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Vacuolar H + -ATPases (V-ATPases) transport protons across cellular membranes to acidify various organelles.  ATP6V0A1  encodes the a1-subunit of the V0 domain of V-ATPases, which is strongly expressed in neurons. However, its role in brain development is unknown. Here we report four individuals with developmental and epileptic encephalopathy with  ATP6V0A1  variants: two individuals with a de novo missense variant (R741Q) and the other two individuals with biallelic variants comprising one almost complete loss-of-function variant and one missense variant (A512P and N534D). Lysosomal acidification is significantly impaired in cell lines expressing three missense ATP6V0A1 mutants. Homozygous mutant mice harboring human R741Q ( Atp6v0a1   R741Q  ) and A512P ( Atp6v0a1   A512P  ) variants show embryonic lethality and early postnatal mortality, respectively, suggesting that R741Q affects V-ATPase function more severely. Lysosomal dysfunction resulting in cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling and synaptic connectivity, and lowered neurotransmitter contents of synaptic vesicles are observed in the brains of  Atp6v0a1   A512P/A512P   mice. These findings demonstrate the essential roles of  ATP6V0A1/Atp6v0a1  in neuronal development in terms of integrity and connectivity of neurons in both humans and mice.

ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H+-ATPases is essential for brain development in humans and mice