This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Larsson, T. Articles by White, K. E. Search for Related Content PubMed PubMed Citation Articles by Larsson, T. Articles by White, K. E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Calcium and Bone Metabolism

A Novel Recessive Mutation in Fibroblast Growth Factor-23 Causes Familial Tumoral Calcinosis

Department of Medical and Molecular Genetics (T.L., X.Y., S.I.D., S.D.M., K.E.W.), Indiana University School of Medicine, Indianapolis, Indiana 46202; and Department of Endocrinology (M.S.D., M.J.C.), Saint James’s Hospital and Trinity College Dublin Medical School, Dublin 8, Ireland

Address all correspondence and requests for reprints to: Kenneth E. White, 975 West Walnut Street, IB130, Indianapolis, Indiana 46202. E-mail: kenewhit{at}iupui.edu.

Abstract

Gain-of-function mutations in fibroblast growth factor-23 (FGF23) are responsible for autosomal dominant hypophosphatemic rickets, a disorder of isolated renal phosphate wasting. Patients with the disorder display hypophosphatemia with normocalcemia as well as inappropriately normal 1,25-dihydroxyvitamin D [1,25(OH)₂D₃] concentrations. Reciprocally tumoral calcinosis (TC) patients are often hyperphosphatemic with inappropriately normal or elevated serum 1,25(OH)₂D₃ levels and have ectopic and vascular calcifications, a phenotype similar to that of Fgf23 null mice. Therefore, the goal of the present studies was to test whether FGF23 was a candidate gene for TC. Two sisters in a consanguineous TC family had hyperphosphatemia and normal 1,25(OH)₂D₃ levels with characteristic ectopic and vascular calcifications. Interestingly, these patients had low-normal intact serum FGF23 levels but demonstrated FGF23 concentrations approximately 40 times normal when assessed with a C-terminal FGF23 serum assay. Mutational analyses identified a homozygous S71G mutation in FGF23 in the TC patients, which was not found in control alleles. Finally, modeling demonstrated that the S71G mutation most likely destabilizes full-length FGF23. In summary, recessive FGF23 mutations can lead to TC. Additionally, our findings indicate that FGF23 may adopt an unstable conformation in some TC patients, possibly leading to nonfunctional FGF23 protein.

This article has been cited by other articles:

				C. Bergwitz, S. Banerjee, H. Abu-Zahra, H. Kaji, A. Miyauchi, T. Sugimoto, and H. Juppner Defective O-Glycosylation due to a Novel Homozygous S129P Mutation Is Associated with Lack of Fibroblast Growth Factor 23 Secretion and Tumoral Calcinosis J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4267 - 4274. [Abstract] [Full Text] [PDF]

				R. Samadfam, C. Richard, L. Nguyen-Yamamoto, I. Bolivar, and D. Goltzman Bone Formation Regulates Circulating Concentrations of Fibroblast Growth Factor 23 Endocrinology, November 1, 2009; 150(11): 4835 - 4845. [Abstract] [Full Text] [PDF]

				S. Ichikawa, A. H. Sorenson, A. M. Austin, D. S. Mackenzie, T. A. Fritz, A. Moh, S. L. Hui, and M. J. Econs Ablation of the Galnt3 Gene Leads to Low-Circulating Intact Fibroblast Growth Factor 23 (Fgf23) Concentrations and Hyperphosphatemia Despite Increased Fgf23 Expression Endocrinology, June 1, 2009; 150(6): 2543 - 2550. [Abstract] [Full Text] [PDF]

				L. Masi, A. Gozzini, A. Franchi, D. Campanacci, A. Amedei, A. Falchetti, F. Franceschelli, G. Marcucci, A. Tanini, R. Capanna, et al. A Novel Recessive Mutation of Fibroblast Growth Factor-23 in Tumoral Calcinosis J. Bone Joint Surg. Am., May 1, 2009; 91(5): 1190 - 1198. [Abstract] [Full Text] [PDF]

