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

Kazushi Aoto*, Mitsuhiro Kato, Tenpei Akita, Mitsuko Nakashima, Hiroki Mutoh, Noriyuki Akasaka, Jun Tohyama, Yoshiko Nomura, Kyoko Hoshino, Yasuhiko Ago, Ryuta Tanaka, Orna Epstein, Revital Ben-Haim, Eli Heyman, Takehiro Miyazaki, Hazrat Belal, Shuji Takabayashi, Chihiro Ohba, Atsushi Takata, Takeshi MizuguchiSatoko Miyatake, Noriko Miyake, Atsuo Fukuda, Naomichi Matsumoto*, Hirotomo Saitsu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 (Atp6v0a1R741Q) and A512P (Atp6v0a1A512P) 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 Atp6v0a1A512P/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.

Original languageEnglish
Article number2107
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2021
Externally publishedYes


FundersFunder number
Takeda Science Foundation
Japan Agency for Medical Research and DevelopmentJP15H05872, JP19ek0109297
Japan Society for the Promotion of Science
Ministry of Education, Culture, Sports, Science and TechnologyJP16H05357, JP17K08534, JP17K10080, JP20K07243
Japan Science and Technology AgencyJP20H03641, JP16H05160, JP17H01539
Ministry of Health, Labour and Welfare


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