ATP6V1B1 – Autosomal Recessive Distal Renal Tubular Acidosis

Autosomal recessive distal renal tubular acidosis (dRTA) is characterized by hyperchloremic metabolic acidosis, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis and failure to thrive. The B1 subunit of the vacuolar H+-ATPase, encoded by ATP6V1B1, is essential for proton secretion in α‐intercalated cells, and its disruption leads to dRTA with sensorineural hearing loss. Genetic and functional studies over the past two decades have firmly established ATP6V1B1 as a causative gene for this condition.

In a linkage and mutation screening study of 26 rdRTA kindreds (23 consanguineous), ATP6V1B1 mutations were found in 10 families (PMID:12414817). Nine unrelated Mexican families with dRTA harbored homozygous ATP6V1B1 variants, all of whom developed early‐onset hearing loss (PMID:27247958). A Turkish cohort of five consanguineous families with DRTA and hearing loss revealed four distinct homozygous ATP6V1B1 mutations (PMID:23923981) and a Saudi case report described a single patient with bilateral sensorineural deafness and a novel ATP6V1B1 variant (PMID:25579729).

ATP6V1B1 variant spectrum includes missense changes (e.g., c.469C>T (p.Arg157Cys)), nonsense and frameshift alleles (e.g., c.497delC (p.Thr166ArgfsTer9)), and splicing mutations. These variants segregate with disease in an autosomal recessive pattern, often in consanguineous families, and are absent from population databases. Recurrent alleles have not been reported outside specific founder populations.

Functional assays corroborate genetic findings. In vitro minigene splicing assays confirm aberrant RNA processing for noncanonical intronic variants in ATP6V0A4 and ATP6V1B1 (PMID:29202719). An Atp6v1b1vtx/vtx mouse model on the MRL background exhibits profound sensorineural hearing loss and enlarged vestibular aqueducts, mirroring the human phenotype despite compensated acidosis, highlighting tissue‐specific functional consequences (PMID:28934385).

No conflicting reports dispute the role of ATP6V1B1 in AR dRTA. The concordance of genetic, segregation and functional data over >20 years supports a definitive gene–disease relationship.

Taken together, ATP6V1B1 meets ClinGen criteria for a Definitive association with autosomal recessive distal renal tubular acidosis. This definitive classification guides molecular diagnosis, genetic counseling, and targeted therapies for patients presenting with dRTA and sensorineural hearing loss.

References

• Journal of medical genetics • 2002 • Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. PMID:12414817
• Molecular genetics & genomic medicine • 2016 • Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families. PMID:27247958
• Renal failure • 2013 • ATP6V1B1 mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families. PMID:23923981
• Saudi journal of kidney diseases and transplantation • 2015 • Distal renal tubular acidosis with nerve deafness secondary to ATP6B1 gene mutation. PMID:25579729
• 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
• Human molecular genetics • 2017 • Hearing loss without overt metabolic acidosis in ATP6V1B1 deficient MRL mice, a new genetic model for non-syndromic deafness with enlarged vestibular aqueducts. PMID:28934385

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