title: Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit.
abstract: Congenital distal renal tubular acidosis (RTA) from mutations of the B1 subunit of V-ATPase is considered an autosomal recessive disease. We analyzed a distal RTA kindred with a truncation mutation of B1 (p.Phe468fsX487) previously shown to have failure of assembly into the V1 domain of V-ATPase. All heterozygous carriers in this kindred have normal plasma HCO3- concentrations and thus evaded the diagnosis of RTA. However, inappropriately high urine pH, hypocitraturia, and hypercalciuria were present either individually or in combination in the heterozygotes at baseline. Two of the heterozygotes studied also had inappropriate urinary acidification with acute ammonium chloride loading and an impaired urine-blood Pco2 gradient during bicarbonaturia, indicating the presence of a H+ gradient and flux defects. In normal human renal papillae, wild-type B1 is located primarily on the plasma membrane, but papilla from one of the heterozygote who had kidney stones but not nephrocalcinosis showed B1 in both the plasma membrane as well as diffuse intracellular staining. Titration of increasing amounts of the mutant B1 subunit did not exhibit negative dominance over the expression, cellular distribution, or H+ pump activity of wild-type B1 in mammalian human embryonic kidney-293 cells and in V-ATPase-deficient Saccharomyces cerevisiae. This is the first demonstration of renal acidification defects and nephrolithiasis in heterozygous carriers of a mutant B1 subunit that cannot be attributable to negative dominance. We propose that heterozygosity may lead to mild real acidification defects due to haploinsufficiency. B1 heterozygosity should be considered in patients with calcium nephrolithiasis and urinary abnormalities such as alkalinuria or hypocitraturia.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Nephrology and Hypertension and Institute of Biochemistry and Molecular Medicine, Inselspital, University of Bern, Bern, Switzerland.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Fuster
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Cameron
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Henry
authors.initials: H
authors.lastname: Quiñones
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Carolyn
authors.initials: C
authors.lastname: Griffith
authors.affiliation: McDermott Center of Human Development, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Xie
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas; orson.moe@utsouthwestern.edu.
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
mesh_terms: D000141:Acidosis, Renal Tubular / Q000235:genetics*; D000643:Ammonium Chloride; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D007679:Kidney Medulla / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D000643:Ammonium Chloride; D025262:Vacuolar Proton-Translocating ATPases
keywords: V-ATPase; distal renal tubular acidosis; haploinsufficiency; kidney stones