Renal Tubular Acidosis, Distal, 2, With Progressive Sensorineural Hearing Loss

1. Disease Information

Overview. Renal Tubular Acidosis, Distal, 2, With Progressive Sensorineural Hearing Loss (dRTA2) is a rare, autosomal recessive Mendelian disorder caused by biallelic loss-of-function mutations in ATP6V1B1 (also historically named ATP6B1), which encodes the B1 subunit of the apical vacuolar H⁺-ATPase (V-ATPase) proton pump. The defective proton pump impairs both (1) hydrogen-ion secretion by α-intercalated cells of the renal collecting duct, causing failure of urinary acidification despite systemic metabolic acidosis, and (2) acid–base/fluid homeostasis in the cochlea and endolymphatic sac, causing progressive, often early-onset, sensorineural hearing loss (OMIM #267300; Karet et al. 1999, PMID:9916796).

Key identifiers: - OMIM: #267300 — RENAL TUBULAR ACIDOSIS, DISTAL, 2, WITH PROGRESSIVE SENSORINEURAL HEARING LOSS; DRTA2 (omim.org/entry/267300) - Gene locus (OMIM): ATP6V1B1 (formerly ATP6B1), 267300 gene map locus 2p13.3 - MONDO: MONDO:0009968 (confirmed via ClinGen condition page: search.clinicalgenome.org/kb/conditions/MONDO:0009968) - Orphanet: Grouped historically under ORPHA:93611/93609 "Autosomal recessive distal renal tubular acidosis with deafness" — note this specific entity has since been merged/folded into the broader "Autosomal recessive distal renal tubular acidosis" (ORPHA:18 family) nomenclature (orpha.net) - Related/allelic disorder: OMIM #602722 — Distal RTA, 3, with or without SNHL (ATP6V0A4), the other major V-ATPase-associated recessive dRTA gene - Gene: HGNC:ATP6V1B1 (hgnc:851), chromosome 2p13.3

Synonyms: dRTA2; RTA with progressive nerve deafness; ATP6B1-related distal RTA; ATP6V1B1-related distal renal tubular acidosis with deafness.

Data derivation: Nearly all available information derives from aggregated case series, multi-family cohort studies, and case reports (not large-scale EHR/registry data) — consistent with the disease's rarity (fewer than a few hundred molecularly confirmed cases reported in the literature to date).

2. Etiology

Primary cause — genetic. Biallelic (homozygous or compound heterozygous) loss-of-function pathogenic variants in ATP6V1B1 are necessary and sufficient to cause the disease; it is a monogenic disorder with no known environmental or infectious primary cause.

Genetic risk factors: - Causal gene: ATP6V1B1 — pathogenic variants identified in ~10/26 (38%) of AR dRTA kindreds in early linkage cohorts, with ATP6V0A4 accounting for a further share and residual genetic heterogeneity (further genes not yet linked) (Karet et al. 1999, PMID:9916796; Ren Fail 2013, PMID:23923981). - Consanguinity substantially raises risk, given autosomal recessive inheritance and the prevalence of founder/recurrent alleles in specific populations (Turkish, Algerian, Moroccan, Tunisian, Saudi, Mexican cohorts all report recurrent homozygous variants in consanguineous families) (PMID:23923981; PMID:17216496; PMC12769223). - Population/founder variants: recurrent mutations reported include c.91C>T (p.R31X), IVS6+1G>A (intron 6 splice), c.1181G>A (p.R394Q, in the newly described dominant disease mechanism — see below), c.232G>A (p.G78R), c.497delC, and c.1155dupC. - Novel dominant mechanism (2025): Heterozygous variants at codon Arg394 (p.Arg394Gln, the most common; also p.Arg394Gly) act via a dominant-negative mechanism at the ATP-binding fold of the V1 domain, defining a distinct autosomal dominant form of ATP6V1B1-related dRTA that is clinically milder and has a lower prevalence of hearing loss than the classic recessive form; ~40% of these are de novo (Nephrol Dial Transplant 2025, PMID:39837581).

