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A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia |
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| Authors: | Niccolo E Mencacci Ignacio Rubio-Agusti Anselm Zdebik Friedrich Asmus Marthe HR Ludtmann Mina Ryten Vincent Plagnol Ann-Kathrin Hauser Sara Bandres-Ciga Conceição Bettencourt Paola Forabosco Deborah Hughes Marc MP Soutar Kathryn Peall Huw R Morris Daniah Trabzuni Mehmet Tekman Horia C Stanescu Robert Kleta Miryam Carecchio Giovanna Zorzi Nardo Nardocci Barbara Garavaglia Ebba Lohmann Anne Weissbach Christine Klein John Hardy Alan M Pittman Thomas Foltynie Andrey Y Abramov Thomas Gasser Kailash P Bhatia Nicholas W Wood |
| Institution: | 1 Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK;2 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;3 Unidad de Trastornos del Movimiento, Hospital Universitario La Fe, 46026 Valencia, Spain;4 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK;5 Department of Neuroscience, Physiology and Pharmacology, University College London, WC1E 6BT London, UK;6 Centre for Nephrology, University College London, NW3 2PF London, UK;7 Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany;8 Department of Medical and Molecular Genetics, King’s College London, Guy’s Hospital, SE1 7EH London, UK;9 UCL Genetics Institute, WC1E 6BT London, UK;10 Department of Physiology and Institute of Neurosciences Federico-Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, 18071 Granada, Spain;11 Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042 Cagliari, Italy;12 MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, CF24 4HQ Cardiff, UK;13 Department of Clinical Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK;14 Department of Genetics, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia;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 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, WC1N 3BG London, UK |
| 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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