2. Academic Validation
  3. A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia

A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia

  • Am J Hum Genet. 2015 Jun 4;96(6):938-47. doi: 10.1016/j.ajhg.2015.04.008.
Niccolo E Mencacci 1,  Ignacio Rubio-Agusti 2,  Anselm Zdebik 3,  Friedrich Asmus 4,  Marthe H R Ludtmann 5,  Mina Ryten 6,  Vincent Plagnol 7,  Ann-Kathrin Hauser 4,  Sara Bandres-Ciga 8,  Conceição Bettencourt 5,  Paola Forabosco 9,  Deborah Hughes 5,  Marc M P Soutar 5,  Kathryn Peall 10,  Huw R Morris 11,  Daniah Trabzuni 12,  Mehmet Tekman 13,  Horia C Stanescu 13,  Robert Kleta 13,  Miryam Carecchio 14,  Giovanna Zorzi 15,  Nardo Nardocci 15,  Barbara Garavaglia 16,  Ebba Lohmann 4,  Anne Weissbach 17,  Christine Klein 17,  John Hardy 18,  Alan M Pittman 18,  Thomas Foltynie 19,  Andrey Y Abramov 5,  Thomas Gasser 4,  Kailash P Bhatia 20,  Nicholas W Wood 21
Affiliations

Affiliations

  • 1 Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK; IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Universita degli Studi di Milano, 20149 Milan, Italy.
  • 2 Unidad de Trastornos del Movimiento, Hospital Universitario La Fe, 46026 Valencia, Spain; Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK.
  • 3 Department of Neuroscience, Physiology and Pharmacology, University College London, WC1E 6BT London, UK; Centre for Nephrology, University College London, NW3 2PF London, UK.
  • 4 Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
  • 5 Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK.
  • 6 Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK; Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, SE1 7EH London, UK.
  • 7 UCL Genetics Institute, WC1E 6BT London, UK.
  • 8 Department of Physiology and Institute of Neurosciences Federico-Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, 18071 Granada, Spain.
  • 9 Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042 Cagliari, Italy.
  • 10 MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, CF24 4HQ Cardiff, UK.
  • 11 Department of Clinical Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
  • 12 Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK; Department of Genetics, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
  • 13 Centre for Nephrology, University College London, NW3 2PF London, UK.
  • 14 Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
  • 15 Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
  • 16 Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
  • 17 Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.
  • 18 Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK; Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, WC1N 3BG London, UK.
  • 19 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK.
  • 20 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK. Electronic address: [email protected].
  • 21 Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK. Electronic address: [email protected].
PMID: 25983243 DOI: 10.1016/j.ajhg.2015.04.008
Abstract

Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%-50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D.

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