A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis
A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis
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DOI：
10.1210/jc.2005-0301
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发表时间：
2005-10-01
影响因子：
5.8
通讯作者：
Fujita, T
中科院分区：
文献类型：
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作者：
Araya, K;Fukumoto, S;Fujita, T
背景：肿瘤性钙化症是一种以异位钙化和高磷血症为特征的疾病，由于肾小管磷酸盐重吸收增强。成纤维细胞生长因子（FGF） 23被确定为肾磷泄漏引起的低磷血症的一个重要因素。目的：本研究的目的是分析FGF23在肿瘤钙质沉着症发生中的作用。设计：采用两种ELISA法评估肿瘤钙化症患者血清FGF23水平：全长法（仅检测具有降磷酸盐活性的全长FGF23）和c末端法（测量FGF23的全长和c末端片段）。PCR产物直接测序分析FGF23基因，突变体FGF23在哺乳动物细胞中表达后进行Western blotting分析。结果：c -末端法测定血清FGF23含量极高。相比之下，全长测定为低正常。FGF23基因分析发现密码子129有丝氨酸到苯丙氨酸的突变。该患者未发现该密码子的野生型等位基因。先证者的兄弟也表现出相同的碱基变化。当该突变体FGF23在体外表达时，Western blotting几乎检测不到全长和n端片段，而可以检测到与野生型FGF23相同分子量的c端片段。结论：FGF23 c端片段的产生及血清中FGF23 c端片段的水平在肿瘤钙质沉着症患者中升高。与最近类似的FGF23突变报道一起，全长FGF23的作用受损似乎导致了肿瘤钙质沉积。
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.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.