title: A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia.
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.
authors.affiliation: 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.
authors.forename: Niccolo E
authors.initials: NE
authors.lastname: Mencacci
authors.affiliation: 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.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Rubio-Agusti
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, WC1E 6BT London, UK; Centre for Nephrology, University College London, NW3 2PF London, UK.
authors.forename: Anselm
authors.initials: A
authors.lastname: Zdebik
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Asmus
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK.
authors.forename: Marthe H R
authors.initials: MH
authors.lastname: Ludtmann
authors.affiliation: 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.
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.affiliation: UCL Genetics Institute, WC1E 6BT London, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Hauser
authors.affiliation: Department of Physiology and Institute of Neurosciences Federico-Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, 18071 Granada, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Bandres-Ciga
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK.
authors.forename: Conceição
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042 Cagliari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Forabosco
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hughes
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK.
authors.forename: Marc M P
authors.initials: MM
authors.lastname: Soutar
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, CF24 4HQ Cardiff, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Peall
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
authors.forename: Huw R
authors.initials: HR
authors.lastname: Morris
authors.affiliation: 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.
authors.forename: Daniah
authors.initials: D
authors.lastname: Trabzuni
authors.affiliation: Centre for Nephrology, University College London, NW3 2PF London, UK.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Tekman
authors.affiliation: Centre for Nephrology, University College London, NW3 2PF London, UK.
authors.forename: Horia C
authors.initials: HC
authors.lastname: Stanescu
authors.affiliation: Centre for Nephrology, University College London, NW3 2PF London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
authors.forename: Miryam
authors.initials: M
authors.lastname: Carecchio
authors.affiliation: Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zorzi
authors.affiliation: Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
authors.forename: Nardo
authors.initials: N
authors.lastname: Nardocci
authors.affiliation: Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Garavaglia
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
authors.forename: Ebba
authors.initials: E
authors.lastname: Lohmann
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Weissbach
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: 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.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Pittman
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Foltynie
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK.
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK. Electronic address: k.bhatia@ucl.ac.uk.
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK. Electronic address: n.wood@ucl.ac.uk.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002874:Chromosome Mapping; D020821:Dystonic Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D059472:Exome / Q000235:genetics; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics; D005858:Germany; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics*; D017422:Sequence Analysis, DNA; D009435:Synaptic Transmission / Q000235:genetics; D006113:United Kingdom
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000600308:KCTD17 protein, human; D015221:Potassium Channels