Genetic rescue of glycosylation-deficient FGF23 in the GALNT3 knockout mouse

Shoji Ichikawa, Amie K. Gray, Leah R. Padgett, Matthew R. Allen, Erica L. Clinkenbeard, Nicole M. Sarpa, Kenneth E. White, Michael J. Econs

Research output: Contribution to journalArticle

6 Scopus citations


Fibroblast growth factor 23 (FGF23) is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. The FGF23 subtilisin-like proprotein convertase recognition sequence (176RHTR179↓) is protected by O-glycosylation through ppGalNAc-T3 (GALNT3) activity. Thus, inactivating GALNT3 mutations render FGF23 susceptible to proteolysis, thereby reducing circulating intact hormone levels and leading to hyperphosphatemic familial tumoral calcinosis. To further delineate the role of glycosylation in the Fgf23 function, we generated an inducible FGF23 transgenic mouse expressing human mutant FGF23 (R176Q and R179Q) found in patients with autosomal dominant hypophosphatemic rickets (ADHR) and bred this animal to Galnt3 knockout mice, a model of familialtumoralcalcinosis.DuetothelowintactFgf23level,Galnt3knockoutmicewithwild-typeFgf23 alleles were hyperphosphatemic. In contrast, carriers of the mutant FGF23 transgene, regardless of Galnt3 mutation status, had significantly higher serum intact FGF23, resulting in severe hypophosphatemia. Importantly, serum phosphorus and FGF23 were comparable between transgenic mice with or without normal Galnt3 alleles. To determine whether the presence of the ADHR mutation could improve biochemical and skeletal abnormalities in Galnt3-null mice, these mice were also mated to Fgf23 knock-in mice, carrying heterozygous or homozygous R176Q ADHR Fgf23 mutations. The knock-in mice with functional Galnt3 had normal Fgf23 but were slightly hypophosphatemic. The stabilized Fgf23 ADHRallele reversed the Galnt3-nullphenotypeandnormalized total Fgf23,serumphosphorus,andbone Fgf23 mRNA. However, the skeletal phenotype was unaffected. In summary, these data demonstrate that O-glycosylation by ppGaINAc-T3 is only necessary for proper secretion of intact Fgf23 and, once secreted, does not affect Fgf23 function. Furthermore, themorestable Fgf23ADHRmutantprotein could normalize serum phosphorus in Galnt3 knockout mice. Copyright

Original languageEnglish (US)
Pages (from-to)3891-3898
Number of pages8
Issue number10
StatePublished - Oct 1 2014

ASJC Scopus subject areas

  • Endocrinology

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