De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment
Catherine Rodger1, Elisabetta Flex2, Rachel J Allison1
1Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.
American Journal of Human Genetics
|November 13, 2020
Summary
Mutations in VPS4A, crucial for cellular transport, cause a severe multisystem disorder affecting brain development, growth, and cellular processes. This research identifies new genetic links to developmental abnormalities.
Area of Science:
- Cell Biology
- Genetics
- Developmental Biology
Background:
- Endosomal sorting complexes required for transport (ESCRTs) regulate essential membrane and non-membrane cellular functions.
- VPS4A is a critical enzyme within the ESCRT pathway, vital for cellular organization and trafficking.
Purpose of the Study:
- To investigate the cellular and clinical consequences of de novo missense variants in the VPS4A gene.
- To elucidate the role of VPS4A in human development and cellular processes.
Main Methods:
- Analysis of six individuals with de novo VPS4A variants.
- Cellular studies involving overexpression of VPS4A mutants in cultured cells.
- Examination of patient-derived fibroblasts and induced pluripotent stem cell (iPSC)-derived neurons.
Main Results:
- Identified de novo missense variants in the VPS4A ATPase domain in six probands presenting with structural brain abnormalities, neurodevelopmental delay, cataracts, growth impairment, and anemia.
- VPS4A mutants induced enlarged endosomal vacuoles and abnormal IST1 accumulation in cellular models.
- VPS4A is essential for endosomal morphology, IST1 localization, centrosome number, primary cilia, nuclear membrane, chromosome segregation, and cell cycle progression.
Conclusions:
- VPS4A mutations cause a distinct multisystem developmental disorder.
- VPS4A is indispensable for numerous human developmental and cellular processes, highlighting its broad biological significance.
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