Biallelic and de novo variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy

The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Here we identified 17 individuals from 14 unrelated families with variants in ATP6V0A1, the brain-enriched isoform in the V0 domain. Five affected subjects carried biallelic variants in this gene and presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals were found as de novo cases (missense variants) and showed severe developmental and epileptic encephalopathy. We describe that the disease-associated variants lead to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment. The R740Q mutation, which alone accounts for almost 50% of the variants identified in this cohort, causes autophagic dysfunction and a severe developmental defect in C. elegans. Altogether, our findings establish a novel cause of lysosomal disease and provide a direct link with endolysosomal acidification in the pathophysiology of these conditions.