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

Dora Steel^#^{1

2}, Michael Zech^#^{3

4}, Chen Zhao³, Katy E S Barwick¹, Derek Burke⁵, Diane Demailly⁶, Kishore R Kumar^{7

8

9

10}, Giovanna Zorzi¹¹, Nardo Nardocci¹¹, Rauan Kaiyrzhanov¹², Matias Wagner^{3

4}, Arcangela Iuso^{3

4}, Riccardo Berutti⁴, Matej Škorvánek^{13

14}, Ján Necpál¹⁵, Ryan Davis^{7

9

10}, Sarah Wiethoff^{16

17}, Kshitij Mankad¹⁸, Sniya Sudhakar¹⁸, Arianna Ferrini¹, Suvasini Sharma¹⁹, Erik-Jan Kamsteeg²⁰, Marina A Tijssen²¹, Corien Verschuuren^{22

23}, Martje E van Egmond^{21

22}, Joanna M Flowers²⁴, Meriel McEntagart²⁵, Arianna Tucci²⁶, Philippe Coubes⁶, Bernabe I Bustos²⁷, Paulina Gonzalez-Latapi²⁷, Stephen Tisch²⁸, Paul Darveniza²⁸, Kathleen M Gorman^{29

30}, Kathryn J Peall³¹, Kai Bötzel³², Jan C Koch³³, Tomasz Kmieć³⁴, Barbara Plecko³⁵, Sylvia Boesch³⁶, Bernhard Haslinger³⁷, Robert Jech³⁸, Barbara Garavaglia¹¹, Nick Wood¹⁶, Henry Houlden¹², Paul Gissen³⁹, Steven J Lubbe²⁷, Carolyn M Sue^{7

9

10

40}, Laura Cif⁶, Niccolò E Mencacci²⁷, Glenn Anderson⁴¹, Manju A Kurian^{1

2}, Juliane Winkelmann^{3

4

42

43}; Genomics England Research Consortium

Affiliations

¹ Department of Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
² Department of Neurology, Great Ormond Street Hospital, London, UK.
³ Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
⁴ Institute of Human Genetics, Technical University of Munich, Munich, Germany.
⁵ Enzyme Laboratory, Great Ormond Street Hospital for Children, London, UK.
⁶ Unités des Pathologies Cérébrales Résistantes, Département de Neurochirurgie, Centre Hospitalier Universitaire, Montpellier, France.
⁷ Department of Neurogenetics, Kolling Institute of Medical Research, University of Sydney and Northern Sydney Local Health District, Sydney, New South Wales, Australia.
⁸ Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, New South Wales, Australia.
⁹ Translational Genomics, Kinghorn Centre for Clinical Genomics, Garvan Institute for Medical Research, Sydney, New South Wales, Australia.
¹⁰ Department of Neurogenetics, University of Sydney and Northern Sydney Local Health District, Sydney, New South Wales, Australia.
¹¹ Department of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
¹² Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London, UK.
¹³ Department of Neurology, P. J. Safarik University, Kosice, Slovak Republic.
¹⁴ Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic.
¹⁵ Department of Neurology, Zvolen Hospital, Zvolen, Slovakia.
¹⁶ UCL Queen Square Institute of Neurology, London, UK.
¹⁷ Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Tübingen, Germany.
¹⁸ Department of Radiology, Great Ormond Street Hospital for Children, London, UK.
¹⁹ Neurology Division, Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India.
²⁰ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
²¹ Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²² Expertise Center Movement Disorders Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²³ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²⁴ Department of Neurology, St. George's Hospital, London, UK.
²⁵ Department of Clinical Genetics, St. George's Hospital, London, UK.
²⁶ Genomics England, London, UK.
²⁷ Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
²⁸ Department of Neurology, St. Vincent's Hospital, Sydney, Australia.
²⁹ Department of Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.
³⁰ UCD School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
³¹ University of Cardiff, Cardiff, Wales, UK.
³² Department of Neurology, Ludwig Maximilian University, Munich, Germany.
³³ Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
³⁴ Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, Poland.
³⁵ Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria.
³⁶ Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
³⁷ Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
³⁸ Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
³⁹ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.
⁴⁰ Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, New South Wales, Australia.
⁴¹ Department of Histopathology, Great Ormond Street Hospital for Children, London, UK.
⁴² Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.
⁴³ Munich Cluster for Systems Neurology, Munich, Germany.

^# Contributed equally.

PMID: 32808683
DOI: 10.1002/ana.25879

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

Dora Steel et al. Ann Neurol. 2020 Nov.

