title: 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.
  
  
  OBJECTIVE
  The aim of this study was to define the role of FGF23 allelic variants in the pathogenesis of hypophosphatemic nephrolithiasis.
  
  
  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 T allele and of the CT genotype 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, FGF23(716T) subjects showed levels of serum phosphate and TmPi/GFR significantly lower compared to FGF23(716C) subjects. In vitro studies showed that the T239M change increases FGF23 secretion and that the FGF23(239M) variant induces a higher activation of the FGF receptor/ERK pathway compared to FGF23(239T).
  
  
  CONCLUSIONS
  Our results highlight a novel significant association between the C716T missense variation in the FGF23 gene and calcium nephrolithiasis with renal phosphate leak.
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University Medical School, via S. Pansini, 5-80131 Naples, Italy. domenico.rendina@unina.it
authors.forename: Domenico
authors.initials: D
authors.lastname: Rendina
authors.forename: Teresa
authors.initials: T
authors.lastname: Esposito
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mossetti
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: De Filippo
authors.forename: Fernando
authors.initials: F
authors.lastname: Gianfrancesco
authors.forename: Anna
authors.initials: A
authors.lastname: Perfetti
authors.forename: Sara
authors.initials: S
authors.lastname: Magliocca
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.forename: Dominique
authors.initials: D
authors.lastname: Prié
authors.forename: Pasquale
authors.initials: P
authors.lastname: Strazzullo
mesh_terms: D000328:Adult; D000483:Alleles; D002118:Calcium / Q000097:blood*; D004252:DNA Mutational Analysis; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics*; D006801:Humans; D017674:Hypophosphatemia / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D053040:Nephrolithiasis / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D010710:Phosphates / Q000097:blood*
chemical_list: C000717427:FGF23 protein, human; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002118:Calcium