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Steel, D.* ; Zech, M. ; Zhao, C. ; Barwick, K.E.* ; Burke, D.* ; Demailly, D.* ; Kumar, K.R.* ; Zorzi, G.* ; Nardocci, N.* ; Kaiyrzhanov, R.* ; Wagner, M. ; Iuso, A. ; Berutti, R. ; Škorvánek, M.* ; Necpál, J.* ; Davis, R.* ; Wiethoff, S.* ; Mankad, K.* ; Sudhakar, S.* ; Ferrini, A.* ; Sharma, S.* ; Kamsteeg, E.J.* ; Tijssen, M.A.* ; Verschuuren, C.* ; van Egmond, M.E.* ; Flowers, J.M.* ; McEntagart, M.* ; Tucci, A.* ; Coubes, P.* ; Bustos, B.I.* ; Gonzalez-Latapi, P.* ; Tisch, S.* ; Darveniza, P.* ; Gorman, K.M.* ; Peall, K.J.* ; Bötzel, K.* ; Koch, J.C.* ; Kmieć, T.* ; Plecko, B.* ; Boesch, S.* ; Haslinger, B.* ; Jech, R.* ; Garavaglia, B.* ; Wood, N.* ; Houlden, H.* ; Gissen, P.* ; Lubbe, S.J.* ; Sue, C.M.* ; Cif, L.* ; Mencacci, N.E.* ; Anderson, G.* ; Kurian, M.A.* ; Winkelmann, J.

Loss-of-function variants in HOPS complex genes VPS16 and VPS41 cause early onset dystonia associated with lysosomal abnormalities.

Ann. Neurol. 88, 867-877 (2020)
Postprint DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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 forVPS16(Fisher's exact testpvalue, 6.9 x 10(9)).VPS16encodes 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-functionVPS16variants, 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 inVPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients withVPS16andVPS41showed 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
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Hops; Gene; Trafficking; Mutation; Fusion; Vps41; Vps16; Snare
ISSN (print) / ISBN 0364-5134
e-ISSN 1531-8249
Journal Annals of Neurology
Quellenangaben Volume: 88, Issue: 5, Pages: 867-877 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants National Health Service
Michael J. Fox Foundation
Aligning Science Across Parkinson's initiative
internal research program at Helmholtz Zentrum Munchen, Munich, Germany
Rosetrees Trust
Sir Jules Thorn Trust
National Institute for Health Research (NIHR) Research Professorship
Slovak Research and Grant Agency
Slovak Grant and Development Agency
European Joint Programme on Rare Diseases (EJP RD COFUND-EJP)
Czech Ministry of Education under the frame of EJP RD
Czech Ministry of Education under grant AZV
Charles University, Prague, Czech Republic (PROGRES Q27)
Medizinische Universitat Innsbruck, Innsbruck, Austria
Helmholtz Zentrum Munchen, Munich, Germany
Technische Universitat Munchen, Munich, Germany
Ministry of Science, Research and the Arts of Baden-Wurttemberg
European Social Fund (ESF) of Baden-Wurttemberg
Medical Research Council
Cancer Research UK
Wellcome Trust
NHS England
National Institute for Health Research
AOP Orphan Pharmaceuticals AG
Actelion
Phelps Stichting
Fonds Psychische Gezondheid
Stichting Wetenschapsfonds Dystonie Vereniging
Dystonia Medical Research Foundation
province of Friesland
European Fund for Regional Development from the European Union
Netherlands Organisation for Health Research and Development ZonMW Topsubsidie
National Health and Medical Research Council
Else Kroner-Fresenius-Stiftung