2. Academic Validation
  3. De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment

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.
Catherine Rodger 1,  Elisabetta Flex 2,  Rachel J Allison 1,  Alba Sanchis-Juan 3,  Marcia A Hasenahuer 4,  Serena Cecchetti 5,  Courtney E French 6,  James R Edgar 7,  Giovanna Carpentieri 8,  Andrea Ciolfi 9,  Francesca Pantaleoni 9,  Alessandro Bruselles 2,  Genomics England Research Consortium 10,  Roberta Onesimo 11,  Giuseppe Zampino 12,  Francesca Marcon 13,  Ester Siniscalchi 13,  Melissa Lees 14,  Deepa Krishnakumar 15,  Emma McCann 16,  Dragana Yosifova 17,  Joanna Jarvis 18,  Michael C Kruer 19,  Warren Marks 20,  Jonathan Campbell 21,  Louise E Allen 22,  Stefano Gustincich 23,  F Lucy Raymond 1,  Marco Tartaglia 24,  Evan Reid 25
Affiliations

Affiliations

  • 1 Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.
  • 2 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
  • 3 Department of Haematology, NHS Blood and Transplant Centre, University of Cambridge, Cambridge CB2 0XY, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • 4 Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK; European Molecular Biology Laboratory - European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
  • 5 Microscopy Area, Core Facilities, Istituto Superiore di Sanità, Rome 00161, Italy.
  • 6 Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.
  • 7 Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
  • 8 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
  • 9 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
  • 10 Genomics England, London, UK.
  • 11 Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome 00168, Italy.
  • 12 Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome 00168, Italy; Università Cattolica del Sacro Cuore, Rome 00168, Italy.
  • 13 Unit of Mechanisms, Biomarkers and Models, Department of Environment and Health, Istituto Superiore di Sanità, Rome 00161, Italy.
  • 14 Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.
  • 15 Department of Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.
  • 16 Department of Clinical Genetics, Liverpool Women's Hospital, Liverpool L8 7SS, UK.
  • 17 Department of Medical Genetics, Guys' and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.
  • 18 Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.
  • 19 Phoenix Children's Hospital, Phoenix, AZ 76109, USA.
  • 20 Cook Children's Medical Centre, Fort Worth, TX 76104, USA.
  • 21 Colchester Hospital, East Suffolk and North Essex NHS Foundation Trust, Essex CO4 5JL, UK.
  • 22 Ophthalmology Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.
  • 23 Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova 16163, Italy; Area of Neuroscience, SISSA, Trieste 34136, Italy.
  • 24 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy. Electronic address: marco.tartaglia@opbg.net.
  • 25 Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address: ealr4@cam.ac.uk.
PMID: 33186545 DOI: 10.1016/j.ajhg.2020.10.012
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.

Keywords

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

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