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Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities

D. Steel, M. Zech, C. Zhao, KES. Barwick, D. Burke, D. Demailly, KR. Kumar, G. Zorzi, N. Nardocci, R. Kaiyrzhanov, M. Wagner, A. Iuso, R. Berutti, M. Škorvánek, J. Necpál, R. Davis, S. Wiethoff, K. Mankad, S. Sudhakar, A. Ferrini, S. Sharma, EJ....

. 2020 ; 88 (5) : 867-877. [pub] 20200921

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20027658

Grantová podpora
Medical Research Council - United Kingdom
Cancer Research UK - United Kingdom
Wellcome Trust - United Kingdom
Department of Health - United Kingdom

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.

Department of Child Neurology Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Department of Clinical Genetics St George's Hospital London UK

Department of Developmental Neurosciences UCL Great Ormond Street Institute of Child Health London UK

Department of Developmental Neurosciences UCL Great Ormond Street Institute of Child Health London UK Department of Neurology Great Ormond Street Hospital London UK

Department of Histopathology Great Ormond Street Hospital for Children London UK

Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands

Department of Neurogenetics Kolling Institute of Medical Research University of Sydney and Northern Sydney Local Health District Sydney New South Wales Australia Molecular Medicine Laboratory Concord Repatriation General Hospital Concord New South Wales Australia Translational Genomics Kinghorn Centre for Clinical Genomics Garvan Institute for Medical Research Sydney New South Wales Australia Department of Neurogenetics University of Sydney and Northern Sydney Local Health District Sydney New South Wales Australia

Department of Neurogenetics Kolling Institute of Medical Research University of Sydney and Northern Sydney Local Health District Sydney New South Wales Australia Translational Genomics Kinghorn Centre for Clinical Genomics Garvan Institute for Medical Research Sydney New South Wales Australia Department of Neurogenetics University of Sydney and Northern Sydney Local Health District Sydney New South Wales Australia

Department of Neurogenetics Kolling Institute of Medical Research University of Sydney and Northern Sydney Local Health District Sydney New South Wales Australia Translational Genomics Kinghorn Centre for Clinical Genomics Garvan Institute for Medical Research Sydney New South Wales Australia Department of Neurogenetics University of Sydney and Northern Sydney Local Health District Sydney New South Wales Australia Department of Neurology Royal North Shore Hospital Northern Sydney Local Health District Sydney New South Wales Australia

Department of Neurology and Clinical Neurophysiology Children's Health Ireland at Temple Street Dublin Ireland UCD School of Medicine and Medical Science University College Dublin Dublin Ireland

Department of Neurology and Epileptology Children's Memorial Health Institute Warsaw Poland

Department of Neurology Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Neurology Ludwig Maximilian University Munich Germany

Department of Neurology Medical University Innsbruck Innsbruck Austria

Department of Neurology P J Safarik University Kosice Slovak Republic Department of Neurology University Hospital of L Pasteur Kosice Slovak Republic

Department of Neurology St George's Hospital London UK

Department of Neurology St Vincent's Hospital Sydney Australia

Department of Neurology University Medical Center Göttingen Göttingen Germany

Department of Neurology University of Groningen University Medical Center Groningen Groningen The Netherlands

Department of Neurology University of Groningen University Medical Center Groningen Groningen The Netherlands Expertise Center Movement Disorders Groningen University Medical Center Groningen Groningen The Netherlands

Department of Neurology Zvolen Hospital Zvolen Slovakia

Department of Neuromuscular Diseases University College London Queen Square Institute of Neurology London UK

Department of Pediatrics and Adolescent Medicine Division of General Pediatrics Medical University of Graz Graz Austria

Department of Radiology Great Ormond Street Hospital for Children London UK

Enzyme Laboratory Great Ormond Street Hospital for Children London UK

Expertise Center Movement Disorders Groningen University Medical Center Groningen Groningen The Netherlands Department of Genetics University of Groningen University Medical Center Groningen Groningen The Netherlands

Genetics and Genomic Medicine UCL Great Ormond Street Institute of Child Health London UK

Genomics England London UK

Institute of Human Genetics Technical University of Munich Munich Germany

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany Institute of Human Genetics Technical University of Munich Munich Germany

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany Institute of Human Genetics Technical University of Munich Munich Germany Lehrstuhl für Neurogenetik Technische Universität München Munich Germany Munich Cluster for Systems Neurology Munich Germany

Ken and Ruth Davee Department of Neurology Northwestern University Feinberg School of Medicine Chicago IL USA

Klinik und Poliklinik für Neurologie Klinikum rechts der Isar Technische Universität München Munich Germany

Neurology Division Department of Pediatrics Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital New Delhi India

UCL Queen Square Institute of Neurology London UK

UCL Queen Square Institute of Neurology London UK Department of Neurodegenerative Disease Hertie Institute for Clinical Brain Research and Center for Neurology University of Tübingen Tübingen Germany

Unités des Pathologies Cérébrales Résistantes Département de Neurochirurgie Centre Hospitalier Universitaire Montpellier France

University of Cardiff Cardiff Wales UK

Citace poskytuje Crossref.org

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$a Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities / $c D. Steel, M. Zech, C. Zhao, KES. Barwick, D. Burke, D. Demailly, KR. Kumar, G. Zorzi, N. Nardocci, R. Kaiyrzhanov, M. Wagner, A. Iuso, R. Berutti, M. Škorvánek, J. Necpál, R. Davis, S. Wiethoff, K. Mankad, S. Sudhakar, A. Ferrini, S. Sharma, EJ. Kamsteeg, MA. Tijssen, C. Verschuuren, ME. van Egmond, JM. Flowers, M. McEntagart, A. Tucci, P. Coubes, BI. Bustos, P. Gonzalez-Latapi, S. Tisch, P. Darveniza, KM. Gorman, KJ. Peall, K. Bötzel, JC. Koch, T. Kmieć, B. Plecko, S. Boesch, B. Haslinger, R. Jech, B. Garavaglia, N. Wood, H. Houlden, P. Gissen, SJ. Lubbe, CM. Sue, L. Cif, NE. Mencacci, G. Anderson, MA. Kurian, J. Winkelmann, Genomics England Research Consortium,
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