2013 Report on the State of the Art of Rare Disease Activities in Europe (Ireland)

This document has been produced by the Scientific Secretariat of the European Union Committee ofExperts on Rare Diseases (EUCERD, formerly the European Commission’s Rare Diseases Task Force)through the EUCERD Joint Action: Working for Rare Diseases (N° 2011 22 01, Coordinator: KateBushby, University of Newcastle, United Kingdom), within the European Union’s Second Programmeof Community Action in the Field of Health. More information on the European Union Committee of Experts on Rare Diseases can be found atwww.eucerd.eu

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

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