				E. G. Farrow, S. I. Davis, L. J. Summers, and K. E. White Initial FGF23-Mediated Signaling Occurs in the Distal Convoluted Tubule J. Am. Soc. Nephrol., May 1, 2009; 20(5): 955 - 960. [Abstract] [Full Text] [PDF]

				K. D. Carmichael, J. A. Bynum, and E. B. Evans Familial Tumoral Calcinosis: A Forty-Year Follow-up on One Family J. Bone Joint Surg. Am., March 1, 2009; 91(3): 664 - 671. [Abstract] [Full Text] [PDF]

				W. W. Brown, H. Juppner, C. B. Langman, H. Price, E. G. Farrow, K. E. White, and K. L. McCormick Hypophosphatemia with Elevations in Serum Fibroblast Growth Factor 23 in a Child with Jansen's Metaphyseal Chondrodysplasia J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 17 - 20. [Abstract] [Full Text] [PDF]

				X. Bai, Q. Dinghong, D. Miao, D. Goltzman, and A. C. Karaplis Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype Am J Physiol Endocrinol Metab, January 1, 2009; 296(1): E79 - E88. [Abstract] [Full Text] [PDF]

				H. J. Garringer, M. Malekpour, F. Esteghamat, S. M. J. Mortazavi, S. I. Davis, E. G. Farrow, X. Yu, D. E. Arking, H. C. Dietz, and K. E. White Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E929 - E937. [Abstract] [Full Text] [PDF]

				H. Olauson, T. Krajisnik, C. Larsson, B. Lindberg, and T. E Larsson A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome. Eur. J. Endocrinol., June 1, 2008; 158(6): 929 - 934. [Abstract] [Full Text] [PDF]

				R. Marsell, E. Grundberg, T. Krajisnik, H. Mallmin, M. Karlsson, D. Mellstrom, E. Orwoll, C. Ohlsson, K. B Jonsson, O. Ljunggren, et al. Fibroblast growth factor-23 is associated with parathyroid hormone and renal function in a population-based cohort of elderly men Eur. J. Endocrinol., January 1, 2008; 158(1): 125 - 129. [Abstract] [Full Text] [PDF]

				P.-A. Westerberg, T. Linde, B. Wikstrom, O. Ljunggren, M. Stridsberg, and T. E. Larsson Regulation of fibroblast growth factor-23 in chronic kidney disease Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3202 - 3207. [Abstract] [Full Text] [PDF]

				T. Krajisnik, P. Bjorklund, R. Marsell, O. Ljunggren, G. Akerstrom, K. B Jonsson, G. Westin, and T. E Larsson Fibroblast growth factor-23 regulates parathyroid hormone and 1{alpha}-hydroxylase expression in cultured bovine parathyroid cells J. Endocrinol., October 1, 2007; 195(1): 125 - 131. [Abstract] [Full Text] [PDF]

				S. Ichikawa, V. Guigonis, E. A. Imel, M. Courouble, S. Heissat, J. D. Henley, A. H. Sorenson, B. Petit, A. Lienhardt, and M. J. Econs Novel GALNT3 Mutations Causing Hyperostosis-Hyperphosphatemia Syndrome Result in Low Intact Fibroblast Growth Factor 23 Concentrations J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1943 - 1947. [Abstract] [Full Text] [PDF]

				D. Shoback Update in Osteoporosis and Metabolic Bone Disorders J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 747 - 753. [Abstract] [Full Text] [PDF]

				D. Sitara, M. S. Razzaque, R. St-Arnaud, W. Huang, T. Taguchi, R. G. Erben, and B. Lanske Genetic Ablation of Vitamin D Activation Pathway Reverses Biochemical and Skeletal Anomalies in Fgf-23-Null Animals Am. J. Pathol., December 1, 2006; 169(6): 2161 - 2170. [Abstract] [Full Text] [PDF]

