ATP6V1A: V-ATPase Catalytic Subunit A – Key Regulator of Acidification and Neurodegeneration
Comprehensive genomic, proteomic, and clinical annotation of ATP6V1A, the V1 catalytic subunit of vacuolar ATPase, with links to distal renal tubular acidosis, neurodevelopmental disorders, and cancer.
Gene Information Card
| Symbol | ATP6V1A |
|---|---|
| Full Name | ATPase H+ Transporting V1 Subunit A |
| Gene Type | protein-coding |
| Chromosomal Location | 3q13.31 |
| NCBI Gene ID | 523 ncbi.nlm.nih.gov/gene/523 |
| Ensembl ID | ENSG00000114573 |
| UniProt ID | P38606 |
| OMIM ID | 607027 |
| HGNC ID | 862 |
| Aliases | VPP2, Vma1, ATP6A1, V1A, ATP6V1A1 |
Description
ATP6V1A encodes the catalytic A subunit of the V1 domain of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments such as lysosomes, endosomes, and Golgi vesicles. The A subunit contains the ATP-binding site and is essential for proton translocation. Mutations in ATP6V1A cause autosomal recessive distal renal tubular acidosis with sensorineural deafness and have been associated with neurodevelopmental disorders. Altered expression is observed in various cancers, where V-ATPase activity supports tumor microenvironment acidification and metastasis.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Distal renal tubular acidosis (dRTA) with deafness | Loss-of-function mutations impair proton secretion in renal intercalated cells, leading to metabolic acidosis and hearing loss | OMIM #267300; multiple homozygous/compound heterozygous mutations reported |
| Neurodevelopmental disorder with microcephaly and seizures | Missense mutations disrupt V-ATPase assembly or catalytic activity, impairing neuronal acidification and synaptic vesicle recycling | ClinVar; de novo and inherited variants |
| Cancer (multiple types) | Overexpression of ATP6V1A enhances extracellular acidification, promoting invasion and chemoresistance | COSMIC; RNA-seq upregulation in breast, lung, and pancreatic cancers |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Kidney | 28.5 | High |
| Brain (cerebellum) | 22.1 | High |
| Liver | 18.3 | Medium |
| Heart | 15.7 | Medium |
| Lung | 12.4 | Medium |
| Pancreas | 10.2 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 32.1 | High expression |
| HeLa | 27.8 | High expression |
| A549 | 24.5 | High expression |
| MCF7 | 19.3 | Medium expression |
| K562 | 14.6 | Medium expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1192C>T (p.Arg398Trp) | Missense | <0.01% | Loss of ATP hydrolysis activity; causes dRTA |
| c.1546G>A (p.Glu516Lys) | Missense | <0.01% | Impaired V1-V0 assembly; neurodevelopmental disorder |
| c.2020_2021del (p.Leu674fs) | Frameshift | <0.01% | Premature truncation; complete loss of function |
| c.947T>C (p.Leu316Pro) | Missense | <0.01% | Reduced catalytic efficiency; dRTA with deafness |
Mutation functional classification
Loss of Function (LOF)
Most pathogenic mutations (nonsense, frameshift, splice-site, and missense affecting ATP-binding or catalysis) lead to loss of V-ATPase activity, causing dRTA and neurodevelopmental phenotypes.
Gain of Function (GOF)
Not reported; no activating mutations are documented in COSMIC or ClinVar.
Dominant Negative (DN)
Heterozygous missense mutations in the catalytic domain may exert dominant-negative effects by incorporating mutant A subunits into the V1 complex, impairing overall V-ATPase function.
View complete mutation data：
Gene Ontology (GO)
Pathways
• V-ATPase mediated acidification (Reactome R-HSA-1222556)
• Lysosome (KEGG hsa04142)
• Oxidative phosphorylation (KEGG hsa00190)
• Synaptic vesicle cycle (KEGG hsa04721)
Protein Summary
The ATP6V1A protein (UniProt P38606) is a 617-amino-acid catalytic subunit of the V1 peripheral domain of V-ATPase. It contains the nucleotide-binding pocket (Walker A motif) and is responsible for ATP hydrolysis that drives proton translocation. The protein is highly conserved across eukaryotes. Post-translational modifications include phosphorylation at Ser384 and Lys268, which regulate activity. Structural studies show that the A subunit forms a hexameric ring with the B subunit in the V1 domain. Defects in ATP6V1A disrupt organellar acidification, leading to impaired receptor recycling, lysosomal degradation, and neurotransmitter loading.
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