De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment.
Am J Hum Genet
; 107(6): 1129-1148, 2020 12 03.
Article
en 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Mutación Missense
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ATPasas de Translocación de Protón Vacuolares
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Complejos de Clasificación Endosomal Requeridos para el Transporte
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Trastornos del Neurodesarrollo
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ATPasas Asociadas con Actividades Celulares Diversas
Límite:
Animals
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Humans
Idioma:
En
Revista:
Am J Hum Genet
Año:
2020
Tipo del documento:
Article
País de afiliación:
Reino Unido