Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.
AuthorsSanderson, Leslie E
Al-Muhaizea, Mohammad A
van der Linde, Herma C
Kühn, Nikolas A
Owaidah, Tarek Mustafa
Vieira, Luana Gabriela Dalla Rosa
Silveira, Tainá Regina Damaceno
Sabbagh, Raghda M
Albader, Anoud A
Binhumaid, Faisal S
Mustafa, Osama M
Aksoy, Durdane Bekar
Basak, A Nazli
Rosenfeld, Jill A
Karimiani, Ehsan Ghayoor
Meyer, Brian F
Arold, Stefan T.
Bertoli-Avella, Aida M
Barakat, Tahsin Stefan
van Ham, Tjakko J
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Structural Biology and Engineering
Permanent link to this recordhttp://hdl.handle.net/10754/668296
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AbstractMembrane 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.
CitationSanderson, L. E., Lanko, K., Alsagob, M., Almass, R., Al-Ahmadi, N., Najafi, M., … Perenthaler, E. (2021). Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking. Brain. doi:10.1093/brain/awaa459
SponsorsWe are grateful to the families for their participation. We thank the Saudi Human Genome Program, Core Facilities, and Purchasing Departments at King Faisal Specialist Hospital and Research Center (KFSHRC) and special thanks to Mr Faisal Al-Otaibi for quickly handling our orders and requests. Wim Quint and Kirke Tadema (Erasmus MC) are acknowledged for their expertise in OKR analysis.
PublisherOxford University Press (OUP)
JournalBrain : a journal of neurology
Except where otherwise noted, this item's license is described as This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
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