Alternative titles; symbols
HGNC Approved Gene Symbol: ATP6V0A1
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:42,458,878-42,522,579 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | Developmental and epileptic encephalopathy 104 | 619970 | Autosomal dominant | 3 |
| Neurodevelopmental disorder with epilepsy and brain atrophy | 619971 | Autosomal recessive | 3 |
ATP-driven proton pumps associated with the clathrin-coated vesicles and synaptic vesicles are a group of polypeptides involved in basic cellular processes through acidification of intracellular organelles. These functions include intracellular targeting of enzymes to lysosomes and secretory granules, and receptor-ligand dissociation in receptor-mediated endocytosis (summary by Ozcelik et al., 1991).
Using a rat cDNA clone for the 116-kD subunit of the vacuolar proton pump, Ozcelik et al. (1991) mapped the gene to human chromosome 17 by study of rodent-human hybrid cell lines and the homologous gene to mouse chromosome 11 by a study of Chinese hamster or rat/mouse hybrid cell lines. In hybrid cell lines with fragments of chromosome 17, the VPP1 gene was shown to be located in region 17q21-qter.
In the course of constructing a transcription map of approximately 600 kb of genomic DNA surrounding the BRCA1 (113705) gene, Brody et al. (1995) identified the VPP1 gene, thus regionalizing it to 17q21.
Developmental and Epileptic Encephalopathy 104
In 2 unrelated patients (patients 1 and 2) with developmental and epileptic encephalopathy-104 (DEE104; 619970), Aoto et al. (2021) identified heterozygosity for the same mutation in the ATP6V0A1 gene (R741Q; 192130.0001). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The variant was not present in the gnomAD database. HEK293FT cells transfected with ATP6V0A1 containing the R741Q mutation had impaired lysosomal acidification. Homozygous mutant mice harboring the R741Q mutation in the Atp6v0a1 gene had embryonic lethality.
In 12 patients from 4 families with DEE104, Bott et al. (2021) identified de novo heterozygous mutations in the ATP6V0A1 gene (192130.0006-192130.0009). The mutations were identified by whole-exome sequencing.
Neurodevelopmental Disorder with Epilepsy and Brain Atrophy
In 2 unrelated patients (patients 3 and 4) with neurodevelopmental disorder with epilepsy and brain atrophy (NEDEBA; 619971), Aoto et al. (2021) identified compound heterozygosity for 2 mutations in the ATP6V0A1 gene (192130.0002-192130.0004). Each patient had one missense mutation and one likely loss-of function allele. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. HEK293FT cells transfected with ATP6V0A containing each of the 2 identified missense mutations, A512P or N534D, had impaired lysosomal acidification.
In 4 members of an Italian family (family I) and an unrelated Italian patient with NEDEBA, Bott et al. (2021) identified compound heterozygous mutations in the ATP6V0A1 gene (192130.0010-192130.0011). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies were not performed.
Aoto et al. (2021) developed mutant mice that were homozygous for an R741Q or an A512P mutation in the Atp6v0a1 gene. Homozygous mutant mice harboring the R741Q mutation had embryonic lethality. Homozygous mutant mice with the A512P mutation had lower body weight compared to wildtype mice and died at around 2 weeks of age. The mutant pups exhibited ataxia and had smaller brain size compared to wildtype. Lysosomal dysfunction and abnormal lysosome distribution, corresponding to increased cell death, was identified in neurons from the mutant mice. Impaired autophagy, reduced mTORC1 signaling, and lower neurotransmitter content in synaptic vessels were also seen. Aoto et al. (2021) concluded that Atp6v0a1 had an essential role in brain development in mice.
In C. elegans knockdown of unc32, the ortholog of ATP6V0A1, Bott et al. (2021) identified reduced expression of components of the autophagic machinery and lysosomal hydrolytic enzymes as well as increased expression of sqst1, a stress responsive autophagy receptor. Bott et al. (2021) then used CRISPR editing to introduce a mutation in unc32 at the site corresponding to the human R740Q mutation (192130.0006) in the ATP6V0A1 gene. The resulting worms showed developmental arrest at early larval stages.
