PUBLICATION
Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking
- Authors
- Sanderson, L.E., Lanko, K., Alsagob, M., Almass, R., Al-Ahmadi, N., Najafi, M., Al-Muhaizea, M.A., Alzaidan, H., AlDhalaan, H., Perenthaler, E., van der Linde, H.C., Nikoncuk, A., Kühn, N.A., Antony, D., Owaidah, T.M., Raskin, S., Vieira, L.G.D.R., Mombach, R., Ahangari, N., Silveira, T.R.D., Ameziane, N., Rolfs, A., Alharbi, A., Sabbagh, R.M., AlAhmadi, K., Alawam, B., Ghebeh, H., AlHargan, A., Albader, A.A., Binhumaid, F.S., Goljan, E., Monies, D., Mustafa, O.M., Aldosary, M., AlBakheet, A., Alyounes, B., Almutairi, F., Al-Odaib, A., Aksoy, D.B., Basak, A.N., Palvadeau, R., Trabzuni, D., Rosenfeld, J.A., Karimiani, E.G., Meyer, B.F., Karakas, B., Al-Mohanna, F., Arold, S.T., Colak, D., Maroofian, R., Houlden, H., Bertoli-Avella, A.M., Schmidts, M., Barakat, T.S., van Ham, T.J., Kaya, N.
- ID
- ZDB-PUB-210326-10
- Date
- 2021
- Source
- Brain : a journal of neurology 144(3): 769-780 (Journal)
- Registered Authors
- van Ham, Tjakko
- Keywords
- VPS41, cerebellar ataxia, membrane trafficking, neurodevelopmental disorder, zebrafish disease modelling
- MeSH Terms
-
- Adolescent
- Adult
- Animals
- Cerebellar Ataxia/genetics*
- Child
- Child, Preschool
- Female
- Genetic Predisposition to Disease/genetics*
- Genetic Variation
- Humans
- Male
- Neurodevelopmental Disorders/genetics*
- Pedigree
- Protein Transport/genetics*
- Vesicular Transport Proteins/genetics*
- Young Adult
- Zebrafish
- PubMed
- 33764426 Full text @ Brain
Citation
Sanderson, L.E., Lanko, K., Alsagob, M., Almass, R., Al-Ahmadi, N., Najafi, M., Al-Muhaizea, M.A., Alzaidan, H., AlDhalaan, H., Perenthaler, E., van der Linde, H.C., Nikoncuk, A., Kühn, N.A., Antony, D., Owaidah, T.M., Raskin, S., Vieira, L.G.D.R., Mombach, R., Ahangari, N., Silveira, T.R.D., Ameziane, N., Rolfs, A., Alharbi, A., Sabbagh, R.M., AlAhmadi, K., Alawam, B., Ghebeh, H., AlHargan, A., Albader, A.A., Binhumaid, F.S., Goljan, E., Monies, D., Mustafa, O.M., Aldosary, M., AlBakheet, A., Alyounes, B., Almutairi, F., Al-Odaib, A., Aksoy, D.B., Basak, A.N., Palvadeau, R., Trabzuni, D., Rosenfeld, J.A., Karimiani, E.G., Meyer, B.F., Karakas, B., Al-Mohanna, F., Arold, S.T., Colak, D., Maroofian, R., Houlden, H., Bertoli-Avella, A.M., Schmidts, M., Barakat, T.S., van Ham, T.J., Kaya, N. (2021) Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking. Brain : a journal of neurology. 144(3):769-780.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping