Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit

Jianning Zhang, Daniel G. Fuster, Mary Ann Cameron, Henry Quiñones, Carolyn Griffith, Xiao Song Xie, Orson W. Moe

Research output: Contribution to journalArticle

31 Scopus citations

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 V1domain 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.

Original languageEnglish (US)
Pages (from-to)F1063-F1071
JournalAmerican Journal of Physiology - Renal Physiology
Volume307
Issue number9
DOIs
StatePublished - Nov 1 2014

Keywords

  • Distal renal tubular acidosis
  • Haploinsufficiency
  • Kidney stones
  • V-ATPase

ASJC Scopus subject areas

  • Physiology
  • Urology

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