ArticleBrain : a journal of neurology2023
ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.
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Article in Brain : a journal of neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 29 citations in OpenAlex.
- Maternal sleep deprivation reshapes offspring hippocampal development through a Trem2-centered microglial program revealed by single-nucleus and spatial transcriptomics.Molecular psychiatry · 2026Article
- Vacuolar ATPase subunit Atp6v0c transgene promotes neuroprotection and long-distance axon regeneration in injured retinal ganglion neurons.Molecular therapy. Nucleic acids · 2026Article
- Urine-Derived iPSC Neurospheres Uncover Proteomic Correlates of Clinical Severity in Dravet Syndrome.Journal of neurochemistry · 2026Article
- The genomic medicine center Karolinska 10-year report on genome sequencing for rare diseases and a strategy for stepwise clinical implementation.Genome medicine · 2026Article
- Spectrum and functions of ion channels and transporters in osteoclasts.Bone research · 2026Review
- Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia.American journal of human genetics · 2026Article
- Enzyme Activity-Based Genome-wide Screening for Modifiers of Lysosomal Glucocerebrosidase Uncovers Candidate Risk Factors for Parkinson's Disease.ACS central science · 2025Article
- Mechanistic insights into 16p13.3 microdeletions encompassing TBC1D24 and ATP6V0C through advanced sequencing approaches.European journal of human genetics : EJHG · 2025Article
- V-ATPase and Lysosomal Energy Sensing in Periodontitis and Medicine-Related Osteonecrosis of the Jaw.Biomolecules · 2025Review
- Variants in ATP6V0C are associated with Dravet-like developmental and epileptic encephalopathy.Epilepsia · 2025Article
- Comprehensive Multi-Omics Analysis of Muscle Tissue Alterations in MaleInternational journal of molecular sciences · 2025Article
- Article
- Exploring the effect of skim milk on the membrane stability of frozen-thawed Inner Mongolia cashmere goat sperm based on proteomics.Frontiers in cell and developmental biology · 2025Article
- Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.HGG advances · 2024Article
- Review
- Transcriptomic analysis reveals cross-talk genes between type 2 diabetes and recurrent benign paroxysmal positional vertigo.Heliyon · 2024Article
- Article
- ATP6V0C gene variants were identified in individuals with epilepsy, with or without developmental delay.Journal of human genetics · 2023Article
- Reprogramming the Circadian Dynamics of Epileptic Genes in Mouse Temporal Lobe Epilepsy.International journal of molecular sciences · 2023Article
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Authors and funding
57 authors at 20 institutions in 9 countries.
Kari A MattisonGenetics and Molecular Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA, USA.ORCID 0000-0003-2130-5228
Gilles TossingDepartment of Neuroscience, University of Montreal, Montreal, QC, Canada.
Fred MulroeDivision of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Center, Manchester, UK.
Callum SimmonsDivision of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Center, Manchester, UK.
Kameryn M ButlerDepartment of Human Genetics, Emory University, Atlanta, GA, USA.
Alison SchreiberCenter for Personalized Genetic Healthcare, Cleveland Clinic, Cleveland, OH, USA.
Adnan AlsadahCenter for Personalized Genetic Healthcare, Cleveland Clinic, Cleveland, OH, USA.
Derek E NeilsonDivision of Genetics and Metabolism, Department of Child Health, The University of Arizona College of Medicine, Phoenix, AZ, USA.
Karin NaessCenter for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
Anna WedellCenter for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
Anna WredenbergCenter for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
Arthur SorlinNational Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg.
Emma McCannLiverpool Center for Genomic Medicine, Liverpool Women's Hospital, Liverpool, UK.
George J BurghelGenomic Diagnostic Laboratory, St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
Beatriz MenendezUI Health, Chicago, IL, USA.
George E HogansonDivision of Genetics, Department of Pediatrics, University of Illinois College of Medicine, Chicago, IL, USA.
Lorenzo D BottoDivision of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
Francis M FillouxDivision of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
Ángel Aledo-SerranoGenetic Epilepsy Program, Department of Neurology, Ruber International Hospital, Madrid, Spain.
Antonio Gil-NagelGenetic Epilepsy Program, Department of Neurology, Ruber International Hospital, Madrid, Spain.
Katrina Tatton-BrownMedical Genetics, St. George's University Hospitals NHS Foundation Trust and Institute for Molecular and Cell Sciences, St. George's, University of London, London, UK.
Nienke E VerbeekDepartment of Genetics, University Medical Center Utrecht, Member of the ERN EpiCARE, Utrecht, The Netherlands.
Bert van der ZwaagDepartment of Genetics, University Medical Center Utrecht, Member of the ERN EpiCARE, Utrecht, The Netherlands.
