<i>ATP6V0C</i> variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy
Kari A. Mattison, Gilles Tossing, Fred Mulroe, Callum Simmons, Kameryn M. Butler, Alison Schreiber, Adnan Alsadah, Derek Neilson, K Naess, Anna Wedell, Anna Wredenberg, Arthur Sorlin, Emma McCann, George J. Burghel, Beatriz Menéndez, George Hoganson, Lorenzo D. Botto, Francis Filloux, Ángel Aledo‐Serrano, António Gil‐Nagel, Katrina Tatton‐Brown, Nienke E. Verbeek, Bert van der Zwaag, Kyrieckos A. Aleck, Andrew C. Fazenbaker, Jorune Balciuniene, Holly Dubbs, Eric D. Marsh, Kathryn B. Garber, Jakob Ek, Morten Dunø, Christina Engel Hoei‐Hansen, Matthew A. Deardorff, Gordana Raca, Catherine Quindipan, Michèle 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 May, James X. Tao, Emanuela Argilli, Elliot H. Sherr, William B. Dobyns, Richard A. Baines, Jim Warwicker, Jennifer Parker, Siddharth Banka, Philippe M Campeau, Andrew Escayg
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.