ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy

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 po...

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Published in:	Brain (London, England : 1878) Vol. 146; no. 4; pp. 1357 - 1372
Main Authors:	Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van der Zwaag, Bert, Aleck, Kyrieckos A, Fazenbaker, Andrew C, Balciuniene, Jorune, Dubbs, Holly A, Marsh, Eric D, Garber, Kathryn, Ek, Jakob, Duno, Morten, Hoei-Hansen, Christina E, Deardorff, Matthew A, Raca, Gordana, Quindipan, Catherine, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argilli, Emanuela, Sherr, Elliot H, Dobyns, William B, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, Escayg, Andrew
Format:	Journal Article
Language:	English
Published:	US Oxford University Press 19-04-2023
Subjects:	Adenosine Triphosphate Epilepsy - genetics Humans Medicin och hälsovetenskap Original Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae - metabolism Vacuolar Proton-Translocating ATPases - genetics Vacuolar Proton-Translocating ATPases - metabolism VMA3 V-ATPase epilepsy genetics ATP6V0C neurodevelopmental disorders
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Summary:	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. Mattison et al. identify ATP6V0C variants in patients with a neurodevelopmental syndrome. Using computational modelling and studies in Drosophila, yeast and worms, they show that the variants result in decreased V-ATPase function, providing evidence for their pathogenicity as well as insights into the underlying disease mechanisms.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Kari A Mattison, Gilles Tossing, Siddharth Banka, Philippe M Campeau and Andrew Escayg contributed equally to this work.
ISSN:	0006-8950 1460-2156 1460-2156
DOI:	10.1093/brain/awac330