				S. Ichikawa, E. A. Imel, A. H. Sorenson, R. Severe, P. Knudson, G. J. Harris, J. L. Shaker, and M. J. Econs Tumoral Calcinosis Presenting with Eyelid Calcifications due to Novel Missense Mutations in the Glycosyl Transferase Domain of the GALNT3 Gene J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4472 - 4475. [Abstract] [Full Text] [PDF]

				H. J. Garringer, C. Fisher, T. E. Larsson, S. I. Davis, D. L. Koller, M. J. Cullen, M. S. Draman, N. Conlon, A. Jain, N. S. Fedarko, et al. The Role of Mutant UDP-N-Acetyl-{alpha}-D-Galactosamine-Polypeptide N-Acetylgalactosaminyltransferase 3 in Regulating Serum Intact Fibroblast Growth Factor 23 and Matrix Extracellular Phosphoglycoprotein in Heritable Tumoral Calcinosis J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4037 - 4042. [Abstract] [Full Text] [PDF]

				G. J. Strewler Disordered Secretion of FGF23 Links Three Disorders of Phosphate Transport IBMS BoneKEy, August 1, 2006; 3(8): 14 - 17. [Full Text] [PDF]

				D. M. Antoniucci, T. Yamashita, and A. A. Portale Dietary Phosphorus Regulates Serum Fibroblast Growth Factor-23 Concentrations in Healthy Men J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 3144 - 3149. [Abstract] [Full Text] [PDF]

				K. E. White, T. E. Larsson, and M. J. Econs The Roles of Specific Genes Implicated as Circulating Factors Involved in Normal and Disordered Phosphate Homeostasis: Frizzled Related Protein-4, Matrix Extracellular Phosphoglycoprotein, and Fibroblast Growth Factor 23 Endocr. Rev., May 1, 2006; 27(3): 221 - 241. [Abstract] [Full Text] [PDF]

				S. Liu, W. Tang, J. Zhou, J. R. Stubbs, Q. Luo, M. Pi, and L. D. Quarles Fibroblast Growth Factor 23 Is a Counter-Regulatory Phosphaturic Hormone for Vitamin D J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1305 - 1315. [Abstract] [Full Text] [PDF]

				D. Rendina, G. Mossetti, G. De Filippo, M. Cioffi, and P. Strazzullo Fibroblast Growth Factor 23 Is Increased in Calcium Nephrolithiasis with Hypophosphatemia and Renal Phosphate Leak J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 959 - 963. [Abstract] [Full Text] [PDF]

				X. Yu, O. A. Ibrahimi, R. Goetz, F. Zhang, S. I. Davis, H. J. Garringer, R. J. Linhardt, D. M. Ornitz, M. Mohammadi, and K. E. White Analysis of the Biochemical Mechanisms for the Endocrine Actions of Fibroblast Growth Factor-23 Endocrinology, November 1, 2005; 146(11): 4647 - 4656. [Abstract] [Full Text] [PDF]

				K. Araya, S. Fukumoto, R. Backenroth, Y. Takeuchi, K. Nakayama, N. Ito, N. Yoshii, Y. Yamazaki, T. Yamashita, J. Silver, et al. A Novel Mutation in Fibroblast Growth Factor 23 Gene as a Cause of Tumoral Calcinosis J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5523 - 5527. [Abstract] [Full Text] [PDF]

				T. Larsson, S. I. Davis, H. J. Garringer, S. D. Mooney, M. S. Draman, M. J. Cullen, and K. E. White Fibroblast Growth Factor-23 Mutants Causing Familial Tumoral Calcinosis Are Differentially Processed Endocrinology, September 1, 2005; 146(9): 3883 - 3891. [Abstract] [Full Text] [PDF]

				E. A. Imel and M. J. Econs Fibroblast Growth Factor 23: Roles in Health and Disease J. Am. Soc. Nephrol., September 1, 2005; 16(9): 2565 - 2575. [Full Text] [PDF]

				S. M. J. de Beur Tumoral Calcinosis: A Look into the Metabolic Mirror of Phosphate Homeostasis J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2469 - 2471. [Full Text] [PDF]