FGF23 mutants causing familial tumoral calcinosis are differentially processed

Tobias Larsson, Siobhan I. Davis, Holly J. Garringer, Sean D. Mooney, Mohamad S. Draman, Michael J. Cullen, Kenneth E. White

Research output: Contribution to journalArticle

106 Scopus citations


Familial tumoral calcinosis (TC, OMIM 211900) is a heritable disorder characterized by hyperphosphatemia, normal or elevated serum 1,25-dihydroxyvitamin D, and often severe ectopic calcifications. Two recessive mutations in Fibroblast growth factor-23 (FGF23), serine 71/glycine (S71G) and serine 129/phenylalanine (S129F), were identified as causing TC. Herein, we undertook comprehensive biochemical analyses of an extended TC family carrying the S71G FGF23 mutation, which revealed that heterozygous (serine/glycine, S/G) individuals had elevated serum FGF23 C-terminal fragments compared to wild type (serine/serine, S/S) family members (P<0.025). To understand the differential processing of FGF23 in TC patients, we transiently expressed S71G as well as S129F FGF23. FGF23 ELISA in tandem with Western analyses revealed increased proteolytic cleavage of mutant FGF23 and a limited secretion of intact protein. Furthermore, S71G and S129F FGF23 carrying mutations that disrupt the furin-like protease RXXR motif in FGF23 rescued the secretion of the intact protein, and both TC mutant proteins harboring the R176Q mutation revealed no altered sensitivity to trypsin compared to the native (R176Q)FGF23. Finally, S71G, but not S129F mutant FGF23, is rescued by temperature. In summary, FGF23 mutations causing TC lead to increased intracellular proteolysis of FGF23, most likely by furin-like proteases, and due to conformational changes of the mutant protein. The destabilizing nature of these mutations provides new insight into the pathophysiology of TC, and exemplifies the physiological importance of FGF23 in Pi and vitamin D metabolism.

Original languageEnglish (US)
Pages (from-to)3883-3891
Number of pages9
Issue number9
StatePublished - Sep 2005


  • FGF23
  • Fibroblast Growth Factor 23
  • GALNT3
  • Hyperphosphatemia
  • Hypophosphatemia
  • Mutant
  • PHEX
  • SPC
  • Subtisilin-like pro-protein convertases
  • Tumoral calcinosis

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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