After identifying fibroblast growth factor 23 (FGF23) and demonstrating that the mutations causing autosomal dominant hypophosphatemic rickets (ADHR) protect FGF23 protein from degradation, we focused our studies during the current cycle on defining the role of FGF23 and cofactors in several disorders of phosphate homeostasis. Our work, and that of others, has established that FGF23 is a critical mediator of phosphate and vitamin D homeostasis. During the current award period we have: 1) demonstrated that blood FGF23 concentrations are elevated in X-linked hypophosphatemic rickets (XLH) and tumor induced osteomalacia (TIO);2) shown that plasma FGF23 concentrations correspond to disease severity in ADHR and, more recently, obtained preliminary data indicating that serum iron concentrations are inversely correlated to FGF23 concentrations in individuals with ADHR causing mutations;3) discovered that osteoglophonic dysplasia is caused by missense mutations in the FGF receptor 1 gene and defined the mechanisms by which these mutations result in disease;4) demonstrated that fibrous dysplasia lesions produce FGF23, resulting in phosphate wasting;5) established that mutations in the gene encoding GalNAc transferase 3 (GALNT3) cause familial hyperphosphatemic tumoral calcinosis (TC) by increasing degradation of FGF23;6) created an animal model of TC, the Galnt3 knockout mouse, and defined its phenotype;7) identified the first human klotho mutation (H193R) and demonstrated that this mutation resulted in TC, but not premature aging;8) elucidated how the H193R klotho mutation results in disease;and 9) obtained data indicating that current therapy for XLH with calcitriol and phosphate may worsen elevated FGF23 concentrations. These and other accomplishments are detailed in the 23 original research articles and 7 reviews and chapters that have originated from the current award. The unifying concept of the proposed research is the critical role of FGF23 in several disorders of phosphate homeostasis, and the over-arching goal is deeper understanding of FGF23 related diseases. The proposed investigations use both human studies, animal models, and primary cell culture to test hypotheses about the association between iron and FGF23 in ADHR patients and controls;the relationship between PHEX and FGF23 in causing the phenotypic manifestations of XLH;disregulated phosphate sensing;and the importance of glycosylation to FGF23 protein function. Importantly, the proposed investigations will yield important data regardless of whether these hypotheses are correct and these investigations will influence treatment of patients with both hypo and hyperphosphatemic disorders over both the short and long term.

Public Health Relevance

Disorders that cause the kidney to waste phosphorus, an important mineral in bone, are the most common forms of rickets and osteomalacia in western countries. FGF23 is a critical mediator of blood levels of phosphorus and vitamin D and plays a central role in several of these diseases. This research will explore the relationship between iron and FGF23 in human and cell culture studies and uses animal models to better understand the causes of disorders that affect blood phosphorus and vitamin D levels.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Sharrock, William J
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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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
Keskar, Vaibhav S; Imel, Erik A; Kulkarni, Manjunath et al. (2015) The Case | Ectopic calcifications in a child. Kidney Int 87:1079-81
Ichikawa, Shoji; Gray, Amie K; Padgett, Leah R et al. (2014) Genetic rescue of glycosylation-deficient Fgf23 in the Galnt3 knockout mouse. Endocrinology 155:3891-8
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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