De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment

Catherine Rodger, Elisabetta Flex, Rachel J. Allison, Alba Sanchis-Juan, Marcia A. Hasenahuer, Serena Cecchetti, Courtney E. French, James R. Edgar, Giovanna Carpentieri, Andrea Ciolfi, Francesca Pantaleoni, Alessandro Bruselles, Roberta Onesimo, Giuseppe Zampino, Francesca Marcon, Ester Siniscalchi, Melissa Lees, Deepa Krishnakumar, Emma Mccann, Dragana YosifovaJoanna Jarvis, Michael C. Kruer, Warren Marks, Jonathan Campbell, Louise E. Allen, Stefano Gustincich, F. Lucy Raymond, Marco Tartaglia, Evan Reid, Sheena Elisabeth Campbell Reid

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

3 Citazioni (Scopus)


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.
Lingua originaleEnglish
pagine (da-a)1129-1148
Numero di pagine20
RivistaAmerican Journal of Human Genetics
Stato di pubblicazionePubblicato - 2020


  • ATPases Associated with Diverse Cellular Activities
  • Alleles
  • Animals
  • Brain
  • Cell Cycle
  • Centrosome
  • DNA damage
  • Endosomal Sorting Complexes Required for Transport
  • Endosomes
  • Fibroblasts
  • Genomics
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Mutation, Missense
  • Neurodevelopmental Disorders
  • Neurons
  • Protein Domains
  • Protein Transport
  • Spindle Apparatus
  • Vacuolar Proton-Translocating ATPases
  • centrosome
  • cerebellar hypoplasia
  • endosomal sorting
  • endosomal sorting complex required for transport
  • microcephaly
  • mitosis
  • nuclear envelope
  • primary cilium


Entra nei temi di ricerca di 'De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment'. Insieme formano una fingerprint unica.

Cita questo