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A Novel Mutation in Fibroblast Growth Factor 23 Gene as a Cause of Tumoral Calcinosis

Department of Pediatrics (K.A., T.I.) and Division of Nephrology and Endocrinology (S.F., Y.T., K.N., N.I., T.F.), Department of Medicine, University of Tokyo Hospital, Tokyo 113-8655, Japan; Minerva Center for Calcium and Bone Metabolism, Nephrology, and Hypertension Services (R.B., J.S.), Hebrew University Hadassah Medical Center, Jerusalem 91120, Israel; and Pharmaceutical Research Laboratories (N.Y., Y.Y., T.Y.), KIRIN Brewery, Takasaki 370-1295, Japan

Address all correspondence and requests for reprints to: Seiji Fukumoto, M.D., Ph.D., Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo Hospital, 3-28-6, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: fukumoto-tky{at}umin.ac.jp.

Abstract

Context: Tumoral calcinosis is a disease characterized by ectopic calcification and hyperphosphatemia due to enhanced renal tubular phosphate reabsorption. Fibroblast growth factor (FGF)23 was identified as a responsible factor in hypophosphatemic diseases caused by renal phosphate leak.

Objective: The objective of the study was to analyze the involvement of FGF23 in the development of tumoral calcinosis.

Design: Serum FGF23 level was evaluated in a patient with tumoral calcinosis by two kinds of ELISA: full-length assay that detects only full-length FGF23 with phosphate-lowering activity and C-terminal assay that measures full-length as well as C-terminal fragment of FGF23. FGF23 gene was analyzed by direct sequencing of PCR products, and mutant FGF23 was analyzed by Western blotting after expression in mammalian cells.

Patients: A family of tumoral calcinosis patients were studied.

Results: Serum FGF23 was extremely high when measured by C-terminal assay. In contrast, it was low normal by full-length assay. Analysis of FGF23 gene detected a serine to phenylalanine mutation in codon 129. No wild-type allele of this codon was found in the patient. The brother of the proband showed the same base change. When this mutant FGF23 was expressed in vitro, full-length and N-terminal fragments were barely detectable by Western blotting, whereas C-terminal fragment with the same molecular weight as that from wild-type FGF23 could be detected.

Conclusion: The production and serum level of C-terminal fragment of FGF23 are increased in this patient with tumoral calcinosis. Together with the recent similar report of FGF23 mutation, impaired action of full-length FGF23 seems to result in tumoral calcinosis.

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