Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking
Leslie E. Sanderson, Kristina Lanko, Maysoon Alsagob, Rawan Almass, Nada Al-Ahmadi, Maryam Najafi, Mohammad A. Al–Muhaizea, Hamad Alzaidan, Hesham Aldhalaan, Elena Perenthaler, Herma C. van der Linde, Anita Nikoncuk, Nikolas A. Kühn, Dinu Antony, Tarek Mustafa Owaidah, Salmo Raskin, Luana Gabriela Dalla Rosa Vieira, Romulo Mombach, Najmeh Ahangari, Tainá Regina Damaceno Silveira, Najim Ameziane, Arndt Rolfs, Aljohara Alharbi, Raghda M Sabbagh, Khalid AlAhmadi, Bashayer S. Alawam, Hazem Ghebeh, Aljouhra AlHargan, Anoud Albader, Faisal S. BinHumaid, Ewa Goljan, Dorota Monies, Osama M Mustafa, Mazhor Aldosary, Albandary AlBakheet, Banan Al‐Younes, Faten Almutairi, Ali Al‐Odaib, Dürdane Aksoy, A. Nazlı Başak, Robin Palvadeau, Daniah Trabzuni, Jill A. Rosenfeld, Ehsan Ghayoor Karimiani, Brian F. Meyer, Bedri Karakas, Futwan Al‐Mohanna, Stefan T. Arold, Dilek Çolak, Reza Maroofian, Henry Houlden, Aida M. Bertoli‐Avella, Miriam Schmidts, Tahsin Stefan Barakat, Tjakko J. van Ham, Namik Kaya
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.