title: Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency.
abstract: Inherited metabolic disorders associated with nephrocalcinosis are rare conditions. The aim of this study was to identify the genetic cause of an Israeli-Arab boy from a consanguineous family with severe nephrocalcinosis and kidney insufficiency.
  
  
  
  Clinical and biochemical data of the proband and family members were obtained from both previous and recent medical charts. Genomic DNA was isolated from peripheral blood cells. The coding sequence and splice sites of candidate genes (CYP24A1, CYP27B1, FGF23, KLOTHO, SLC34A3 and SLC34A1) were sequenced directly. Functional studies were performed in Xenopus laevis oocytes and in transfected opossum kidney (OK) cells.
  
  
  
  Our patient was identified as having nephrocalcinosis in utero, and at the age of 16.5 years, he had kidney insufficiency but no bone disease. Genetic analysis revealed a novel homozygous missense mutation, Arg215Gln, in SLC34A1, which encodes the renal sodium phosphate cotransporter NaPiIIa. Functional studies of the Arg215Gln mutant revealed reduced transport activity in Xenopus laevis oocytes and increased intracellular cytoplasmic accumulation in OK cells.
  
  
  
  Our findings show that dysfunction of the human NaPiIIa causes severe renal calcification that may eventually lead to reduced kidney function, rather than complications of phosphate loss.
authors.affiliation: Department of Nephrology and Hypertension, The Chaim Sheba Medical Center, Tel-Hashomer, Israel. Dganit.Dinour@sheba.health.gov.il.
authors.forename: Dganit
authors.identifier: 0000-0002-9311-7376
authors.initials: D
authors.lastname: Dinour
authors.affiliation: Institute of Pediatric Nephrology, Schneider Children's Medical Center, Petah Tiqwa, Israel.
authors.forename: Miriam
authors.initials: M
authors.lastname: Davidovits
authors.affiliation: Department of Nephrology and Hypertension, The Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Ganon
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Ruminska
authors.affiliation: Institute of Pediatric Nephrology, Schneider Children's Medical Center, Petah Tiqwa, Israel.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Forster
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Nati
authors.initials: N
authors.lastname: Hernando
authors.affiliation: Cancer Research Center, The Chaim Sheba Medical Center, Tehomer, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Eyal
authors.affiliation: Department of Nephrology and Hypertension, The Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Eli J
authors.initials: EJ
authors.lastname: Holtzman
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D000293:Adolescent; D000818:Animals; D003198:Computer Simulation; D004247:DNA / Q000235:genetics; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D009397:Nephrocalcinosis / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism; D009893:Opossums; D051437:Renal Insufficiency / Q000235:genetics*; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis
chemical_list: C000717427:FGF23 protein, human; C493554:SLC34A1 protein, human; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D000089703:Fibroblast Growth Factor-23; D004247:DNA
keywords: NaPiIIa; Nephrocalcinosis; SLC34A1 mutation; Vitamin D