Sequence; D020013:Calcium Signaling; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004421:Dystonia; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059472:Exome; D005260:Female; D005347:Fibroblasts; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D008040:Genetic Linkage; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D014103:Torticollis / Q000235:genetics* / Q000378:metabolism
chemical_list: C577591:ANO3 protein, human; D000075368:Anoctamins; D018118:Chloride Channels; D007473:Ion Channels