De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment.
Am J Hum Genet
; 107(6): 1129-1148, 2020 12 03.
Article
em En
| MEDLINE
| ID: mdl-33186545
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Mutação de Sentido Incorreto
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ATPases Vacuolares Próton-Translocadoras
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Complexos Endossomais de Distribuição Requeridos para Transporte
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Transtornos do Neurodesenvolvimento
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ATPases Associadas a Diversas Atividades Celulares
Limite:
Animals
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Humans
Idioma:
En
Revista:
Am J Hum Genet
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Reino Unido