De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment

Am J Hum Genet. 2020 Dec 3;107(6):1129-1148. doi: 10.1016/j.ajhg.2020.10.012. Epub 2020 Nov 12.


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.

Keywords: CIMDAG; DNA damage; centrosome; cerebellar hypoplasia; endosomal sorting; endosomal sorting complex required for transport; microcephaly; mitosis; nuclear envelope; primary cilium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • Endosomal Sorting Complexes Required for Transport
  • Vacuolar Proton-Translocating ATPases
  • ATPases Associated with Diverse Cellular Activities
  • VPS4A protein, human
  • VPS4B protein, human
  • Vps4b protein, mouse