ATP6V0A4 – Distal Renal Tubular Acidosis

ATP6V0A4 encodes the a4 subunit of the vacuolar H⁺-ATPase pump, critical for proton secretion in type A intercalated cells of the distal nephron. Pathogenic variants in ATP6V0A4 result in autosomal recessive distal renal tubular acidosis (dRTA), characterized by hyperchloremic metabolic acidosis, hypokalemia, nephrocalcinosis, and variable sensorineural hearing impairment (PMID:16611712). The hearing phenotype ranges from normal to early-onset progressive sensorineural loss, reflecting allelic heterogeneity. dRTA typically presents in infancy or early childhood but may also manifest later in life with incomplete acidification defects.

Genetic studies in cohorts and consanguineous families have identified over 12 distinct ATP6V0A4 pathogenic variants across 21 unrelated families, including nonsense, frameshift, splice-site, and missense changes (PMID:16611712; PMID:22854161). A recurrent frameshift c.1221del (p.Met408CysfsTer10) variant has been described in a homozygous state in a Tunisian infant presenting with classical dRTA and preserved hearing (PMID:22854161). Ensemble sequencing approaches in diverse populations have expanded the mutational spectrum to deep-intronic and founder alleles. Segregation of loss-of-function variants in multiple consanguineous pedigrees provides robust evidence for recessive inheritance.

Case-level reports document at least 25 affected probands with ATP6V0A4-associated dRTA, many with multigenerational segregation or homozygosity mapping, supporting a high penetrance of renal and extrarenal manifestations. Specific variant classes include frameshifts (e.g., c.1221del (p.Met408CysfsTer10)), splice-site alterations (e.g., c.1029+5G>A), and critical missense substitutions. Progressive sensorineural hearing loss has been directly observed by sequential audiometry in a Chinese patient harboring novel ATP6V0A4 mutations (PMID:22093743). Ethnically diverse cohorts reveal both recurrent founder variants and private mutations, underscoring the importance of comprehensive gene testing.

Functional assays have confirmed the pathogenicity of ATP6V0A4 variants by minigene splicing analyses and heterologous expression studies. A novel intronic change, c.1029+5G>A, leads to aberrant exon inclusion in vitro and absent transcript in patient leukocytes (PMID:29202719). Co-immunoprecipitation and acidification assays demonstrate that missense mutations disrupt a4–B1 subunit assembly and decrease pump activity, consistent with haploinsufficiency. Conversely, a recently described gain-of-function p.Val512Leu variant enhances V-ATPase stability and activity, broadening the phenotypic spectrum to include metabolic alkalosis (PMID:40299568). These concordant cellular studies provide moderate functional evidence in line with ClinGen criteria.

No studies to date have refuted the association between ATP6V0A4 variants and autosomal recessive distal RTA; all conflicting reports involve other genes or alternative inheritance modes. Occasional heterozygous carriers may present with incomplete dRTA, but segregation and functional data consistently support recessive pathogenicity for truncating and canonical splice-site variants.

In summary, ATP6V0A4 is definitively established as a cause of autosomal recessive distal RTA. Genetic testing for ATP6V0A4 variants should be part of diagnostic panels for patients with dRTA, particularly those with late-onset or progressive hearing loss. Functional assays aid in variant classification, and identification of gain-of-function alleles may guide novel therapeutic approaches.

References

• Journal of the American Society of Nephrology • 2006 • Genetic investigation of autosomal recessive distal renal tubular acidosis: evidence for early sensorineural hearing loss associated with mutations in the ATP6V0A4 gene PMID:16611712
• Clinical Nephrology • 2014 • Novel ATP6V0A4 mutation described in a Tunisian patient with distal renal tubular acidosis PMID:22854161
• International Journal of Pediatric Otorhinolaryngology • 2012 • Novel mutations in ATP6V0A4 are associated with atypical progressive sensorineural hearing loss in a Chinese patient with distal renal tubular acidosis PMID:22093743
• BMC Nephrology • 2017 • An in vitro splicing assay reveals the pathogenicity of a novel intronic variant in ATP6V0A4 for autosomal recessive distal renal tubular acidosis PMID:29202719
• The Journal of Clinical Investigation • 2025 • A gain-of-function mutation in ATP6V0A4 drives primary distal renal tubular alkalosis with enhanced V-ATPase activity PMID:40299568

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