A functional allelic variant of the FGF23 gene is associated with renal phosphate leak in calcium nephrolithiasis

Abstract

Background: A significant percentage of patients with calcium nephrolithiasis and normal parathyroid function have renal phosphate leak. This disorder is characterized by idiopathic hypophosphatemia and reduced renal phosphate threshold normalized for the glomerular filtration rate (TmPi/GFR).The majority of these patients harbor high or inappropriately normal circulating levels of fibroblast growth factor 23(FGF23), a hormone regulating phosphate homeostasis. Aim: The aim of this study was to define the role of FGF23 allelic variants in the pathogenesis of hypophosphatemic nephrolithiasis. Subjects and Methods: We sequenced the regulative and coding regions of the FGF23 gene in 106 stone formers, 17 of which had renal phosphate leak, and in 87 healthy controls. We subsequently performed in vitro studies. Results: A C716T nonsynonymous change (T239M, rs7955866) in the FGF23 gene was detected in seven of the 17 stone formers with renal phosphate leak. The prevalence of the Tallele and of the CTgenotype in stone formers with renal phosphate leak was significantly higher compared to that observed in stone formers without renal phosphate leak and in controls (P < 0.03 in all cases). In the whole study population, FGF23716T subjects showed levels of serum phosphate and TmPi/GFR significantly lower compared to FGF23716Csubjects. In vitro studies showed that the T239M change increases FGF23 secretion and that the FGF23239M variant induces a higher activation of the FGF receptor/ERK pathway compared to FGF23239T. Conclusion: Our results highlight a novel significant association between the C716Tmissense variation in the FGF23 gene and calcium nephrolithiasis with renal phosphate leak. Copyright © 2012 by The Endocrine Society.