Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency
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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.
KeywordsNaPiIIa Nephrocalcinosis SLC34A1 mutation Vitamin D
We thank the patient and his family. This study was supported in part by the Swiss National Science Foundation through the National Center for Competence in Research NCCR Kidney.CH and by the EU FP7 E-rare project “Idiopathic Infantile Hypercalcemia” to C.A. Wagner.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflicts of interest.
The study protocol was approved by the institutional review board of the Chaim Sheba Medical Center, Israel. Informed consent for genetic analysis and medical evaluation was obtained from all subjects studied. Consent of the minors was given by their parents.
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