Environmental/lifestyle risk factors: None established as primary causes; this is a pure Mendelian disorder. (Acquired forms of dRTA exist — e.g., secondary to Sjögren syndrome, SLE, or drug toxicity — but these are etiologically and genetically distinct from ATP6V1B1-related dRTA2 and should not be conflated.)

Protective factors: None specific identified; there is no known modifier variant that reduces penetrance of biallelic loss-of-function ATP6V1B1 alleles reported in the literature reviewed.

Gene–environment interaction: Not applicable/documented — this is a fully penetrant monogenic condition once biallelic pathogenic variants are present.

3. Phenotypes

Renal/systemic phenotypes

Otologic phenotype

Onset/severity/progression: Metabolic/renal features typically present in infancy with failure to thrive; if untreated, nephrocalcinosis and rickets progress and chronic kidney disease can develop. Hearing loss is progressive and, in the recessive ATP6V1B1 form, frequently congenital or early-onset — distinguishing it clinically from the later-onset hearing loss seen with ATP6V0A4 mutations. One reported patient in a genotype-confirmed family had normal hearing despite the renal phenotype, indicating incomplete penetrance for the auditory component (PMID:17216496).

Quality of life impact: Untreated acidosis causes growth failure and bone disease impacting mobility and development; hearing loss, if uncorrected, impairs speech/language development in affected children, motivating early hearing-aid or cochlear-implant intervention and speech therapy (PMC12769223).

4. Genetic/Molecular Information

Causal gene: ATP6V1B1 (HGNC gene symbol; historically ATP6B1), located at 2p13.3. Encodes the kidney/cochlea-enriched B1 subunit of the cytoplasmic V1 domain of the vacuolar H⁺-ATPase.

Variant spectrum (illustrative, from cited cohorts): - c.91C>T (p.Arg31Ter) — nonsense, recurrent founder allele in multiple Mediterranean/Middle Eastern cohorts - c.[IVS6+1G>A] (intron 6 splice donor) — recurrent, loss of function - c.232G>A (p.Gly78Arg) — missense - c.497delC (p.Thr166ArgfsTer9) — frameshift - c.1155dupC (p.Ile386HisfsTer56) — frameshift - c.988G>A (p.Glu330Lys, "E330K") — novel missense (PMID:17216496) - c.1037C>G (p.Pro346Arg) — homozygous, Saudi consanguineous family (PMC12769223) - c.1181G>A (p.Arg394Gln) and c.1180C>G (p.Arg394Gly) — heterozygous, dominant-negative mechanism defining a distinct AD subtype (19/20 and 1/20 index cases respectively in the largest cohort to date) (PMID:39837581)

Variant classification: Most reported alleles are pathogenic/likely pathogenic per ACMG criteria (nonsense, frameshift, canonical splice-site); the Arg394 variants are notable exceptions of uncertain historical significance now reclassified as pathogenic via a dominant-negative mechanism.

Functional consequence: Predominantly loss of function (nonsense-mediated decay, truncation, splice disruption) for the classic recessive disease; the Arg394 substitutions instead act via a dominant-negative mechanism, disrupting ATP binding/hydrolysis at the nucleotide-binding fold of the V1 domain without eliminating the protein (PMID:39837581).

Allele frequency: Population database (gnomAD) frequency data specifically for the classic recessive pathogenic alleles were not comprehensively retrievable in this search; the dominant p.Arg394Gln/Gly variants are reported as rare/absent in gnomAD in the discovery cohort, consistent with pathogenicity.

Zygosity: Recessive disease requires homozygous or compound heterozygous biallelic variants; the newly described dominant subtype requires only a single heterozygous Arg394 variant (often de novo, ~40% of cases).

Modifier genes: None specifically established in humans; in the MRL-Atp6v1b1^vtx^ mouse model, the inner-ear phenotype is strain-dependent and lost on a C57BL/6J background, demonstrating strain-specific genetic modifiers of the inner ear phenotype (PMID:28934385).

