Mutations in the PHEX gene cause
X-linked hypophosphatemia (XLH).
Hypophosphatemia in XLH results from increased circulating levels of a phosphaturic
hormone,
fibroblast growth factor 23 (FGF23), which inhibits renal
phosphate reabsorption and
1,25-dihydroxyvitamin D (
calcitriol) synthesis. The current standard
therapy for XLH--high-dose
phosphate and
calcitriol--further increases FGF23 concentrations, suggesting that patients with XLH may have an altered response to extracellular
phosphate. To test for the presence of abnormal
phosphate responsiveness, we compared serum biochemistries and femoral Fgf23
mRNA expression between wild-type mice, murine models of XLH (Phex(K496X)) and hyperphosphatemic
tumoral calcinosis (Galnt3(-/-)), and Galnt3/Phex double-mutant mice. Phex mutant mice had not only increased Fgf23 expression but also reduced proteolytic cleavage of intact Fgf23
protein, resulting in markedly elevated intact Fgf23 levels and consequent
hypophosphatemia. In contrast, despite markedly increased Fgf23 expression, Galnt3 knockout mice had significantly high proteolytic cleavage of Fgf23
protein, leading to low intact Fgf23 concentrations and
hyperphosphatemia. Galnt3/Phex double-mutant mice had an intermediate biochemical phenotype between wild-type and Phex mutant mice, including slightly elevated intact Fgf23 concentrations with milder
hypophosphatemia. Despite the
hypophosphatemia, double-mutant mice attempted to reduce serum
phosphate back to the level of Phex mutant mice by upregulating Fgf23 expression as much as 24-fold higher than Phex mutant mice. These data suggest that Phex mutations alter the responsiveness of bone cells to extracellular
phosphate concentrations and may create a lower set point for "normal"
phosphate levels.