Kyrieckos A AleckDivision of Genetics and Metabolism, Department of Child Health, The University of Arizona College of Medicine, Phoenix, AZ, USA.
Andrew C FazenbakerDepartment of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix Children's Medical Group, Phoenix, AZ, USA.
Jorune BalciunieneDivison of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Holly A DubbsDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Eric D MarshDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Kathryn GarberDepartment of Human Genetics, Emory University, Atlanta, GA, USA.
Jakob EkDepartment of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark.
Morten DunoDepartment of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark.
Christina E Hoei-HansenDepartment of Pediatrics, University Hospital of Copenhagen, Copenhagen, Denmark.
Matthew A DeardorffDepartment of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Gordana RacaDepartment of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Catherine QuindipanCenter for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Michele van Hirtum-DasDepartment of Pediatrics, Division of Medical Genetics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Jeroen BreckpotCenter for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
Trine Bjørg HammerDepartment of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Fildelfia, Dianalund, Denmark.
Rikke S MøllerDepartment of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Fildelfia, Dianalund, Denmark.
Andrea WhitneyPediatric Neurology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Andrew G L DouglasWessex Clinical Genetics Service, University of Southampton, Southampton, UK.
Mira KharbandaHuman Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
Nicola Brunetti-PierriTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.ORCID 0000-0002-6895-8819
Manuela MorleoTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Vincenzo NigroTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.ORCID 0000-0002-3378-5006
Halie J MayInstitute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
James X TaoDepartment of Neurology, University of Chicago, Chicago, IL, USA.
Emanuela ArgilliDepartment of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Elliot H SherrDepartment of Neurology, University of California, San Francisco, San Francisco, CA, USA.
William B DobynsDepartment of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN, USA.ORCID 0000-0002-7681-2844
Genomics England Research Consortium
Richard A BainesDivision of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Center, Manchester, UK.ORCID 0000-0001-8571-4376
Jim WarwickerSchool of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Institute of Biotechnology, University of Manchester, Manchester, UK.
J Alex ParkerDepartment of Neuroscience, University of Montreal, Montreal, QC, Canada.
Siddharth BankaDivision of Evolution, Infection, and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.ORCID 0000-0002-8527-2210
Philippe M CampeauDepartment of Pediatrics, University of Montreal, Montreal, QC, Canada.ORCID 0000-0002-0139-8239
Andrew EscaygDepartment of Human Genetics, Emory University, Atlanta, GA, USA.ORCID 0000-0001-9713-7107
Emory University · USChildren's Hospital of Philadelphia · USKarolinska University Hospital · SEManchester Academic Health Science Centre · GBUniversité de Montréal · CAUniversity of Southern California · USCleveland Clinic · USCopenhagen University Hospital · DKHospital Ruber Internacional · ESUniversity of Arizona · USUniversity of California, San Francisco · USUniversity of Campania "Luigi Vanvitelli" · ITUniversity of Manchester · GBUniversity of Southampton · GBUniversity of Utah · USUtrecht University · NLChildren's Hospital of Los Angeles · USColumbia University · USLaboratoire National de Santé · LUPhoenix Children's Hospital · US
Funding
Winship Cancer Institute Cancer Center Support GrantP30CA138292 · NCI · EMORY UNIVERSITY · PI Suresh S Ramalingam · 2009 to 2026
$47.5MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5M3 of 7 Epi4K: Sequencing, Biostatistics & Bioinformatics CoreU01NS077303 · NINDS · DUKE UNIVERSITY · PI EICHLER, EVAN, GOLDSTEIN, DAVID B. · 2011 to 2018
$13.3MDe novo copy number variation and gene discovery in human brain malformationsR01NS058721 · NINDS · UNIVERSITY OF CHICAGO · PI ARGILLI, EMANUELA · 2008 to 2025
$10.9MPREDOCTORAL TRAINING PROGRAM IN GENETICST32GM008490 · NIGMS · EMORY UNIVERSITY · PI BOSS, JEREMY M. · 1993 to 2022
$8.0MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MNCI NIH HHS P30 CA138292NHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG008900NIGMS NIH HHS T32 GM008490NINDS NIH HHS R01 NS058721NINDS NIH HHS U01 NS077303Wellcome Trust
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.
Indexed as
EpilepsyVacuolar Proton-Translocating ATPasesAdenosine TriphosphateHumansSaccharomyces cerevisiaeAdenosine TriphosphateATP6V0C protein, humanVacuolar Proton-Translocating ATPasesATP6V0Cepilepsy geneticsneurodevelopmental disordersV-ATPaseVMA3
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