Related/allelic disease genes (differential diagnosis within hereditary dRTA): ATP6V0A4 (dRTA3, OMIM #602722, later-onset hearing loss ~39%), SLC4A1 (AE1 anion exchanger; both AD and AR dRTA, ~15% of cases, less commonly with deafness), FOXI1 (transcription factor for acid-secreting cell differentiation), WDR72 (trafficking; also causes amelogenesis imperfecta) — together these five genes account for the great majority of hereditary dRTA (NCBI GeneReviews NBK547595).

Epigenetic/chromosomal information: No epigenetic mechanism reported. One case report describes a contiguous gene deletion at 2p13.3 encompassing ATP6V1B1 and the neighboring VAX2 gene, producing dRTA plus retinal dysfunction from VAX2 haploinsufficiency — illustrating that large structural deletions at this locus can extend the phenotype (PMC4630852, "A role for VAX2 in correct retinal function revealed by a novel genomic deletion at 2p13.3").

5. Environmental Information

This is a monogenic Mendelian disorder; no toxin, occupational exposure, radiation, or infectious trigger is described as causal. Environmental factors are not primary drivers, though secondary/acquired dRTA (a phenotypically overlapping but etiologically distinct entity) can arise from autoimmune disease (Sjögren syndrome, SLE), drug toxicity (amphotericin B, lithium, ifosfamide), or toxin exposure — these should not be curated under this Mendelian gene-disease entry.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

1. Molecular defect: Biallelic loss-of-function variants in ATP6V1B1 → absent/non-functional B1 subunit of the V1 cytoplasmic domain of the vacuolar H⁺-ATPase.
2. Cellular consequence — kidney: The V-ATPase, normally trafficked to the apical membrane of α-intercalated cells in the cortical and medullary collecting duct, fails to secrete H⁺ into the tubular lumen. This proton pump is functionally coupled to the basolateral Cl⁻/HCO₃⁻ exchanger AE1 (encoded by SLC4A1) (Oxford NDT review, "Genetic causes and mechanisms of distal renal tubular acidosis").
3. Physiological consequence — kidney: Failure of net acid excretion → inability to lower urine pH below ~5.3 despite systemic metabolic acidosis → hyperchloremic, normal-anion-gap metabolic acidosis with hypokalemia (potassium wasting driven by aldosterone-mediated compensation).
4. Downstream systemic consequences: Chronic acidosis mobilizes bone buffer (causing rickets/osteomalacia and growth failure), promotes hypercalciuria and hypocitraturia (low urinary citrate, itself a stone/nephrocalcinosis inhibitor), driving nephrocalcinosis and nephrolithiasis, which can progress to chronic kidney disease if untreated.
5. Cellular consequence — inner ear: ATP6V1B1 is co-expressed in the cochlea and endolymphatic sac epithelium, where V-ATPase activity is required for normal endolymph pH/ion homeostasis. Loss of function disrupts this regulation, producing endolymphatic sac/duct and cochlear duct enlargement (hydrops), sometimes visualized as Mondini malformation or enlarged vestibular aqueduct, culminating in progressive sensorineural hearing loss (Karet et al. 1999, PMID:9916796; mouse model data, PMID:28934385).

Molecular pathway/complex: Vacuolar H⁺-ATPase (V-ATPase) multi-subunit proton pump — V1 (cytosolic, ATP hydrolysis) and V0 (membrane, proton translocation) domains; B1 subunit specifically confers kidney/cochlea tissue-specific apical targeting and ATP-binding function.

Molecular function (GO): proton-transporting ATPase activity, rotational mechanism (GO:0046961); proton-transporting V-type ATPase, V1 domain (GO:0033180).

