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
Barakat, Stefan, Sanderson, Leslie, van Ham, Tjakko
Keywords
VPS41, cerebellar ataxia, membrane trafficking, neurodevelopmental disorder, zebrafish disease modelling
MeSH Terms
  • Neurodevelopmental Disorders/genetics*
  • Pedigree
  • Zebrafish
  • Adolescent
  • Humans
  • Male
  • Young Adult
  • Child
  • Adult
  • Female
  • Vesicular Transport Proteins/genetics*
  • Animals
  • Cerebellar Ataxia/genetics*
  • Genetic Variation
  • Child, Preschool
  • Protein Transport/genetics*
  • Genetic Predisposition to Disease/genetics*
(all 17)
PubMed
33764426 Full text @ Brain
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
Figures
Figure Gallery (3 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
aldocaWT + CRISPR1-vps41standard conditionsDay 5ISH
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Phenotype
Mutations / Transgenics
No data available
Human Disease / Model
Human Disease Fish Conditions Evidence
cerebellar ataxiaTAS
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Sequence Targeting Reagents
Target Reagent Reagent Type
vps41CRISPR1-vps41CRISPR
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Fish
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Antibodies
No data available
Orthology
Gene Orthology
vps41
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Engineered Foreign Genes
No data available
Mapping
No data available