This variant is designated ARG740GLN based on a different numbering system.
In 2 unrelated patients with developmental and epileptic encephalopathy-104 (DEE104; 619970), Aoto et al. (2021) identified heterozygosity for a c.2222G-A transition (c.2222G-A, NM_001130020.1) in the ATP6V0A gene, resulting in an arg741-to-gln (R741Q) substitution. The mutation was identified by whole-exome sequencing. In patient 1, the mutation was shown to be de novo. In patient 2, the mutation was not present in the mother but was not tested in the father. The variant was not present in the gnomAD database. HEK293FT cells transfected with ATP6V0A containing the R741Q mutation had impaired lysosomal acidification.
In 8 unrelated patients with DEE104, Bott et al. (2021) identified heterozygosity for a c.2219G-A transition (c.2219G-A, NM_001130021.3) in the ATP6V0A gene resulting in an arg740-to-gln (R741Q) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were all shown to be de novo. Neuro2a cell lines expressing ATP6V0A1 with the R740Q mutation showed impaired lysosomal acidification and autophagosome turnover.
In a patient (patient 3) with neurodevelopmental disorder with epilepsy and brain atrophy (NEDEBA; 619971), Aoto et al. (2021) identified compound heterozygosity for 2 mutations in the ATP6V0A1 gene: a c.1534G-C transversion (c.1534G-C, NM_001130020.1), resulting in an ala512-to-pro (A512P) substitution, and a 50-kb deletion (192130.0003) involving exons 1-13. The mutations were identified by whole-exome sequencing and the deletion breakpoints (chr17:40,599,557 and chr17:40,649,783, GRCh37), encompassing 835 bp, were confirmed by CGH array and long-range PCR. The parents were shown to be mutation carriers. The A512P mutation was not present in the gnomAD database. HEK293FT cells transfected with ATP6V0A containing the A512P mutation had impaired lysosomal acidification.
For discussion of the 50-kb deletion (chr17.40,599,557-40,649,783, GRCh37) in the ATP6V0A1 gene involving exons 1-13 that was identified in compound heterozygous state in a patient with neurodevelopmental disorder with epilepsy and brain atrophy (NEDEBA; 619971) by Aoto et al. (2021), see 192130.0002.
In a patient (patient 4) with neurodevelopmental disorder with epilepsy and brain atrophy (NEDEBA; 619971), Aoto et al. (2021) identified compound heterozygosity for 2 mutations in the ATP6V0A1 gene: a c.1600A-G transition (c.1600A-G, NM_001130020.1), resulting in an asn534-to-asp (N534D) substitution, and a c.196+1G-A transition in intron 2 (192130.0005), predicted to result in a splicing abnormality. The mutations, which were identified by whole-exome sequencing, were present in the carrier state in the parents. The N534D mutation was present in the gnomAD database at an allele frequency of 2/251,286, and the c.196+1G-A was present in gnomAD at an allele frequency of 2/251,356. HEK293FT cells transfected with ATP6V0A containing the N534D mutation had impaired lysosomal acidification.
For discussion of the c.196+1G-A transition (c.196+1G-A, NM_001130020.1) in intron 2 of the ATP6V0A1 gene, predicted to result in a splicing abnormality, that was identified in compound heterozygous state in a patient with neurodevelopmental disorder with epilepsy and brain atrophy (NEDEBA; 619971) by Aoto et al. (2021), see 192130.0004.
In a patient with developmental and epileptic encephalopathy-104 (DEE104; 619970), Bott et al. (2021) identified heterozygosity for a c.1429T-C transition (c.1429T-C, NM_001130021.3) in the ATP6V0A gene resulting in a ser477-to-pro (S477P) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was shown to be de novo. Functional studies were not performed.
In a patient with developmental and epileptic encephalopathy-104 (DEE104; 619970), Bott et al. (2021) identified heterozygosity for a c.1652G-A transition (c.1652G-A, NM_001130021.3) in the ATP6V0A gene, resulting in a gly551-to-glu (G551E) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was shown to be de novo. Functional studies were not performed.
In 2 unrelated patients with developmental and epileptic encephalopathy-104 (DEE104; 619970), Bott et al. (2021) identified heterozygosity for a c.2411G-A transition (c.2411G-A, NM_001130021.3) in the ATP6V0A gene, resulting in an arg804-to-his (R804H) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were all shown to be de novo. Functional studies were not performed.
In 4 members of an Italian family (family I), previously reported by Coppola et al. (2005), and an unrelated Italian patient with neurodevelopmental disorder with epilepsy and brain atrophy (NEDEBA; 619971), Bott et al. (2021) identified compound heterozygous mutations in the ATP6V0A1 gene: a 1-bp deletion (c.445delG, NM_001130021.3), predicted to result in a frameshift and premature termination (Glu149LysfsTer18), and a c.1483C-T transition, resulting in an arg495-to-trp (R495W) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in family I. The c.445delG mutation was not present in the gnomAD database, and the R495W mutation was present at an allele frequency of 0.00001315 in gnomAD. Neither mutation was present in a cohort of 200 Italian individuals.
For discussion of the c.1483C-T transition (c.1483C-T, NM_001130021.3) in the ATP6V0A1 gene, resulting in an arg495-to-trp (R495W) substitution, that was identified in compound heterozygous state in 5 patients with neurodevelopmental disorder with epilepsy and brain atrophy (NEDEBA; 619971) by Bott et al. (2021), see 192130.0010.
Aoto, K., Kato, M., Akita, T., Nakashima, M., Mutoh, H., Akasaka, N., Tohyama, J., Nomura, Y., Hoshino, K., Ago, Y., Tanaka, R., Epstein, O., and 13 others. ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H+-ATPases is essential for brain development in humans and mice. Nature Commun. 12: 2107, 2021. [PubMed: 33833240] [Full Text: https://doi.org/10.1038/s41467-021-22389-5]
Bott, L. C., Forouhan, M., Lieto, M., Sala, A. J., Ellerington, R., Johnson, J. O., Speciale, A. A., Criscuolo, C., Filla, A., Chitayat, D., Alkhunaizi, E., Shannon, P., and 15 others. Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy. Brain Commun. 3: fcab245, 2021. [PubMed: 34909687] [Full Text: https://doi.org/10.1093/braincomms/fcab245]
Brody, L. C., Abel, K. J., Castilla, L. H., Couch, F. J., McKinley, D. R., Yin, G.-Y., Ho, P. P., Merajver, S., Chandrasekharappa, S. C., Xu, J., Cole, J. L., Struewing, J. P., Valdes, J. M., Collins, F. S., Weber, B. L. Construction of a transcription map surrounding the BRCA1 locus of human chromosome 17. Genomics 25: 238-247, 1995. [PubMed: 7774924] [Full Text: https://doi.org/10.1016/0888-7543(95)80131-5]
Coppola, G., Criscuolo, C., De Michele, G., Striano, S., Barbieri, F., Striano, P., Perretti, A., Santoro, L., Brescia Morra, V., Sacca, F., Scarano, V., D'Adamo, A. P., Banfi, S., Gasparini, P., Santorelli, F. M., Lehesjoki, A. E., Filla, A. Autosomal recessive progressive myoclonus epilepsy with ataxia and mental retardation. J. Neurol. 252: 897-900, 2005. [PubMed: 15742102] [Full Text: https://doi.org/10.1007/s00415-005-0766-3]
Ozcelik, T., Suedhof, T. C., Francke, U. Chromosomal assignments of genes for vacuolar (endomembrane) proton pump subunits VPP1/Vpp-1 (116 kDa) and VPP3/Vpp-3 (58 kDa) in human and mouse. (Abstract) Cytogenet. Cell Genet. 58: 2008-2009, 1991.