Biological process (GO suggestions): - GO:0035494 — SNARE complex disassembly (unrelated—omit) - GO:0015992 — proton transport - GO:0006885 — regulation of pH - GO:0072659 — protein localization to plasma membrane (apical V-ATPase trafficking) - GO:0070295 — renal water absorption (adjacent process) - GO:0034220 — monoatomic ion transmembrane transport

Cell types (CL suggestions): - CL:1001432 — kidney collecting duct intercalated cell, or more specifically CL:1001225 — kidney collecting duct type A intercalated cell (α-intercalated cell) - CL:0000601 — inner ear hair cell (auditory), CL:0002210 — vestibular hair cell, or cochlear/endolymphatic sac epithelial cell (no highly specific CL term found for endolymphatic sac epithelium specifically — consider free text with CL:0000066 epithelial cell as fallback)

Biochemical abnormalities: Defective apical H⁺-ATPase → failure of luminal acidification; secondary hypokalemia via aldosterone-driven distal Na⁺ reabsorption/K⁺ secretion; hypocitraturia from intracellular acidosis increasing citrate reabsorption in proximal tubule.

Tissue damage mechanism: Chronic acidosis-driven bone demineralization (buffering) and nephrocalcinosis-related tubulointerstitial injury; in the inner ear, endolymphatic hydrops/structural malformation rather than classical "damage," reflecting a developmental/homeostatic ion-transport defect.

Omics/advanced technology data: No single-cell, spatial transcriptomic, or large-scale multi-omics dataset specific to this Mendelian disease was identified in this search; mechanistic understanding derives chiefly from candidate-gene physiology and mouse models (see Model Organisms, below).

7. Anatomical Structures Affected

Organ level: - Primary: Kidney (collecting duct — cortical and medullary segments); inner ear (cochlea, endolymphatic sac/duct, vestibular apparatus) - Secondary: Skeletal system (rickets/osteomalacia from chronic acidosis); occasionally eye (in contiguous 2p13.3 deletion cases involving VAX2, PMC4630852) - Body systems: Renal/urinary, auditory/vestibular, skeletal, endocrine (secondary hyperparathyroidism from chronic acidosis and hypercalciuria)

Tissue/cell level: - Renal collecting duct α-intercalated cells (apical H⁺-ATPase-expressing epithelium) - Cochlear epithelium and endolymphatic sac epithelium

Subcellular level (GO Cellular Component): - GO:0016324 — apical plasma membrane (site of V-ATPase mislocalization/dysfunction) - GO:0033180 — proton-transporting V-type ATPase, V1 domain - GO:0016471 — vacuolar proton-transporting V-type ATPase complex

Localization (UBERON suggestions): - UBERON:0001293 — kidney collecting duct - UBERON:0001982 — intercalated cell (if available) or UBERON:0004134 — collecting duct epithelium - UBERON:0002365 — cochlear duct - UBERON:0009663 — endolymphatic sac - UBERON:0001846 — vestibular aqueduct region (or closest available UBERON term for the osseous/membranous vestibular aqueduct)

Laterality: Bilateral, symmetric involvement of both kidneys and both ears is typical.

8. Temporal Development

• Onset: Renal/metabolic features classically present in infancy (failure to thrive, vomiting, dehydration episodes); hearing loss in the ATP6V1B1-associated recessive form also frequently has infantile/early-childhood onset, distinguishing it from the typically later pediatric/adult-onset hearing loss of ATP6V0A4-related disease (GeneReviews NBK547595).
• Onset pattern: Insidious/chronic for the metabolic and skeletal manifestations; the hearing loss is explicitly progressive, per the disease name.
• Progression: Without alkali therapy, progressive nephrocalcinosis, rickets/osteomalacia, and growth failure occur; with adequate alkali replacement, renal and skeletal manifestations are largely controlled and growth normalizes, but hearing loss progression is not halted by metabolic treatment — it requires audiologic management independently (hearing aids, cochlear implants) (search synthesis from GeneReviews and PMC12769223).
• Disease course: Chronic, lifelong condition requiring continuous alkali therapy; renal function can be preserved long-term with good metabolic control, though nephrocalcinosis, once established, is generally irreversible.
• Critical periods: Early diagnosis and initiation of alkali therapy in infancy is critical to prevent growth failure/rickets; early identification of hearing loss (audiometry) and early hearing intervention are critical for speech/language development.

