title: Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing.
abstract: The 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 acidification. 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 growth. Mutations in the gene encoding the B-subunit of the apical pump (ATP6B1) cause dRTA accompanied by deafness. 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.
authors.affiliation: Wellcome Trust Centre for Molecular Mechanisms in Disease, University of Cambridge, Cambridge, UK.
authors.forename: A N
authors.initials: AN
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Skaug
authors.forename: K A
authors.initials: KA
authors.lastname: Choate
authors.forename: A
authors.initials: A
authors.lastname: Nayir
authors.forename: A
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: S
authors.initials: S
authors.lastname: Ozen
authors.forename: S A
authors.initials: SA
authors.lastname: Hulton
authors.forename: S A
authors.initials: SA
authors.lastname: Sanjad
authors.forename: E A
authors.initials: EA
authors.lastname: Al-Sabban
authors.forename: R P
authors.initials: RP
authors.lastname: Lifton
authors.forename: S W
authors.initials: SW
authors.lastname: Scherer
authors.forename: F E
authors.initials: FE
authors.lastname: Karet
mesh_terms: D000141:Acidosis, Renal Tubular / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001299:Audiometry; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002897:Chromosomes, Human, Pair 7; D020451:Contig Mapping; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D005260:Female; D017353:Gene Deletion; D005808:Genes, Recessive; D008040:Genetic Linkage; D005819:Genetic Markers; D006309:Hearing / Q000235:genetics* / Q000502:physiology; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D025261:Mitochondrial Proton-Translocating ATPases; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020161:Physical Chromosome Mapping; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011257:Pregnancy Proteins; D014176:Protein Biosynthesis; D020033:Protein Isoforms; D017494:Proton Pumps / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics*; D006180:Proton-Translocating ATPases; D012326:RNA Splicing; D011995:Recombination, Genetic; D017386:Sequence Homology, Amino Acid; D013491:Suppressor Factors, Immunologic; D014018:Tissue Distribution; D025262:Vacuolar Proton-Translocating ATPases
chemical_list: D018076:DNA, Complementary; D005819:Genetic Markers; C501005:MT-ATP6 protein, human; D011257:Pregnancy Proteins; D020033:Protein Isoforms; D017494:Proton Pumps; D013491:Suppressor Factors, Immunologic; C490181:ATP6V0A4 protein, human; D000251:Adenosine Triphosphatases; D025262:Vacuolar Proton-Translocating ATPases; D025261:Mitochondrial Proton-Translocating ATPases; D006180:Proton-Translocating ATPases