Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

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.
King Salman Center for Disability Research; NSTIP/King Abdulaziz City for Science and Technology; King Abdullah University of Science and Technology, Office of Sponsored Research; NSTIP/KACST; Netherlands Organisation for Scientific Research (ZonMW Veni); European Union (EU); Horizon 2020; LEaDing Fellowship; Marie Sklodowska-Curie Grant Agreement; Deutsche Forschungsgemeinschaft; European Union (EU); Horizon 2020; European Research Council (ERC); ERC StG TREATCilia; NTSIP/King Abdulaziz City for Science and Technology; King Faisal Specialist Hospital and Research Centre; KFSHRC Research Grant; Brain & Behavior Research Foundation NARSAD Young Investigator Grant; Erasmus MC Fellowship 2017; Erasmus MC Human Disease Model Award 2018; Erasmus University Rotterdam (EUR) Fellowship; Suna and İnan Kıraç Foundation; Koç University Research Center for Translational Medicine (KUTTAM)