9. Inheritance and Population

Epidemiology: Precise prevalence for the specific ATP6V1B1-associated subtype is not separately tabulated in major epidemiologic databases. For hereditary dRTA overall, UK data estimate a prevalence of 0.46–1.60 per 10,000 (i.e., roughly 1 in 6,250–21,700), of which hereditary causes account for ~22% of cases (GeneReviews NBK547595). ATP6V0A4 and ATP6V1B1 together account for approximately 70% of hereditary dRTA cases; ~350 total cases of hereditary dRTA have been reported in the literature to date.

Inheritance pattern: Autosomal recessive (classic form) — biallelic pathogenic ATP6V1B1 variants required, 25% recurrence risk for future siblings of an affected proband when both parents are carriers. A newly recognized autosomal dominant subtype exists for heterozygous p.Arg394Gln/Gly variants (50% transmission risk to offspring; ~40% de novo) (PMID:39837581).

Penetrance/expressivity: The renal phenotype is essentially fully penetrant in biallelic loss-of-function carriers; the auditory phenotype shows incomplete penetrance — approximately 70% of ATP6V1B1-mutation-positive patients develop hearing loss, and at least one reported sibling with confirmed biallelic variants had normal hearing (PMID:17216496; PMID:23923981).

Consanguinity: A major risk factor and frequently reported in case series (Turkish, Saudi, Algerian, Moroccan, Tunisian cohorts), consistent with recessive inheritance and enrichment of recurrent founder alleles in these populations.

Founder effects: Recurrent alleles (e.g., c.91C>T/p.R31X, IVS6+1G>A) reported repeatedly within specific consanguineous/regional populations (Turkey, North Africa) suggest founder mutations.

Population demographics: No strong sex predilection reported (autosomal disease). Geographic clustering of specific pathogenic alleles has been described in Turkish, Algerian, Moroccan, Tunisian, Mexican, Chinese, and Saudi cohorts, likely reflecting consanguinity/founder effects rather than true regional prevalence differences.

Carrier frequency: Specific gnomAD-derived carrier frequency data for ATP6V1B1 pathogenic alleles were not comprehensively retrieved in this search; given disease rarity, expected carrier frequency for common pathogenic alleles is low in outbred populations but may be substantially elevated in specific consanguineous or founder populations.

10. Diagnostics

Laboratory tests: - Serum electrolytes/venous or arterial blood gas: hyperchloremic, normal-anion-gap metabolic acidosis, hypokalemia (e.g., case report: serum K+ 3.0 mmol/L, TCO₂ 11 mmol/L; PMC12769223) - Urine pH: inappropriately elevated (>5.3–5.5, e.g., 8.5 in one reported case) despite systemic acidosis - Urine anion gap: positive (reflecting impaired ammonium excretion) - Urinary calcium/citrate: hypercalciuria, hypocitraturia - Ammonium chloride loading test / furosemide-fludrocortisone test: used historically to confirm the urinary acidification defect in equivocal (incomplete) cases

Imaging: - Renal ultrasound: medullary nephrocalcinosis (hyperechoic pyramids), the dominant imaging finding (present in up to ~86–90% of cohorts) - Temporal bone/brain MRI or CT: cochlear malformation (e.g., Mondini deformity), enlarged vestibular aqueduct, enlarged endolymphatic sac (PMC12769223; PMC3433113 "Endolymphatic Sac Enlargement in a Girl with a Novel Mutation for Distal Renal Tubular Acidosis and Severe Deafness") - Skeletal survey/DEXA for rickets/osteomalacia assessment when clinically indicated

Audiologic testing: Auditory brainstem response (ABR) in infants; standard audiometry in older children/adults; recommended as part of annual surveillance in genetically at-risk individuals (GeneReviews NBK547595).

