Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Leslie E. Sanderson; Kristina Lanko; Maysoon Alsagob; Rawan Almass; Nada Al-Ahmadi; Maryam Najafi; Mohammad A. Al-Muhaizea; Hamad Alzaidan; Hesham AlDhalaan; Elena Perenthaler; Herma C. van der Linde; Anita Nikoncuk; Nikolas A. Kuhn; Dinu Antony; Tarek Mustafa Owaidah; Salmo Raskin; Luana Gabriela Dalla Rosa Vieira; Romulo Mombach; Najmeh Ahangari; Taina Regina Damaceno Silveira; Najim Ameziane; Arndt Rolfs; Aljohara Alharbi; Raghda M. Sabbagh; Khalid AlAhmadi; Bashayer Alawam; Hazem Ghebeh; Aljouhra AlHargan; Anoud A. Albader; Faisal S. Binhumaid; Ewa Goljan; Dorota Monies; Osama M. Mustafa; Mazhor Aldosary; Albandary AlBakheet; Banan Alyounes; Faten Almutairi; Ali Al-Odaib; Durdane Bekar Aksoy; A. Nazli Basak; Robin Palvadeau; Daniah Trabzuni; Jill A. Rosenfeld; Ehsan Ghayoor Karimiani; Brian F. Meyer; Bedri Karakas; Futwan Al-Mohanna; Stefan T. Arold; Dilek Colak; Reza Maroofian; Henry Houlden; Aida M. Bertoli-Avella; Miriam Schmidts; Tahsin Stefan Barakat; Tjakko J. van Ham; Namik Kaya

doi:10.1093/brain/awaa459

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Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Journal article

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Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Leslie E. Sanderson, Kristina Lanko, Maysoon Alsagob, Rawan Almass, Nada Al-Ahmadi, Maryam Najafi, Mohammad A. Al-Muhaizea, Hamad Alzaidan, Hesham AlDhalaan, Elena Perenthaler, …

Brain (London, England : 1878), Vol.144(3), pp.769-780

12/04/2021

DOI: https://doi.org/10.1093/brain/awaa459

Abstract

Clinical Neurology

Life Sciences & Biomedicine

Neurosciences

Neurosciences & Neurology

Science & Technology

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

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Title: Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking
Creators - without role: Leslie E. Sanderson - Erasmus MC
Kristina Lanko - Erasmus MC
Maysoon Alsagob - King Abdulaziz City for Science and Technology
Rawan Almass - King Faisal Specialist Hospital & Research Centre
Nada Al-Ahmadi - Imam Abdulrahman Bin Faisal University
Maryam Najafi - Radboud University Nijmegen
Mohammad A. Al-Muhaizea - King Fahd Security College
Hamad Alzaidan - College Station Medical Center
Hesham AlDhalaan - King Fahd Security College
Elena Perenthaler - Erasmus MC
Herma C. van der Linde - Erasmus MC
Anita Nikoncuk - Erasmus MC
Nikolas A. Kuhn - Erasmus MC
Dinu Antony - University Medical Center Freiburg
Tarek Mustafa Owaidah - King Faisal Specialist Hospital & Research Centre
Salmo Raskin - Universidade Positivo
Luana Gabriela Dalla Rosa Vieira - Univ Regiao Joinville, Posgrad Saude & Meio Ambiente, BR-89219710 Joinville, SC, Brazil
Romulo Mombach - AO
Najmeh Ahangari - Mashhad University of Medical Sciences
Taina Regina Damaceno Silveira - Centogene
Najim Ameziane - Centogene
Arndt Rolfs - Centogene
Aljohara Alharbi - King Faisal Specialist Hospital & Research Centre
Raghda M. Sabbagh - King Faisal Specialist Hospital & Research Centre
Khalid AlAhmadi - King Fahd Security College
Bashayer Alawam - King Faisal Specialist Hospital & Research Centre
Hazem Ghebeh - King Faisal Specialist Hospital & Research Centre
Aljouhra AlHargan - King Faisal Specialist Hospital & Research Centre
Anoud A. Albader - King Faisal Specialist Hospital & Research Centre
Faisal S. Binhumaid - King Faisal Specialist Hospital & Research Centre
Ewa Goljan - King Faisal Specialist Hospital & Research Centre
Dorota Monies - King Faisal Specialist Hospital & Research Centre
Osama M. Mustafa - King Faisal Specialist Hospital & Research Centre
Mazhor Aldosary - King Faisal Specialist Hosp & Res Ctr KFSHRC, Dept Genet, Riyadh 11211, Saudi Arabia
Albandary AlBakheet - King Faisal Specialist Hosp & Res Ctr KFSHRC, Dept Genet, Riyadh 11211, Saudi Arabia
Banan Alyounes - King Faisal Specialist Hosp & Res Ctr KFSHRC, Dept Genet, Riyadh 11211, Saudi Arabia
Faten Almutairi - King Faisal Specialist Hospital & Research Centre
Ali Al-Odaib - King Faisal Specialist Hospital & Research Centre
Durdane Bekar Aksoy - Gaziosmanpaşa University
A. Nazli Basak - Koç University
Robin Palvadeau - Koç University
Daniah Trabzuni - University College London
Jill A. Rosenfeld - Baylor Genetics
Ehsan Ghayoor Karimiani - St George's, University of London
Brian F. Meyer - King Abdulaziz City for Science and Technology
Bedri Karakas - King Faisal Specialist Hospital & Research Centre
Futwan Al-Mohanna - King Fahd Security College
Stefan T. Arold - King Abdullah University of Science and Technology
Dilek Colak - King Faisal Specialist Hospital & Research Centre
Reza Maroofian - National Hospital for Neurology and Neurosurgery
Henry Houlden - National Hospital for Neurology and Neurosurgery
Aida M. Bertoli-Avella - Centogene
Miriam Schmidts - Radboud University Nijmegen
Tahsin Stefan Barakat - Erasmus MC
Tjakko J. van Ham - Erasmus MC
Namik Kaya - King Faisal Specialist Hospital & Research Centre
Publication Details: Brain (London, England : 1878), Vol.144(3), pp.769-780
Publisher: Oxford Univ Press
Number of pages: 12
Grant note: 11-BIO2072-20 / NSTIP/KACST 91617021 / Netherlands Organisation for Scientific Research (ZonMW Veni) 2180004; 2180022; 2120022; 14-MED2007-20 / King Salman Center for Disability Research and NSTIP/King Abdulaziz City for Science and Technology NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation; NARSAD DFG CRC1140 KIDGEM; SFB1453 NEPHGEN / Deutsche Forschungsgemeinschaft; German Research Foundation (DFG) Suna and Inan Kirac Foundation 707404 / European Union; European Commission Erasmus University Rotterdam (EUR) fellowship 2110006 / KFSHRC Research grant Koc University-KUTTAM King Faisal Specialist Hospital and Research Centre 716344 / European Research Council (ERC StG TREATCilia); European Research Council (ERC) FCC/1/1976-25 / King Abdullah University of Science and Technology, Office of Sponsored Research; King Abdullah University of Science & Technology Erasmus MC Fellowship 08-MED499-20 / NTSIP/King Abdulaziz City for Science and Technology Erasmus MC Human Disease Model Award
Identifiers: 9913267408331
Academic Unit: King Faisal University; Alfaisal University; King Abdullah University of Science & Technology; King Abdulaziz City for Science & Technology; Imam Abdulrahman Bin Faisal University
Language: English
Resource Type: Journal article