Journal
BRAIN
Volume -, Issue -, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awac330
Keywords
V-ATPase; ATP6V0C; VMA3; epilepsy genetics; neurodevelopmental disorders
Categories
Funding
- Emory University Research Council grant [5T32GM008490]
- senior clinical investigator fellowship of the FWO-Flanders
- Emory University Integrated Cellular Imaging Core (EICIC)
- Emory Integrated Genomics Core (EIGC) shared resources of Winship Cancer Institute of Emory University, National Cancer Institute [P30CA138292]
- Canadian Rare Disease Models and Mechanisms Network (RDMM), Citizens United for Research in Epilepsy [339143]
- Telethon Undiagnosed Diseases Program (TUDP) [GSP15001]
- Broad Institute of MIT and Harvard Center for Mendelian Genetics (Broad CMG) - National Human Genome Research Institute
- National Eye Institute
- National Heart, Lung and Blood Institute [UM1-HG008900, R01-HG009141]
- National Institute for Neurological Disorders and Stroke [U01-NS077303-04S1, R01-NS058721]
- European Reference Network ITHACA
- European Union [35444]
- Genomes Project
- National Institute for Health Research
- NHS England
- National Health Service
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This study identifies ATP6V0C as an important disease gene associated with neurodevelopmental abnormalities. The mutations in ATP6V0C affect the activity of vacuolar H+-ATPase and lead to decreased cell growth, motor dysfunction, and reduced lifespan.
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.
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