. 2020 Nov;88(5):867-877.

doi: 10.1002/ana.25879. Epub 2020 Sep 21.

Authors

Affiliations

¹ Department of Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
² Department of Neurology, Great Ormond Street Hospital, London, UK.
³ Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
⁴ Institute of Human Genetics, Technical University of Munich, Munich, Germany.
⁵ Enzyme Laboratory, Great Ormond Street Hospital for Children, London, UK.
⁶ Unités des Pathologies Cérébrales Résistantes, Département de Neurochirurgie, Centre Hospitalier Universitaire, Montpellier, France.
⁷ Department of Neurogenetics, Kolling Institute of Medical Research, University of Sydney and Northern Sydney Local Health District, Sydney, New South Wales, Australia.
⁸ Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, New South Wales, Australia.
⁹ Translational Genomics, Kinghorn Centre for Clinical Genomics, Garvan Institute for Medical Research, Sydney, New South Wales, Australia.
¹⁰ Department of Neurogenetics, University of Sydney and Northern Sydney Local Health District, Sydney, New South Wales, Australia.
¹¹ Department of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
¹² Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London, UK.
¹³ Department of Neurology, P. J. Safarik University, Kosice, Slovak Republic.
¹⁴ Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic.
¹⁵ Department of Neurology, Zvolen Hospital, Zvolen, Slovakia.
¹⁶ UCL Queen Square Institute of Neurology, London, UK.
¹⁷ Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Tübingen, Germany.
¹⁸ Department of Radiology, Great Ormond Street Hospital for Children, London, UK.
¹⁹ Neurology Division, Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India.
²⁰ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
²¹ Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²² Expertise Center Movement Disorders Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²³ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²⁴ Department of Neurology, St. George's Hospital, London, UK.
²⁵ Department of Clinical Genetics, St. George's Hospital, London, UK.
²⁶ Genomics England, London, UK.
²⁷ Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
²⁸ Department of Neurology, St. Vincent's Hospital, Sydney, Australia.
²⁹ Department of Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.
³⁰ UCD School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
³¹ University of Cardiff, Cardiff, Wales, UK.
³² Department of Neurology, Ludwig Maximilian University, Munich, Germany.
³³ Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
³⁴ Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, Poland.
³⁵ Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria.
³⁶ Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
³⁷ Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
³⁸ Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
³⁹ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.
⁴⁰ Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, New South Wales, Australia.
⁴¹ Department of Histopathology, Great Ormond Street Hospital for Children, London, UK.
⁴² Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.
⁴³ Munich Cluster for Systems Neurology, Munich, Germany.

^# Contributed equally.

PMID: 32808683
DOI: 10.1002/ana.25879

Abstract

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.

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Comment in

Reply to "Truncating VPS16 Mutations are Rare in Early-Onset Dystonia".
Zech M, Steel D, Kurian MA, Winkelmann J. Zech M, et al. Ann Neurol. 2021 Mar;89(3):626. doi: 10.1002/ana.25988. Epub 2020 Dec 22. Ann Neurol. 2021. PMID: 33305837 No abstract available.
Truncating VPS16 Mutations Are Rare in Early Onset Dystonia.
Pott H, Brüggemann N, Reese R, Zeuner KE, Gandor F, Gruber D; DysTract Study Group; Klein C, Volkmann J, Lohmann K. Pott H, et al. Ann Neurol. 2021 Mar;89(3):625-626. doi: 10.1002/ana.25990. Epub 2020 Dec 28. Ann Neurol. 2021. PMID: 33305852 No abstract available.
VPS16 and VPS41: The List of Genes Causing Early-Onset Dystonia Keeps Expanding.
Gorodetsky C, Fasano A. Gorodetsky C, et al. Mov Disord. 2021 Mar;36(3):609. doi: 10.1002/mds.28511. Epub 2021 Jan 26. Mov Disord. 2021. PMID: 33497487 No abstract available.

References

1. Balint B, Mencacci NE, Valente EM, et al. Dystonia. Nat Rev Dis Primers 2018;4:25.
1. Lumsden DE, King MD, Allen NM. Status dystonicus in childhood. Curr Opin Pediatr 2017;29:674-682.
1. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013;28:863-873.
1. Kumar KR, Davis RL, Tchan MC, et al. Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes. Parkinsonism Relat Disord 2019;69:111-118.
1. Jiang P, Nishimura T, Sakamaki Y, et al. The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17. Mol Biol Cell 2014;25:1327-1337.

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

Affiliations

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

Authors

Affiliations

Abstract

Comment in

References

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LinkOut - more resources

Full Text Sources

Medical

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