ATP6V1B1

ATP6V1B1 encodes the B1 catalytic subunit of the vacuolar H⁺-ATPase (V-ATPase), functioning as an essential driver of proton secretion in specialized epithelial cells of the kidney collecting duct and inner ear. In the kidney, B1 is required both for apical H⁺ secretion in acid-secreting type A intercalated cells and for basolateral V-ATPase assembly and pendrin-dependent HCO₃⁻ secretion in non-type A intercalated cells, as demonstrated by knockout mice that exhibit impaired urinary acidification under acid load and blunted defense against alkalosis (PMID:29843146, PMID:37990364). In the inner ear, loss of ATP6V1B1 disrupts endolymph pH homeostasis, causing enlarged endolymphatic compartments and sensorineural hearing loss, a phenotype modulated by strain-specific genetic modifiers (PMID:28934385). Autosomal recessive loss-of-function mutations in ATP6V1B1 cause distal renal tubular acidosis with sensorineural deafness in humans (PMID:12414817).

1. 2000 High

   Identification of ATP6V1B1 as the disease gene for autosomal recessive distal renal tubular acidosis with sensorineural deafness established the B1 subunit as a non-redundant component of renal acid secretion and inner ear ion homeostasis.

   Evidence Linkage analysis and mutational screening in multiple rdRTA kindreds

   PMID:12414817 PMID:12500243 PMID:12579397

   Open questions at the time

   • The molecular mechanism by which B1 loss impairs inner ear function was not resolved
   • Compensation by the B2 isoform was not assessed
   • No animal model existed to dissect renal vs. otic phenotypes
2. 2003 High

   Cloning and tissue-level mapping of murine Atp6v1b1 confirmed restricted expression in kidney intercalated cells and testis, providing an animal system to study B1 function.

   Evidence Molecular cloning, Northern blotting, and immunolocalization in mouse kidney

   PMID:14585495

   Open questions at the time

   • Functional consequences of B1 loss in vivo were not yet tested
   • Expression in non-renal, non-testicular tissues was not systematically examined
3. 2017 High

   A spontaneous Atp6v1b1 mutant mouse demonstrated that B1 is required for endolymph pH homeostasis and that the severity of hearing loss is governed by strain-specific genetic modifiers, explaining variable penetrance of deafness in human patients.

   Evidence ABR thresholds, inner ear morphology, and backcross linkage analysis in MRL-background vtx mutant mice versus B6 knockouts

   PMID:28934385

   Open questions at the time

   • The modifier gene(s) on chromosome 13 were not identified
   • Whether endolymphatic pH change directly damages hair cells or acts indirectly was not resolved
4. 2018 High

   Atp6v1b1 knockout and heterozygous mice under acid load revealed that even partial B1 loss impairs urinary acidification, and that compensatory downregulation of pendrin occurs without redistribution of other V-ATPase subunits, indicating non-redundancy of B1 in acid-secreting intercalated cells.

   Evidence Atp6v1b1+/+, +/−, and −/− mice with HCl acid loading; renal membrane fractionation and immunolocalization

   PMID:29843146

   Open questions at the time

   • Whether B2 partially compensates at the functional level was not quantified
   • The mechanism linking B1 loss to pendrin downregulation in type A cells was unclear
5. 2020 Medium

   CRISPR knockout of ATP6V1B1 in HER2⁺ breast cancer cells showed that B1-dependent V-ATPase activity maintains intracellular pH permissive for granzyme bioactivity, extending the functional relevance of B1 beyond kidney and ear to tumor immune evasion.

   Evidence CRISPR/Cas9 KO in SKBR3 and JIMT-1 cells; intracellular pH measurement; ADCC assays

   PMID:33000417

   Open questions at the time

   • Whether B1 is normally expressed at physiologically relevant levels in breast cancer tissue in vivo is unclear
   • Direct biochemical link between pH change and granzyme inactivation was not reconstituted
6. 2021 Medium

   Minigene assays demonstrated that several exonic ATP6V1B1 variants cause disease not through missense effects but by disrupting exonic splicing enhancers, revealing an underappreciated mutational mechanism in rdRTA pathogenesis.

   Evidence Minigene splicing assays and RT-PCR for four exonic variants

   PMID:34157794

   Open questions at the time

   • Splicing effects were shown in heterologous minigene systems, not patient-derived cells
   • Impact on V-ATPase assembly and proton transport was not measured
7. 2023 High

   Studies in non-type A intercalated cells resolved that B1 is essential not only for apical acid secretion but also for basolateral V-ATPase assembly and pendrin-mediated bicarbonate secretion during alkalosis, fundamentally expanding the role of B1 to alkali defense.

   Evidence Atp6v1b1−/− mice with alkali loading; ex vivo microperfused collecting ducts; proximity ligation assays for V0–V1 assembly

   PMID:37990364

   Open questions at the time

   • Whether B1 directly facilitates V0–V1 assembly or acts indirectly through scaffolding interactions was not determined
   • Relevance of this basolateral role to inner ear pathology is unknown
8. 2025 Medium

   Knockdown of ATP6V1B1 in primary dendritic cells increased HIV-1 entry by altering endosomal pH and impairing endocytosis, demonstrating a role for B1-dependent acidification in innate antiviral restriction.

   Evidence shRNA knockdown in monocyte-derived dendritic cells; HIV-1 infection, endocytosis, and phagocytosis assays

   PMID:40029073

   Open questions at the time

   • Whether this reflects physiological B1 expression levels in dendritic cells in vivo is unknown
   • The specific endosomal compartment affected was not identified

• The structural basis of B1 versus B2 isoform-specific functions, the identity of genetic modifiers controlling hearing loss penetrance, and the mechanism by which B1 loss alters V0–V1 assembly remain unresolved.
• No high-resolution structure of B1-containing V-ATPase holoenzyme exists
• Chromosome 13 modifier gene(s) for hearing loss have not been identified
• Direct protein–protein interactions mediating B1-dependent V0–V1 assembly are uncharacterized