Nature Genetics
26, 71 - 75 (2000)
doi:10.1038/79208
Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearingAnnabel N. Smith1, Jennifer Skaug2, Keith A. Choate3, Ahmet Nayir4, Aysin Bakkaloglu5, Seza Ozen5, Sally A. Hulton6, Sami A. Sanjad7, Essam A. Al-Sabban8, Richard P. Lifton3, Stephen W. Scherer2
& Fiona E. Karet11
Wellcome Trust Centre for Molecular Mechanisms in Disease, University of Cambridge, Cambridge, UK. 2
Department of Genetics, Hospital for Sick Children, >Toronto, Canada. 3
Howard Hughes Medical Institute, Departments of Genetics and Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. 4
Department of Pediatric Nephrology, University of Istanbul, Istanbul, Turkey. 5
Department of Pediatric Nephrology, Hacettepe University, Ankara, Turkey. 6
Department of Nephrology, Birmingham Children's Hospital, Birmingham, UK. 7
Department of Pediatrics, American University of Beirut Medical Center, Beirut, Lebanon. 8
Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Correspondence should be addressed to Fiona E. Karet fek1000@cam.ac.ukThe multi-subunit H+-ATPase pump is present at particularly high density on the apical (luminal) surface of  -intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification1. The complete subunit composition of the apical ATPase, however, has not been fully agreed upon. Functional failure of -intercalated cells results in a group of disorders, the distal renal tubular acidoses (dRTA), whose features include metabolic acidosis accompanied by disturbances of potassium balance, urinary calcium solubility, bone physiology and growth2. Mutations in the gene encoding the B-subunit of the apical pump (ATP6B1) cause dRTA accompanied by deafness3. We previously localized a gene for dRTA with preserved hearing to 7q33−34 (ref. 4). We report here the identification of this gene, ATP6N1B, which encodes an 840 amino acid novel kidney-specific isoform of ATP6N1A, the 116-kD non-catalytic accessory subunit of the proton pump. Northern-blot analysis demonstrated ATP6N1B expression in kidney but not other main organs. Immunofluorescence studies in human kidney cortex revealed that ATP6N1B localizes almost exclusively to the apical surface of -intercalated cells. We screened nine dRTA kindreds with normal audiometry that linked to the ATP6N1B locus, and identified different homozygous mutations in ATP6N1B in eight. These include nonsense, deletion and splice-site changes, all of which will truncate the protein. Our findings identify a new kidney-specific proton pump 116-kD accessory subunit that is highly expressed in proton-secreting cells in the distal nephron, and illustrate its essential role in normal vectorial acid transport into the urine by the kidney.
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