Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking
| Autor: | Faten Almutairi, Tarek Mustafa Owaidah, Najmeh Ahangari, Nada Al-Ahmadi, Leslie E. Sanderson, Henry Houlden, Romulo Mombach, Mazhor Al-Dosary, Anoud Abdulmalik Albader, Banan Al-Younes, Osama M. Mustafa, Tainá Regina Damaceno Silveira, Dilek Colak, Namik Kaya, Miriam Schmidts, Hazem Ghebeh, Herma C. van der Linde, Robin Palvadeau, Aida M. Bertoli-Avella, Raghda M Sabbagh, Rawan Almass, Hesham Aldhalaan, Maryam Najafi, Bashayer Alawam, Aljouhra AlHargan, Kristina Lanko, Aljohara Alharbi, Maysoon Alsagob, Bedri Karakas, Reza Maroofian, A. Nazli Basak, Khalid AlAhmadi, Ali Al-Odaib, Arndt Rolfs, Mohammad A. Al-Muhaizea, Elena Perenthaler, Najim Ameziane, Dinu Antony, Futwan Al-Mohanna, Albandary Al-Bakheet, Faisal S. BinHumaid, Anita Nikoncuk, Nikolas A Kühn, Dorota Monies, Ehsan Ghayoor Karimiani, Hamad Al-Zaidan, Tjakko J. van Ham, Ewa Goljan, Luana Gabriela Dalla Rosa Vieira, Jill A. Rosenfeld, Salmo Raskin, Dürdane Aksoy, Brian F. Meyer, Tahsin Stefan Barakat, Daniah Trabzuni, Stefan T. Arold |
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| Přispěvatelé: | Clinical Genetics, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Palvadeau, Robin, 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., Trabzuni, D., Rosenfeld, J. A., Karimiani, E. G., Meyer, B. F., Karakaş, B., Al-Mohanna, F., Arold, S. T., Çolak, D., Maroofian, R., Houlden, H., Bertoli-Avella, A. M., Schmidts, M., Barakat, T. S., van Ham, T. J., Kaya, N., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Adult
Male 0301 basic medicine Ataxia Adolescent Cerebellar Ataxia Protein subunit VPS41 Cerebellar ataxia Membrane trafficking Neurodevelopmental disorder Zebrafish disease modelling Vesicular Transport Proteins Biology medicine.disease_cause Young Adult 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being Protein targeting medicine Animals Humans Genetic Predisposition to Disease Child Zebrafish Vacuolar protein sorting AcademicSubjects/SCI01870 membrane trafficking zebrafish disease modelling Genetic Variation biology.organism_classification neurodevelopmental disorder Clinical neurology Neurosciences Pedigree Transport protein Cell biology Protein Transport 030104 developmental biology Neurodevelopmental Disorders Child Preschool AcademicSubjects/MED00310 Female Cerebellar atrophy Neurology (clinical) medicine.symptom 030217 neurology & neurosurgery Reports |
| Zdroj: | Brain, 144(3), 769-780. Oxford University Press Brain |
| ISSN: | 0006-8950 1460-2156 |
| Popis: | 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. Sanderson et al. describe ten individuals with biallelic variants in the gene encoding the vacuolar protein sorting protein VPS41, presenting with cerebellar dysfunction and abnormal membrane-bound vesicles. Mutant zebrafish recapitulate the cerebellar dysfunction phenotype, further implicating VPS41 as a human disease gene. |
| Databáze: | OpenAIRE |
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