Genetic testing: - Multigene panel covering ATP6V0A4, ATP6V1B1, SLC4A1, FOXI1, WDR72 is the recommended first-tier approach given phenotypic overlap - Single-gene sequencing of ATP6V1B1 appropriate when hearing loss is a prominent early feature (higher pretest probability than ATP6V0A4) - Exome/genome sequencing appropriate when panel testing is non-diagnostic - Testing should also assess for larger deletions (e.g., 2p13.3 contiguous gene deletion involving ATP6V1B1 and VAX2, PMC4630852)

Clinical/differential diagnosis: - Proximal RTA (Type 2) — preserved urinary acidification capacity, elevated fractional HCO₃⁻ excretion, distinguishes from dRTA - Mixed RTA (Type 3, CA2-related) — combined proximal/distal defects, often with osteopetrosis and cerebral calcification - ATP6V0A4-related dRTA3 — later-onset hearing loss (39% vs 70% for ATP6V1B1), otherwise similar renal phenotype - SLC4A1-related dRTA — autosomal dominant (milder, adult-onset) or autosomal recessive (in Southeast Asian populations, often with hemolytic anemia — a separate OMIM entry, "dRTA 4, with hemolytic anemia") - Acquired/secondary dRTA — autoimmune (Sjögren, SLE), drug-induced, obstructive uropathy — distinguished by later onset, absence of family history/biallelic genetic findings

Screening: No population newborn screening program exists specifically for this condition; family/cascade genetic testing and carrier screening are appropriate in consanguineous families or those with a known proband, per standard genetic counseling practice for autosomal recessive disease.

11. Outcome/Prognosis

Survival/mortality: With timely diagnosis and adequate alkali therapy, life expectancy is not thought to be significantly reduced; mortality data specific to this entity were not identified in this search, consistent with it being primarily a morbidity- (not mortality-) associated disorder when treated.

Renal outcome: Adequate, sustained alkali therapy from infancy largely normalizes growth and substantially reduces progression of nephrocalcinosis and skeletal disease; delayed diagnosis or poor treatment adherence is associated with progressive nephrocalcinosis, chronic kidney disease, and persistent growth failure/rickets.

Auditory outcome: Hearing loss is progressive and not preventable by metabolic (alkali) treatment — it requires independent audiologic monitoring and intervention (hearing aids, cochlear implantation) (synthesis from GeneReviews NBK547595 and PMC12769223).

Complications: Nephrocalcinosis/nephrolithiasis, chronic kidney disease (in undertreated/late-diagnosed cases), rickets/osteomalacia, growth failure, and (for the auditory component) speech/language delay if hearing loss is not addressed early.

Prognostic factors: Early diagnosis and treatment initiation is the strongest modifiable prognostic factor for renal/skeletal outcomes; genotype may influence auditory prognosis (ATP6V1B1 loss-of-function variants carry higher risk and earlier onset of hearing loss than ATP6V0A4 variants or the newly described dominant Arg394 ATP6V1B1 variants, which have lower hearing-loss prevalence) (PMID:39837581).

12. Treatment

Pharmacotherapy — alkali replacement (mainstay of therapy): - Oral alkalinizing agents: potassium bicarbonate and/or potassium citrate/sodium citrate combinations (e.g., Polycitra-K), dosed to correct acidosis and hypokalemia; infants typically require higher doses (≥5 mEq/kg/day), tapering to 1–3 mEq/kg/day with age (GeneReviews NBK547595) - ADV7103 / Sibnayal® — an EU-approved prolonged-release combination granule formulation of potassium citrate (1/3) and potassium bicarbonate (2/3), enabling twice-daily dosing and improved adherence/quality of life versus immediate-release formulations (PMC7701073; PMC12351860 "6-year treatment follow-up with an extended-release alkaline formulation (Sibnayal®)")

Suggested NCIT terms: - NCIT:C15986 (Pharmacotherapy) — generic action for alkali therapy - Consider therapeutic_agent binding to CHEBI potassium citrate/potassium bicarbonate where available

Auditory/otologic management: - Hearing aids for mild-moderate loss - Cochlear implantation for severe-profound bilateral sensorineural hearing loss (evaluated in the reported Saudi case, PMC12769223) - NCIT term: consider NCIT:C15747 (Supportive Care) or a device-specific code for cochlear implantation (no clean NCIT clinical-action term identified in this search — verify via OAK before curating per repository convention)

Rehabilitative/supportive care: - Speech and language therapy for children with hearing loss (NCIT:C159273 — Speech Therapy) - Genetic counseling for families (NCIT:C15240 — Genetic Counseling) - Nutritional/vitamin D and calcium management for rickets/osteomalacia where indicated

Surgical/interventional: Generally not indicated for the renal component unless complicated by symptomatic nephrolithiasis requiring urologic intervention; cochlear implant surgery for severe hearing loss, as above.

