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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR042228-11
Application #
6731383
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Mcgowan, Joan A
Project Start
1993-08-01
Project End
2009-04-30
Budget Start
2004-05-20
Budget End
2005-04-30
Support Year
11
Fiscal Year
2004
Total Cost
$331,100
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Ichikawa, Shoji; Gerard-O'Riley, Rita L; Acton, Dena et al. (2017) A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice. Endocrinology 158:470-476
Econs, Michael J (2017) Genetic diseases resulting from disordered FGF23/klotho biology. Bone 100:56-61
Ramnitz, Mary Scott; Gourh, Pravitt; Goldbach-Mansky, Raphaela et al. (2016) Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome. J Bone Miner Res 31:1845-1854
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Alam, Imranul; Padgett, Leah R; Ichikawa, Shoji et al. (2014) SIBLING family genes and bone mineral density: association and allele-specific expression in humans. Bone 64:166-72
Ichikawa, Shoji; Tuchman, Shamir; Padgett, Leah R et al. (2014) Intronic deletions in the SLC34A3 gene: a cautionary tale for mutation analysis of hereditary hypophosphatemic rickets with hypercalciuria. Bone 59:53-6
White, Kenneth E; Hum, Julia M; Econs, Michael J (2014) Hypophosphatemic rickets: revealing novel control points for phosphate homeostasis. Curr Osteoporos Rep 12:252-62
Imel, Erik A; Gray, Amie K; Padgett, Leah R et al. (2014) Iron and fibroblast growth factor 23 in X-linked hypophosphatemia. Bone 60:87-92
Ichikawa, Shoji; Gray, Amie K; Bikorimana, Emmanuel et al. (2013) Dosage effect of a Phex mutation in a murine model of X-linked hypophosphatemia. Calcif Tissue Int 93:155-62

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