The pathophysiological mechanisms that underlie metabolic bone diseases due to disorders of phosphate homeostasis remain incompletely understood. The main regulator of phosphate homeostasis is the kidney and thus it is necessary to identify the pathways that are responsible for regulating renal phosphorus handling to provide insight into both normal and disordered mineral metabolism. During the current grant cycle we have: 1) extended the phenotypic characterization of the renal phosphate wasting disorder autosomal dominant hypophosphatemic rickets (ADHR); 2) found that missense mutations in arginines 176 or 179 of a novel gene, FGF23, cause ADHR; 3) determined that neoplasms that cause tumor induced osteomalacia (TIO) markedly over express FGF23; 4) determined that circulating FGF23 concentrations are elevated in patients with TIO as well as well as with other disorders of renal phosphate wasting including X-linked hypophosphatemic rickets (XLH) and fibrous dysplasia; and 5) recently phenotypically described a novel renal phosphate wasting disorder, CFDH, and identified the mutation that causes it. During the upcoming years we propose to: 1) further clinically and biochemically characterize ADHR and assess whether plasma FGF23 concentrations are correlated to disease severity in ADHR, XLH, and other phosphaturic disorders; 2) determine the molecular mechanism by which the observed mutations cause CFDH; 3) perform studies in animal models to further explore the pathogenesis of XLH; and 4) perform pharmacokinetic studies in rats to better understand the pathogenesis of ADHR. ? ?
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