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

CCDC 208145: Experimental Crystal Structure Determination

Related Article: H.M.Alvarez, T.B.Tran, M.A.Richter, D.M.Alyounes, D.Rabinovich, J.M.Tanski, M.Krawiec|2003|Inorg.Chem.|42|2149|doi:10.1021/ic025780m,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 208142: Experimental Crystal Structure Determination

Related Article: H.M.Alvarez, T.B.Tran, M.A.Richter, D.M.Alyounes, D.Rabinovich, J.M.Tanski, M.Krawiec|2003|Inorg.Chem.|42|2149|doi:10.1021/ic025780m,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 208144: Experimental Crystal Structure Determination

Related Article: H.M.Alvarez, T.B.Tran, M.A.Richter, D.M.Alyounes, D.Rabinovich, J.M.Tanski, M.Krawiec|2003|Inorg.Chem.|42|2149|doi:10.1021/ic025780m,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 208143: Experimental Crystal Structure Determination

Related Article: H.M.Alvarez, T.B.Tran, M.A.Richter, D.M.Alyounes, D.Rabinovich, J.M.Tanski, M.Krawiec|2003|Inorg.Chem.|42|2149|doi:10.1021/ic025780m,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures