期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 107, 期 6, 页码 1129-1148出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2020.10.012
关键词
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资金
- UK Medical Research Council [MR/M00046X/1, MR/R026440/1]
- National Institute of Health Research Biomedical Research Centre at Addenbrooke's Hospital
- Fondazione Bambino Gesu (Vite Coraggiose)
- Italian Ministry of Health [CCR-2017-23669081]
- National Institute for Health Research (NIHR) for the Cambridge Biomedical Research Centre
- NIHR BioResource [RG65966]
- Sir Henry Dale Fellowship - Wellcome Trust [216370/Z/19/Z]
- Sir Henry Dale Fellowship - Royal Society [216370/Z/19/Z]
- National Institute for Health Research
- NHS England
- Cancer Research UK
- Medical Research Council
- Wellcome Trust [100140, 093026]
- Wellcome Trust [216370/Z/19/Z] Funding Source: Wellcome Trust
- MRC [MR/R026440/1, MR/M00046X/1] Funding Source: UKRI
The 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.
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