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 Mizuguchi, Satoko Miyatake, Noriko Miyake, Atsuo Fukuda, Naomichi Matsumoto () and Hirotomo Saitsu ()
Additional contact information
Kazushi Aoto: Hamamatsu University School of Medicine
Mitsuhiro Kato: Showa University School of Medicine
Tenpei Akita: Hamamatsu University School of Medicine
Mitsuko Nakashima: Hamamatsu University School of Medicine
Hiroki Mutoh: Hamamatsu University School of Medicine
Noriyuki Akasaka: National Hospital Organization Nishiniigata Chuo Hospital
Jun Tohyama: National Hospital Organization Nishiniigata Chuo Hospital
Yoshiko Nomura: Segawa Neurological Clinic for Children
Kyoko Hoshino: Segawa Neurological Clinic for Children
Yasuhiko Ago: Ibaraki Children’s Hospital
Ryuta Tanaka: University of Tsukuba
Orna Epstein: Shamir Medical Center, Tzrifin
Revital Ben-Haim: Shamir Medical Center, Tzrifin
Eli Heyman: Shamir Medical Center, Tzrifin
Takehiro Miyazaki: Hamamatsu University School of Medicine
Hazrat Belal: Hamamatsu University School of Medicine
Shuji Takabayashi: Hamamatsu University School of Medicine
Chihiro Ohba: Yokohama City University Graduate School of Medicine
Atsushi Takata: Yokohama City University Graduate School of Medicine
Takeshi Mizuguchi: Yokohama City University Graduate School of Medicine
Satoko Miyatake: Yokohama City University Graduate School of Medicine
Noriko Miyake: Yokohama City University Graduate School of Medicine
Atsuo Fukuda: Hamamatsu University School of Medicine
Naomichi Matsumoto: Yokohama City University Graduate School of Medicine
Hirotomo Saitsu: Hamamatsu University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22389-5

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