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

  • Nat Commun. 2021 Apr 8;12(1):2107. doi: 10.1038/s41467-021-22389-5.
Kazushi Aoto  1 ,  Mitsuhiro Kato  2 ,  Tenpei Akita  3 ,  Mitsuko Nakashima  4 ,  Hiroki Mutoh  4 ,  Noriyuki Akasaka  5  6 ,  Jun Tohyama  5 ,  Yoshiko Nomura  7  8 ,  Kyoko Hoshino  7  9 ,  Yasuhiko Ago  10  11 ,  Ryuta Tanaka  12 ,  Orna Epstein  13 ,  Revital Ben-Haim  13 ,  Eli Heyman  13 ,  Takehiro Miyazaki  4 ,  Hazrat Belal  4 ,  Shuji Takabayashi  14 ,  Chihiro Ohba  15 ,  Atsushi Takata  15 ,  Takeshi Mizuguchi  15 ,  Satoko Miyatake  15 ,  Noriko Miyake  15 ,  Atsuo Fukuda  3 ,  Naomichi Matsumoto  16 ,  Hirotomo Saitsu  17
Affiliations
  • 1. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. [email protected].
  • 2. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan.
  • 3. Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
  • 4. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
  • 5. Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital, Niigata, Japan.
  • 6. Department of Pediatrics, Niigata Prefecture Hamagumi Medical Rehabilitation Center for Disabled Children, Niigata, Japan.
  • 7. Segawa Neurological Clinic for Children, Tokyo, Japan.
  • 8. Yoshiko Nomura Neurological Clinic for Children, Tokyo, Japan.
  • 9. Segawa Memorial Neurological Clinic for Children, Tokyo, Japan.
  • 10. Department of Neonatology, Ibaraki Children's Hospital, Mito, Japan.
  • 11. Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
  • 12. Ibaraki Pediatric Education and Training Station, University of Tsukuba, Mito, Japan.
  • 13. Pediatric Neurology and Development Center, Shamir Medical Center, Tzrifin, Beer Yaakov, Israel.
  • 14. Laboratory Animal Facilities & Services, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan.
  • 15. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 16. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. [email protected].
  • 17. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. [email protected].
PMID: 33833240 DOI: 10.1038/s41467-021-22389-5
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.