2. Academic Validation
  3. Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia

Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia

  • J Am Soc Nephrol. 2016 Feb;27(2):604-14. doi: 10.1681/ASN.2014101025.
Karl P Schlingmann 1,  Justyna Ruminska 2,  Martin Kaufmann 3,  Ismail Dursun 4,  Monica Patti 2,  Birgitta Kranz 1,  Ewa Pronicka 5,  Elzbieta Ciara 5,  Teoman Akcay 6,  Derya Bulus 7,  Elisabeth A M Cornelissen 8,  Aneta Gawlik 9,  Przemysław Sikora 10,  Ludwig Patzer 11,  Matthias Galiano 12,  Veselin Boyadzhiev 13,  Miroslav Dumic 14,  Asaf Vivante 15,  Robert Kleta 16,  Benjamin Dekel 15,  Elena Levtchenko 17,  René J Bindels 18,  Stephan Rust 1,  Ian C Forster 2,  Nati Hernando 2,  Glenville Jones 19,  Carsten A Wagner 2,  Martin Konrad 20
Affiliations

Affiliations

  • 1 Department of General Pediatrics, University Children's Hospital, Münster, Germany;
  • 2 Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland;
  • 3 Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada;
  • 4 Department of General Pediatrics, University Children's Hospital, Münster, Germany; Department of Pediatrics, Kayseri University, Kayseri, Turkey;
  • 5 Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland;
  • 6 Department of Pediatrics, Division of Pediatric Endocrinology, Marmara University, Istanbul, Turkey;
  • 7 Department of Pediatric Endocrinology, Keçiören Research and Educational Hospital, Ankara, Turkey;
  • 8 Pediatric Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands;
  • 9 Department of Pediatrics, Medical University of Silesia, Katowice, Poland;
  • 10 Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland;
  • 11 Children's Hospital St. Elisabeth and St. Barbara, Halle/Saale, Germany;
  • 12 Department of Pediatrics, Friedrich-Alexander-University, Erlangen, Germany;
  • 13 Department of Pediatrics, University Hospital St. Marina, Varna Medical University, Varna, Bulgaria;
  • 14 Department of Pediatrics, University Hospital Center, Zagreb, Croatia;
  • 15 Sheba Medical Center, Tel Aviv, Israel;
  • 16 University College London, London, United Kingdom;
  • 17 Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium;
  • 18 Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands; and.
  • 19 Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Department of Medicine, Queen's University, Kingston, Ontario, Canada.
  • 20 Department of General Pediatrics, University Children's Hospital, Münster, Germany; [email protected].
PMID: 26047794 DOI: 10.1681/ASN.2014101025
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.

Keywords

activated Vitamin D; genetic renal disease; hypercalciuria; mineral metabolism; molecular genetics.

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