Disease relevance of ATP6V1B1

• Previously we have shown that mutations in two kidney-specific genes, ATP6V1B1 and ATP6V0A4, encoding the H(+)-ATPase B1 and a4 subunit isoforms, cause recessive distal renal tubular acidosis (dRTA) [1].
• The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained [2].
• The osteopetrosis is the result of a homozygous deletion in TCIRG1, which encodes an osteoclast specific isoform of subunit a of the H(+)-ATPase, while the dRTA is associated with a homozygous mutation in ATP6V1B1, encoding the kidney specific B1 subunit of H(+)-ATPase [3].
• We demonstrate here that mutations in ATP6B1, encoding the B-subunit of the apical proton pump mediating distal nephron acid secretion, cause distal renal tubular acidosis, a condition characterized by impaired renal acid secretion resulting in metabolic acidosis [4].

High impact information on ATP6V1B1

• The importance in final urinary acidification along the collecting system is highlighted by monogenic defects in two subunits (ATP6V0A4, ATP6V1B1) of the vacuolar H(+)-ATPase in patients with distal renal tubular acidosis [5].
• Patients with ATP6B1 mutations also have sensorineural hearing loss; consistent with this finding, we demonstrate expression of ATP6B1 in cochlea and endolymphatic sac [4].
• Our data, together with the known requirement for active proton secretion to maintain proper endolymph pH, implicate ATP6B1 in endolymph pH homeostasis and in normal auditory function [4].
• Using transfection experiments, we have identified a Foxi1 binding cis-element in the ATP6V1B1 (encoding the B1-subunit) promoter that is critical for reporter gene activation [6].
• Analysis of linkage and molecular examination of ATP6B1 indicated that mutation in ATP6B1 rarely, if ever, accounts for this phenotype, prompting a genomewide linkage search for loci underlying this trait [7].

Biological context of ATP6V1B1

• These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time [2].
• Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity [2].
• Genomic organization is conserved between the murine and human H(+)-ATPase B1-subunits, and Atp6v1b1 maps to a region of mouse chromosome 6 syntenic to human 2p13, the location of ATP6V1B1 [8].
• Mutational analysis of the ATP6B1 gene in a 9-year-old Korean boy with distal RTA and sensorineural hearing loss found 2 heterozygous missense point mutations [9].

Anatomical context of ATP6V1B1

• In cells lacking V(0) genes, Vma2p and Vma5p were still detected on Vid vesicles and vacuoles, suggesting that the distribution of V(1) proteins is independent of V(0) genes [10].
• V-ATPase B1-subunit promoter drives expression of EGFP in intercalated cells of kidney, clear cells of epididymis and airway cells of lung in transgenic mice [11].

Other interactions of ATP6V1B1

• Molecular investigation and long-term clinical progress in Greek Cypriot families with recessive distal renal tubular acidosis and sensorineural deafness due to mutations in the ATP6V1B1 gene [12].

Analytical, diagnostic and therapeutic context of ATP6V1B1

• These results demonstrate that Atp6v1b1 encodes the murine ortholog of human ATP6V1B1 and provides a tool for future development of animal models based on manipulation of the Atp6v1b1 genomic locus [8].

References