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

• Published in: Nature genetics Vol. 21; no. 1; pp. 84 - 90
• Main Authors: Lifton, Richard P, Karet, Fiona E, Finberg, Karin E, Nelson, Raoul D, Nayir, Ahmet, Mocan, Hilal, Sanjad, Sami A, Rodriguez-Soriano, Juan, Santos, Fernando, Cremers, Cor W.R.J, Pietro, Antonio Di, Hoffbrand, Barry I, Winiarski, Jacek, Bakkaloglu, Aysin, Ozen, Seza, Dusunsel, Ruhan, Goodyer, Paul, Hulton, Sally A, Wu, Doris K, Skvorak, Anne B, Morton, Cynthia C, Cunningham, Michael J, Jha, Vivekanand
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.01.1999
• Subjects: Acidosis, Renal Tubular - complications; Acidosis, Renal Tubular - enzymology; Acidosis, Renal Tubular - genetics; Base Sequence; Biological and medical sciences; Child, Preschool; Chromosomes, Human, Pair 2; Cochlea - metabolism; Female; Genes, Recessive; Genetic Linkage; Hearing Loss, Sensorineural - complications; Hearing Loss, Sensorineural - enzymology; Hearing Loss, Sensorineural - genetics; Humans; Infant; Male; Medical sciences; Medicin och hälsovetenskap; Molecular Sequence Data; Mutation; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Pedigree; Proton-Translocating ATPases - genetics; Proton-Translocating ATPases - metabolism; Tubulopathies; Kidney disease; Genetic mapping; Human; Immunohistochemistry; Urinary system disease; Enzyme; Tubulopathy; Auditory disorder; H; Chromosome A2; transporting ATP synthase; Gene expression; Hereditary; Genetic disease; Hearing loss; Gene; Hydrolases; ENT disease; Genetics; Mutation; Acidosis; Localization
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/5022

H+-ATPases are ubiquitous in nature; V-ATPases pump protons against an electrochemical gradient, whereas F-ATPases reverse the process, synthesizing ATP. 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. Patients with ATP6B1 mutations also have sensorineural hearing loss; consistent with this finding, we demonstrate expression of ATP6B1 in cochlea and endolymphatic sac. 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. ATP6B1 is the first member of the H+-ATPase gene family in which mutations are shown to cause human disease.