Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing

The multi-subunit H+-ATPase pump is present at particularly high density on the apical (luminal) surface of alpha-intercalated cells of the cortical c ollecting duct of the distal nephron, where vectorial proton transport is r equired for urinary acidification(1). The complete subunit composition of t he apical ATPase, however, has not been fully agreed upon. Functional failu re of alpha-intercalated cells results in a group of disorders, the distal renal tubular acidoses (dRTA), whose features include metabolic acidosis ac companied by disturbances of potassium balance, urinary calcium solubility, bone physiology and growth(2). Mutations in the gene encoding the B-subuni t of the apical pump (ATP6B1) cause dRTA accompanied by deafness(3). We pre viously localized a gene for dRTA with preserved hearing to 7q33-34 (ref. 4 ). We report here the identification of this gene, ATP6N1B, which encodes a n 840 amino acid novel kidney-specific isoform of ATP6N1A, the 116-kD non-c atalytic accessory subunit of the proton pump. Northern-blot analysis demon strated ATP6N1B expression in kidney but not other main organs. Immunofluor escence studies in human kidney cortex revealed that ATP6N1B localizes almo st exclusively to the apical surface of alpha-intercalated cells. We screen ed nine dRTA kindreds with normal audiometry that linked to the ATP6N1B loc us, and identified different homozygous mutations in ATP6N1B in eight. Thes e include nonsense, deletion and splice-site changes, all of which will tru ncate 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 vectori al acid transport into the urine by the kidney.