ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy
Year: 2022
Type: article
Study design: Observational Study
Abstract: The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.
Source: Brain
Authors: Kari A Mattison, Gilles Tossing, Fred Mulroe, Callum Simmons, Kameryn M Butler, Alison Schreiber, Adnan Alsadah, Derek E Neilson, Karin Naess, Anna Wedell, Anna Wredenberg, Arthur Sorlin, Emma McCann, George J Burghel, Beatriz Menendez, George E Hoganson, Lorenzo D Botto, Francis M Filloux, Ángel Aledo-Serrano, Antonio Gil-Nagel, Katrina Tatton-Brown, Nienke E Verbeek, Bert van der Zwaag, Kyrieckos A Aleck, Andrew C Fazenbaker, Jorune Balciuniene, Holly A Dubbs, Eric D Marsh, Kathryn Garber, Jakob Ek, Morten Duno, Christina E Hoei-Hansen, Matthew A Deardorff, Gordana Raca, Catherine Quindipan, Michele van Hirtum-Das, Jeroen Breckpot, Trine Bjørg Hammer, Rikke S Møller, Andrea Whitney, Andrew G L Douglas, Mira Kharbanda, Nicola Brunetti-Pierri, Manuela Morleo, Vincenzo Nigro, Halie J May, James X Tao, Emanuela Argilli, Elliot H Sherr, William B Dobyns, Richard A Baines, Jim Warwicker, J Alex Parker, Siddharth Banka, Philippe M Campeau, Andrew Escayg
Institutions: Emory University, Université de Montréal, Manchester Academic Health Science Centre, University of Manchester, Greenwood Genetic Center, Cleveland Clinic, Phoenix Children's Hospital, University of Arizona College of Medicine- Phoenix, Karolinska University Hospital, Karolinska Institutet, Laboratoire National de Santé, Liverpool Women's Hospital, St Mary's Hospital, Manchester University NHS Foundation Trust, University of Illinois Hospital & Health Sciences System, University of Illinois Chicago, University of Utah, Hospital Ruber Internacional, St George's, University of London, St George’s University Hospitals NHS Foundation Trust, University Medical Center Utrecht, Children's Hospital of Philadelphia, Revvity (United States), Copenhagen University Hospital, University of Copenhagen, University of Southern California, Children's Hospital Los Angeles, Universitair Ziekenhuis Leuven, Filadelfia, University of Southern Denmark, University Hospital Southampton NHS Foundation Trust, University of Southampton, Telethon Institute Of Genetics And Medicine, University of Naples Federico II, University of Campania "Luigi Vanvitelli", Columbia University Irving Medical Center, University of Chicago, University of California, San Francisco, University of Minnesota
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: Citizens United for Research in Epilepsy, Emory University, Wellcome Trust, Broad Institute, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, European Commission, Fonds Wetenschappelijk Onderzoek, Vlaamse regering, National Institutes of Health, Winship Cancer Institute, Medical Research Council, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Eye Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: A powerful web-based discovery platform for rare disease genetics, G1093531541, G1099494159, Predoctoral Training Program in Genetics, G119964413, 3 of 7 Epi4K: Sequencing, Biostatistics & Bioinformatics Core, G2473961061, G267171126, G2973790809, G3061381831, G3207356259, G393177772, G4103361985, G440452555, G4791904475, G5282417297, Joint Center for Mendelian Genomics, G5567013232, G5702163051, ACC: Callosal Agenesis as a Window into Common Neurodevelopmental Disorders, Winship Cancer Institute Cancer Center Support Grant
OpenAlex ID: W4295088693