Monitoring/surveillance: Regular serum electrolytes and renal function (every 3–4 months in infants/young children, 6–12 months in older children/adults); annual renal ultrasound for nephrocalcinosis; annual audiometry for at-risk individuals (GeneReviews NBK547595).

Experimental/investigational: No gene therapy, targeted molecular therapy, or disease-modifying (non-alkali) pharmacotherapy specific to ATP6V1B1-related dRTA was identified in this search; management remains alkali-replacement plus supportive/audiologic care. No specific NCT-registered trials specific to ATP6V1B1-dRTA2 (as opposed to dRTA broadly) were identified.

Treatment outcomes: Alkali therapy effectively corrects acidosis/hypokalemia and, when initiated early, substantially improves growth and reduces nephrocalcinosis progression; it does not alter the course of the hearing loss.

13. Prevention

Primary prevention: Not applicable in the traditional sense for a monogenic disease — the principal preventive strategy is genetic counseling and, where desired by families, reproductive options (carrier testing, prenatal diagnosis, preimplantation genetic testing) in known-carrier or consanguineous families.

Secondary prevention: Early biochemical diagnosis (screening infants with unexplained failure to thrive/metabolic acidosis) and early audiologic screening in at-risk families/siblings of an affected proband allows earlier intervention.

Tertiary prevention: Sustained alkali therapy prevents/limits progression of nephrocalcinosis, rickets, and growth failure; regular audiologic surveillance enables timely hearing intervention to limit speech/language delay.

Genetic counseling: Standard autosomal recessive counseling (25% recurrence risk per pregnancy for carrier parents); for the newly described dominant Arg394 subtype, 50% transmission risk applies, with ~40% of cases arising de novo (PMID:39837581).

Screening: No dedicated population-level newborn screening program for this specific disorder; cascade testing within affected families is the practical screening approach.

14. Other Species / Natural Disease

No naturally occurring ATP6V1B1-related disease in companion animals or livestock was identified in this search (no OMIA entry surfaced). The primary cross-species data come from engineered/spontaneous laboratory mouse models (see Section 15).

15. Model Organisms

Mouse models (NCBITaxon:10090):

1. Conventional Atp6v1b1 knockout mice (Dou H, Finberg K, Cardell EL, Lifton R, Choo D. "Mice lacking the B1 subunit of H+-ATPase have normal hearing." Hearing Research 2003;180:76-84): These mice demonstrated a requirement for the B1 subunit for maximal urinary acidification upon acid challenge but no spontaneous acidosis and normal hearing — an important negative/discordant model illustrating incomplete phenotype recapitulation, likely due to compensation by the paralogous B2 subunit in this genetic background.

2. MRL-Atp6v1b1^vtx/vtx^ ("vortex") spontaneous mutant mice (PMID:28934385/PMID:28934385, Hum Mol Genet 2017;26(19):3722-3735, "Hearing loss without overt metabolic acidosis in ATP6V1B1 deficient MRL mice, a new genetic model for non-syndromic deafness with enlarged vestibular aqueducts"): A spontaneous Atp6v1b1 mutation on the MRL/MpJ background causes profound hearing impairment associated with enlarged endolymphatic sac, endolymphatic duct, utricle, saccule, and cochlear duct (swollen membranous labyrinth from excess endolymph), modeling non-syndromic EVA-associated deafness — but again without the overt metabolic acidosis seen in human disease. Critically, this inner-ear phenotype is lost when the mutation is bred onto a C57BL/6J background, demonstrating strain-specific genetic modifiers — an important HUMAN_MODEL_MISMATCH-type caveat for translational fidelity curation (relationship: PARTIALLY_RECAPITULATES for hearing loss/EVA; FAILS_TO_RECAPITULATE for systemic acidosis, in both models).

