Abstract
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.
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Acknowledgements
We thank the families for their invaluable contribution to this study; W.G. Walker for provision of kindred RTA2; C. Nelson-Williams for management of the DNA database; T. Mansfield for development and implementation of the fluorescence-labelled genotyping panel; H. Rye for assistance with crystallographic interpretation; C. Hecht for provision of adult cochlear epithelium; T. Hasson for advice and provision of anti-myosin VI antibody; D. Biemesderfer for provision of mouse kidney sections; and H. Craig, D. Geller, A. Gharavi and M. Kashgarian for helpful discussions. C.C.M. and A.B.S. are supported in part by NIH grant DCO3402. F.E.K. is a Fellow of the Wellcome Trust. K.E.F. is an investigator of the Medical Scientist Training Program. R.P.L. is an investigator of the Howard Hughes Medical Institute.
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Karet, F., Finberg, K., Nelson, R. et al. Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet 21, 84–90 (1999). https://doi.org/10.1038/5022
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DOI: https://doi.org/10.1038/5022