Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubularacidosis with sensorineural deafness

H+-ATPases are ubiquitous in nature; V-ATPases pump protons against an elec trochemical gradient, whereas F-ATPases reverse the process, synthesizing A TP. We demonstrate here that mutations in ATP6B1, encoding the B-subunit of the apical proton pump mediating distal nephron acid secretion, cause dist al renal tubular acidosis, a condition characterized by impaired renal acid secretion resulting in metabolic acidosis. Patients with ATP6B1 mutations also have sensorineural hearing loss; consistent with this finding, we demo nstrate expression of ATP6B1 in cochlea and endolymphatic sac. Our data, to gether with the known requirement for active proton secretion to maintain p roper endolymph pH, implicate ATP6B1 in endolymph pH homeostasis and in nor mal auditory function. ATP6B1 is the first member of the H+-ATPase gene fam ily in which mutations are shown to cause human disease.