1. Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.
- Author
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Sanderson LE, Lanko K, Alsagob M, Almass R, Al-Ahmadi N, Najafi M, Al-Muhaizea MA, Alzaidan H, AlDhalaan H, Perenthaler E, van der Linde HC, Nikoncuk A, Kühn NA, Antony D, Owaidah TM, Raskin S, Vieira LGDR, Mombach R, Ahangari N, Silveira TRD, Ameziane N, Rolfs A, Alharbi A, Sabbagh RM, AlAhmadi K, Alawam B, Ghebeh H, AlHargan A, Albader AA, Binhumaid FS, Goljan E, Monies D, Mustafa OM, Aldosary M, AlBakheet A, Alyounes B, Almutairi F, Al-Odaib A, Aksoy DB, Basak AN, Palvadeau R, Trabzuni D, Rosenfeld JA, Karimiani EG, Meyer BF, Karakas B, Al-Mohanna F, Arold ST, Colak D, Maroofian R, Houlden H, Bertoli-Avella AM, Schmidts M, Barakat TS, van Ham TJ, and Kaya N
- Subjects
- Adolescent, Adult, Animals, Child, Child, Preschool, Female, Genetic Variation, Humans, Male, Pedigree, Young Adult, Zebrafish, Cerebellar Ataxia genetics, Genetic Predisposition to Disease genetics, Neurodevelopmental Disorders genetics, Protein Transport genetics, Vesicular Transport Proteins genetics
- Abstract
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., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2021
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