Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23

Kenneth E. White, Gwenaelle Carn, Bettina Lorenz-Depiereux, Anna Benet-Pages, Tim M. Strom, Michael J. Econs

Research output: Contribution to journalArticle

385 Scopus citations


Background. The gene for the renal phosphate wasting disorder autosomal-dominant hypophosphatemic rickets (ADHR) is FGF23, which encodes a secreted protein related to the fibroblast growth factors (FGFs). We previously detected missense mutations R176Q, R179W, and R179Q in FGF23 from ADHR kindreds. The mutations replace R residues within a subtilisin-like proprotein convertase (SPC) cleavage site 176RHTR179 (RXXR motif). The goal of these studies was to determine if the ADHR mutations lead to protease resistance of FGF-23. Methods. The ADHR mutations were introduced into human FGF-23 cDNA clones with or without an N-terminal FLAG tag by site-directed mutagenesis and were transiently transfected into HEK293 cells. Protein expression was determined by Western analyses. Results. Antibodies directed toward the C-terminal portion of FGF-23 revealed that the native FGF-23 protein resolved as 32 kD and 12 kD species in HEK293 conditioned media; however, the three mutated proteins were detected only as the 32 kD band. An N-terminal FLAG-tagged native FGF-23 resolved as two bands of 36 kD and 26 kD when detected with a FLAG antibody, whereas the R176Q mutant resolved primarily as the 36 kD protein species. Cleavage of FGF-23 was not enhanced by extracellular incubation of FGF-23 with HEK293 cells. Native and mutant FGF-23s bound heparin. Conclusions. FGF-23 proteins containing the ADHR mutations are secreted, and produce polypeptides less sensitive to protease cleavage than wild-type FGF-23. Therefore, the ADHR mutations may protect FGF-23 from proteolysis, thereby potentially elevating circulating concentrations of FGF-23 and leading to phosphate wasting in ADHR patients.

Original languageEnglish (US)
Pages (from-to)2079-2086
Number of pages8
JournalKidney international
Issue number6
StatePublished - Dec 2001


  • 12p13
  • Chromosome 12
  • FGF23
  • Fibroblast growth factor
  • Hypophosphatemia
  • Proprotein convertase
  • Renal phosphate wasting
  • Site-directed mutagenesis

ASJC Scopus subject areas

  • Nephrology

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