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This version published online on July 19, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0301
A more recent version of this article appeared on October 1, 2005
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Submitted on February 11, 2005
Accepted on July 13, 2005

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

Kaori Araya, Seiji Fukumoto*, Rebecca Backenroth, Yasuhiro Takeuchi, Kounosuke Nakayama, Nobuaki Ito, Nozomi Yoshii, Yuji Yamazaki, Takeyoshi Yamashita, Justin Silver, Takashi Igarashi, and Toshiro Fujita

Department of Pediatrics, University of Tokyo Hospital, Tokyo, Japan; Division of Nephrology & Endocrinology, Department of Medicine, University of Tokyo Hospital, Tokyo, Japan; Minerva Center for Calcium and Bone Metabolism, Nephrology and Hypertension Services, Hebrew University Hadassah Medical Center, Jerusalem, Israel; Pharmaceutical Research Laboratories, KIRIN Brewery, Takasaki, Japan

* To whom correspondence should be addressed. E-mail: fukumoto-tky{at}umin.ac.jp.

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: 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 enzyme-linked immunosorbent assay: 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 expressed in mammalian cells.

Patients: A family of tumoral calcinosis.

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 fragment were barely detectable by Western blotting while C-terminal fragment with the same molecular weight as that from wild-type FGF23 could be detected.

Conclusion: The production and the 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.
Key words: FGF23 • calcification • hyperphosphatemia




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