title: Mutations in HPCA cause autosomal-recessive primary isolated dystonia.
abstract: Reports of primary isolated dystonia inherited in an autosomal-recessive (AR) manner, often lumped together as "DYT2 dystonia," have appeared in the scientific literature for several decades, but no genetic cause has been identified to date. Using a combination of homozygosity mapping and whole-exome sequencing in a consanguineous kindred affected by AR isolated dystonia, we identified homozygous mutations in HPCA, a gene encoding a neuronal calcium sensor protein found almost exclusively in the brain and at particularly high levels in the striatum, as the cause of disease in this family. Subsequently, compound-heterozygous mutations in HPCA were also identified in a second independent kindred affected by AR isolated dystonia. Functional studies suggest that hippocalcin might play a role in regulating voltage-dependent calcium channels. The identification of mutations in HPCA as a cause of AR primary isolated dystonia paves the way for further studies to assess whether "DYT2 dystonia" is a genetically homogeneous condition or not.
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors: Gavin
authors: G
authors: Charlesworth
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors: Plamena R
authors: PR
authors: Angelova
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors: Fernando
authors: F
authors: Bartolomé-Robledo
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Medical and Molecular Genetics, King's College London, London WC2R 2LS, UK.
authors: Mina
authors: M
authors: Ryten
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Genetics, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
authors: Daniah
authors: D
authors: Trabzuni
authors: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Second Department of Neurology, University of Athens, Iras 39, Gerakas Attikis, Athens 15344, Greece; Movement Disorders Department, Hygeia Hospital, 4 Eyrthrou Stravou Street, Athens 15123, Greece.
authors: Maria
authors: M
authors: Stamelou
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors: Andrey Y
authors: AY
authors: Abramov
authors: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; UCL Genetics Institute, London WC1E 6BT, UK. Electronic address: k.bhatia@ucl.ac.uk.
authors: Kailash P
authors: KP
authors: Bhatia
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; UCL Genetics Institute, London WC1E 6BT, UK. Electronic address: n.wood@ucl.ac.uk.
authors: Nicholas W
authors: NW
authors: Wood
mesh_terms: D001921:Brain / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D004421:Dystonia / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D051597:Hippocalcin / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
chemical_list: D015220:Calcium Channels; C496691:HPCA protein, human; D051597:Hippocalcin