3. Atp6v0a4 knockout mouse (PMC3427075, "Atp6v0a4 knockout mouse is a model of distal renal tubular acidosis with hearing loss, with additional extrarenal phenotype"): A model of the allelic disorder (dRTA3) rather than ATP6V1B1-dRTA2 itself, but relevant as a comparator model within the same V-ATPase pathway and useful for comparative pathway modeling.

Model limitations: No existing mouse model fully recapitulates the combined human phenotype of overt metabolic acidosis plus hearing loss simultaneously — the conventional knockout has neither acidosis nor deafness, while the MRL-vortex model has deafness/EVA but not spontaneous acidosis. This is a significant translational gap worth flagging as a HUMAN_MODEL_MISMATCH in curation, since B-subunit paralog compensation (B1/B2) and genetic background strongly modulate phenotype expression in mice in ways not yet fully mapped to human genotype-phenotype correlations.

Cell-based/in vitro models: No iPSC-derived or organoid model specific to ATP6V1B1-dRTA2 was identified in this search.

Summary of Key Ontology Term Suggestions

Sources

• OMIM #267300 — RENAL TUBULAR ACIDOSIS, DISTAL, 2, WITH PROGRESSIVE SENSORINEURAL HEARING LOSS; DRTA2
• OMIM #602722 — RENAL TUBULAR ACIDOSIS, DISTAL, 3, WITH OR WITHOUT SENSORINEURAL HEARING LOSS; DRTA3
• Karet FE et al. 1999. Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. PMID:9916796
• Subasioglu Uzak A et al. 2013. ATP6V1B1 mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families. Ren Fail. PMID:23923981
• Gil H et al. 2007. Distal RTA with nerve deafness: clinical spectrum and mutational analysis in five children. Pediatr Nephrol. PMID:17216496
• Naveen PS et al. 2015. Distal renal tubular acidosis with nerve deafness secondary to ATP6B1 gene mutation. PMID:25579729
• Distal Renal Tubular Acidosis With Sensorineural Deafness in a Saudi Female: Case Report (PMC12769223)
• NCBI GeneReviews — Hereditary Distal Renal Tubular Acidosis (NBK547595)
• A novel, dominant disease mechanism of distal renal tubular acidosis with specific variants in ATP6V1B1. Nephrol Dial Transplant 2025. PMID:39837581
• Genetic causes and mechanisms of distal renal tubular acidosis. Nephrol Dial Transplant.
• Endolymphatic Sac Enlargement in a Girl with a Novel Mutation for Distal Renal Tubular Acidosis and Severe Deafness (PMC3433113)
• A role for VAX2 in correct retinal function revealed by a novel genomic deletion at 2p13.3 causing distal RTA (PMC4630852)
• Hearing loss without overt metabolic acidosis in ATP6V1B1 deficient MRL mice, a new genetic model for non-syndromic deafness with enlarged vestibular aqueducts. Hum Mol Genet 2017. PMID:28934385
• Mice lacking the B1 subunit of H+-ATPase have normal hearing (Dou et al. 2003, Hearing Research)
• Atp6v0a4 knockout mouse is a model of distal renal tubular acidosis with hearing loss (PMC3427075)
• ClinGen condition page — renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss (MONDO:0009968)
• Orphanet: Autosomal recessive distal renal tubular acidosis with deafness (ORPHA:93611)
• NORD/MONDO disease page — renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss
• Efficacy and safety of an innovative prolonged-release combination drug (ADV7103) in patients with distal renal tubular acidosis (PMC7701073)
• 6-year treatment follow-up with an extended-release alkaline formulation (Sibnayal®) in primary distal renal tubular acidosis (PMC12351860)

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