title: Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia.
abstract: Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.
authors.affiliation: Department of General Pediatrics, University Children's Hospital, Münster, Germany;
authors.forename: Karl P
authors.initials: KP
authors.lastname: Schlingmann
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland;
authors.forename: Justyna
authors.initials: J
authors.lastname: Ruminska
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada;
authors.forename: Martin
authors.initials: M
authors.lastname: Kaufmann
authors.affiliation: Department of General Pediatrics, University Children's Hospital, Münster, Germany; Department of Pediatrics, Kayseri University, Kayseri, Turkey;
authors.forename: Ismail
authors.initials: I
authors.lastname: Dursun
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland;
authors.forename: Monica
authors.initials: M
authors.lastname: Patti
authors.affiliation: Department of General Pediatrics, University Children's Hospital, Münster, Germany;
authors.forename: Birgitta
authors.initials: B
authors.lastname: Kranz
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland;
authors.forename: Ewa
authors.initials: E
authors.lastname: Pronicka
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland;
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Ciara
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Marmara University, Istanbul, Turkey;
authors.forename: Teoman
authors.initials: T
authors.lastname: Akcay
authors.affiliation: Department of Pediatric Endocrinology, Keçiören Research and Educational Hospital, Ankara, Turkey;
authors.forename: Derya
authors.initials: D
authors.lastname: Bulus
authors.affiliation: Pediatric Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands;
authors.forename: Elisabeth A M
authors.initials: EA
authors.lastname: Cornelissen
authors.affiliation: Department of Pediatrics, Medical University of Silesia, Katowice, Poland;
authors.forename: Aneta
authors.initials: A
authors.lastname: Gawlik
authors.affiliation: Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland;
authors.forename: Przemysław
authors.initials: P
authors.lastname: Sikora
authors.affiliation: Children's Hospital St. Elisabeth and St. Barbara, Halle/Saale, Germany;
authors.forename: Ludwig
authors.initials: L
authors.lastname: Patzer
authors.affiliation: Department of Pediatrics, Friedrich-Alexander-University, Erlangen, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Galiano
authors.affiliation: Department of Pediatrics, University Hospital St. Marina, Varna Medical University, Varna, Bulgaria;
authors.forename: Veselin
authors.initials: V
authors.lastname: Boyadzhiev
authors.affiliation: Department of Pediatrics, University Hospital Center, Zagreb, Croatia;
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dumic
authors.affiliation: Sheba Medical Center, Tel Aviv, Israel;
authors.forename: Asaf
authors.initials: A
authors.lastname: Vivante
authors.affiliation: University College London, London, United Kingdom;
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Sheba Medical Center, Tel Aviv, Israel;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dekel
authors.affiliation: Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium;
authors.forename: Elena
authors.initials: E
authors.lastname: Levtchenko
authors.affiliation: Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands; and.
authors.forename: René J
authors.initials: RJ
authors.lastname: Bindels
authors.affiliation: Department of General Pediatrics, University Children's Hospital, Münster, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Rust
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland;
authors.forename: Ian C
authors.initials: IC
authors.lastname: Forster
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland;
authors.forename: Nati
authors.initials: N
authors.lastname: Hernando
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Department of Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Glenville
authors.initials: G
authors.lastname: Jones
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland;
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.affiliation: Department of General Pediatrics, University Children's Hospital, Münster, Germany; konradma@uni-muenster.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
mesh_terms: D000818:Animals; D005808:Genes, Recessive; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D050608:Sodium-Phosphate Cotransporter Proteins / Q000235:genetics*; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics*
chemical_list: C493554:SLC34A1 protein, human; C493555:Slc34a1 protein, mouse; D050608:Sodium-Phosphate Cotransporter Proteins; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa
keywords: activated Vitamin D; genetic renal disease; hypercalciuria; mineral metabolism; molecular genetics