title: The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers.
abstract: Mutations in the vacuolar-type H(+)-ATPase B1 subunit gene ATP6V1B1 cause autosomal-recessive distal renal tubular acidosis (dRTA). We previously identified a single-nucleotide polymorphism (SNP) in the human B1 subunit (c.481G>A; p.E161K) that causes greatly diminished pump function in vitro To investigate the effect of this SNP on urinary acidification, we conducted a genotype-phenotype analysis of recurrent stone formers in the Dallas and Bern kidney stone registries. Of 555 patients examined, 32 (5.8%) were heterozygous for the p.E161K SNP, and the remaining 523 (94.2%) carried two wild-type alleles. After adjustment for sex, age, body mass index, and dietary acid and alkali intake, p.E161K SNP carriers had a nonsignificant tendency to higher urinary pH on a random diet (6.31 versus 6.09; P=0.09). Under an instructed low-Ca and low-Na diet, urinary pH was higher in p.E161K SNP carriers (6.56 versus 6.01; P<0.01). Kidney stones of p.E161K carriers were more likely to contain calcium phosphate than stones of wild-type patients. In acute NH4Cl loading, p.E161K carriers displayed a higher trough urinary pH (5.34 versus 4.89; P=0.01) than wild-type patients. Overall, 14.6% of wild-type patients and 52.4% of p.E161K carriers were unable to acidify their urine below pH 5.3 and thus, can be considered to have incomplete dRTA. In summary, our data indicate that recurrent stone formers with the vacuolar H(+)-ATPase B1 subunit p.E161K SNP exhibit a urinary acidification deficit with an increased prevalence of calcium phosphate-containing kidney stones. The burden of E161K heterozygosity may be a forme fruste of dRTA.
authors.affiliation: Swiss National Centres of Competence in Research Kidney.CH and TransCure and Divisions of Nephrology, Hypertension and Clinical Pharmacology, Clinical Research, Bern University Hospital, University of Bern, Switzerland; and.
authors.forename: Nasser A
authors.initials: NA
authors.lastname: Dhayat
authors.affiliation: Clinical Research, Bern University Hospital, University of Bern, Switzerland; and Human Genetics, and Departments of Pediatrics and.
authors.forename: Andre
authors.initials: A
authors.lastname: Schaller
authors.affiliation: Swiss National Centres of Competence in Research Kidney.CH and TransCure and Divisions of Nephrology, Hypertension and Clinical Pharmacology, Clinical Research, Bern University Hospital, University of Bern, Switzerland; and Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Albano
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, and.
authors.forename: John
authors.initials: J
authors.lastname: Poindexter
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, and.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Griffith
authors.affiliation: Swiss National Centres of Competence in Research Kidney.CH and TransCure and Divisions of Nephrology, Hypertension and Clinical Pharmacology, Clinical Research, Bern University Hospital, University of Bern, Switzerland; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pasch
authors.affiliation: Clinical Research, Bern University Hospital, University of Bern, Switzerland; and Human Genetics, and Departments of Pediatrics and.
authors.forename: Sabina
authors.initials: S
authors.lastname: Gallati
authors.affiliation: Swiss National Centres of Competence in Research Kidney.CH and TransCure and Divisions of Nephrology, Hypertension and Clinical Pharmacology, Clinical Research, Bern University Hospital, University of Bern, Switzerland; and.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vogt
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, and Departments of Internal Medicine and Physiology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
authors.affiliation: Swiss National Centres of Competence in Research Kidney.CH and TransCure and Divisions of Nephrology, Hypertension and Clinical Pharmacology, Clinical Research, Bern University Hospital, University of Bern, Switzerland; and Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland; Daniel.Fuster@ibmm.unibe.ch.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Fuster
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007669:Kidney Calculi / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012008:Recurrence; D014556:Urine; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*
chemical_list: C509766:ATP6V1B1 protein, human; D025262:Vacuolar Proton-Translocating ATPases
keywords: human genetics; kidney stones; renal tubular acidosis