2. Academic Validation
  3. Mutations in HPCA cause autosomal-recessive primary isolated dystonia

Mutations in HPCA cause autosomal-recessive primary isolated dystonia

  • Am J Hum Genet. 2015 Apr 2;96(4):657-65. doi: 10.1016/j.ajhg.2015.02.007.
Gavin Charlesworth 1,  Plamena R Angelova 1,  Fernando Bartolomé-Robledo 1,  Mina Ryten 2,  Daniah Trabzuni 3,  Maria Stamelou 4,  Andrey Y Abramov 1,  Kailash P Bhatia 5,  Nicholas W Wood 6
Affiliations

Affiliations

  • 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
  • 2 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.
  • 3 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.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 25799108 DOI: 10.1016/j.ajhg.2015.02.007
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.

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