De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment.
ATPases Associated with Diverse Cellular Activities
/ genetics
Alleles
Animals
Brain
/ abnormalities
Cell Cycle
Centrosome
/ metabolism
Endosomal Sorting Complexes Required for Transport
/ genetics
Endosomes
/ metabolism
Fibroblasts
/ metabolism
Genomics
HEK293 Cells
HeLa Cells
Humans
Mice
Mutation, Missense
Neurodevelopmental Disorders
/ genetics
Neurons
/ metabolism
Protein Domains
Protein Transport
Spindle Apparatus
/ metabolism
Vacuolar Proton-Translocating ATPases
/ genetics
CIMDAG
DNA damage
centrosome
cerebellar hypoplasia
endosomal sorting
endosomal sorting complex required for transport
microcephaly
mitosis
nuclear envelope
primary cilium
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
03 12 2020
03 12 2020
Historique:
received:
01
07
2020
accepted:
26
10
2020
pubmed:
14
11
2020
medline:
13
1
2021
entrez:
13
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33186545
pii: S0002-9297(20)30370-0
doi: 10.1016/j.ajhg.2020.10.012
pmc: PMC7820634
pii:
doi:
Substances chimiques
Endosomal Sorting Complexes Required for Transport
0
Vacuolar Proton-Translocating ATPases
EC 3.6.1.-
ATPases Associated with Diverse Cellular Activities
EC 3.6.4.-
VPS4A protein, human
EC 3.6.4.6
VPS4B protein, human
EC 3.6.4.6
Vps4b protein, mouse
EC 3.6.4.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1129-1148Subventions
Organisme : Wellcome Trust
ID : 093026
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 216370/Z/19/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M00046X/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R026440/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 100140
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
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