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. Kühn, Dinu Antony, Tarek Mustafa Owaidah, Salmo Raskin, Luana Gabriela Dalla Rosa Vieira, Romulo Mombach, Najmeh Ahangari, Tainá Regina Damaceno SilveiraNajim 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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

29 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)769-780
Number of pages12
Issue number3
Publication statusPublished - 1 Mar 2021

Bibliographical note

N.K. is supported through intramural funds from King Faisal Specialist Hospital and Research Centre, and grants from King Salman Center for Disability Research and NSTIP/King Abdulaziz City for Science and Technology (2180004, 2180022, 2120022, 14-MED2007-20). S.T.A. was supported by King Abdullah University of Science and Technology, Office of Sponsored Research, award number FCC/1/1976-25. D.C. is supported by KFSHRC Research grant (RAC#2110006). D.C. has received funds from NSTIP/KACST (11-BIO2072-20). T.S.B. is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. T.V.H. is supported by an Erasmus University Rotterdam (EUR) fellowship. L.S. is supported by a LEaDing fellowship from the European Union’s Horizon 2020 research and innovation programme, under the Marie Skłodowska-Curie grant agreement No 707404. M.S. acknowledges funding from the “Deutsche Forschungsgemeinschaft” (DFG CRC1140 KIDGEM and SFB1453 NEPHGEN) and the European Research Council (ERC StG TREATCilia, grant No 716344). A.N.B. is supported by the Suna and Inan Kirac Foundation and Koc University- KUTTAM. The views expressed are those of the author(s) and not necessarily those of the funding agencies. B.F.M. acknowledges fund from NTSIP/ King Abdulaziz City for Science and Technology (08-MED499-20).

Publisher Copyright: © 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.


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