Abstract
SummaryThe endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.
Highlights
The endosomal sorting complexes required for transport (ESCRTs) are multifunctional membrane modeling machineries that drive membrane fission or constriction in cellular processes that involve ‘‘inside out’’ membrane topology.[1,2,3]
We have identified and functionally characterized multiple de novo heterozygous missense mutations in VPS4A (MIM: 609982), which cause a neurodevelopmental disorder characterized by severe hypotonia and developmental delay (DD), intellectual disability (ID), structural brain abnormalities including thin corpus callosum and ponto-cerebellar hypoplasia, extrapyramidal neurological dysfunction, congenital cataracts with visual dysfunction, sensorineural deafness, and hematological abnormalities, providing evidence of an essential function of this ATPase in multiple cellular and developmental processes in humans
Genetic Analysis Using data from GeneMatcher, the UK National Institute for Health Research Bioresource and Genomics England Research Consortium,[33] or repositories linked to diagnostic testing (GeneDx Laboratory), six unrelated individuals with de novo variants in VPS4A (GenBank: NM_013245.3) were identified
Summary
The endosomal sorting complexes required for transport (ESCRTs) are multifunctional membrane modeling machineries that drive membrane fission or constriction in cellular processes that involve ‘‘inside out’’ membrane topology.[1,2,3] These are exemplified by fission reactions that cause vesicle budding away from the cytoplasm, in which ESCRT-III complexes assemble on the inner cytosolic face of a vesicle neck and promote membrane constriction from the inside. Modification of ESCRT-III complexes drives fission, and this is performed by the catalytic activity of members of the VPS4 ATPase family (which in vertebrates comprises two paralogs, VPS4A and VPS4B)— VPS4 is an indispensable component of all ESCRT-related membrane modeling.[4] Processes that involve this type of membrane topology include formation of the late endosomal multivesicular body (MVB), nuclear envelope reformation, and the abscission stage of cell division, among others.[1,2,3] In addition, certain ESCRT-III-associated proteins are active in more conventional ‘‘outside in’’ fission, notably in endosomal tubule fission, where atypical ESCRT-III proteins constrict from the outside to promote fission of sorting tubules from the endosomal body.[5,6].
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