HGNC Approved Gene Symbol: FGF23
SNOMEDCT: 237889002;
Cytogenetic location: 12p13.32 Genomic coordinates (GRCh38) : 12:4,368,227-4,379,712 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.32 | Hypophosphatemic rickets, autosomal dominant | 193100 | Autosomal dominant | 3 |
| Tumoral calcinosis, hyperphosphatemic, familial, 2 | 617993 | Autosomal recessive | 3 |
Using the mouse Fgf23 sequence as query, Yamashita et al. (2000) identified FGF23 in a genomic database. They cloned the full-length cDNA from a placenta library. The deduced 251-amino acid protein contains an N-terminal 24-amino acid signal sequence. FGF23 shares 72% sequence identity with mouse Fgf23, and 24% and 22% identity with human FGF21 (609436) and FGF19 (603891), respectively. By quantitative PCR, Yamashita et al. (2000) found highest expression of Fgf23 in mouse brain and lower expression in thymus. In situ hybridization of mouse brain revealed discrete specific labeling only in the ventrolateral thalamic nucleus.
The ADHR Consortium (2000) described a positional cloning approach used to identify the gene mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR; 193100).
The ADHR Consortium (2000) demonstrated that the FGF23 gene is composed of 3 exons, spanning 10 kb of genomic sequence.
Crystal Structure
Chen et al. (2018) presented the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of alpha-klotho (604824), the FGFR1c (see 136350) ligand-binding domain, and FGF23. In this complex, alpha-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signaling. The structure of alpha-klotho is incompatible with its purported glycosidase activity. Thus, Chen et al. (2018) concluded that shed alpha-klotho functions as an on-demand nonenzymatic scaffold protein that promotes FGF23 signaling.
The ADHR Consortium (2000) found that the FGF23 gene lies 54 kb telomeric of FGF6 (134921) on 12p13.
Tumor-induced osteomalacia is one of the paraneoplastic disorders characterized by hypophosphatemia caused by renal phosphate wasting. The fact that removal of responsible tumors normalizes phosphate metabolism is evidence that a humoral phosphaturic factor, sometimes called phosphatonin (Strewler, 2001), is the basis of tumor-induced osteomalacia. Shimada et al. (2001) cloned and characterized FGF23 as a causative factor of tumor-induced osteomalacia. They found that administration of recombinant FGF23 decreased serum phosphate in mice within 12 hours. When Chinese hamster ovary cells stably expressing FGF23 were subcutaneously implanted into nude mice, hypophosphatemia with increased renal phosphate clearance was observed. Continuous production of FGF23 in these animals reproduced the clinical, biochemical, and histologic features of tumor-induced osteomalacia in vivo. Thus, overproduction of FGF23 causes tumor-induced osteomalacia, whereas mutations in the FGF23 gene result in autosomal hypophosphatemic rickets possibly by preventing proteolytic cleavage, which enhances the biologic activity of FGF23. The mutations in FGF23 found in autosomal dominant hypophosphatemic rickets lie within 3 nucleotides of each other in the proprotein convertase cleavage site.
White et al. (2001) investigated whether FGF23 is a secreted factor and whether it is abundantly expressed in oncogenic hypophosphatemic osteomalacia (OHO) tumors. After transient transfection of OK-E, COS-7, and HEK293 cells with a plasmid encoding full-length FGF23, all 3 cell lines efficiently secreted 2 protein species that were approximately 32 and 12 kD upon SDS-PAGE analysis and subsequent Western blot analysis using an affinity-purified polyclonal antibody to FGF23. Northern blot analysis using total RNA from 5 OHO tumors revealed high levels of FGF23 mRNA, and Western blot analysis of extracts from a sixth tumor detected the 32-kD FGF23 protein. The authors concluded that FGF23 is a secreted protein, that its mRNA is abundantly expressed by several different OHO tumors, and that it may be the candidate phosphate wasting factor phosphatonin.
Bowe et al. (2001) found that conditioned medium from COS-7 cells, transfected with either wildtype FGF23 or the FGF23 R179Q mutation (605380.0001), inhibited sodium-dependent phosphate uptake in opossum kidney cells. The R179Q mutant was resistant to degradation by the endopeptidase PHEX (300550), a member of the neutral endopeptidase family of proteins that is mutated in X-linked hypophosphatasia (307800). By RT-PCR, FGF23 was found to be overexpressed in oncogenic osteomalacia but not in other mesenchymal tumors.
Shimada et al. (2002) showed that FGF23 is cleaved between arg179 and ser180, and that this processing abolished biologic activity of FGF23 to induce hypophosphatemia. Yamazaki et al. (2002) developed sandwich ELISA for human FGF23, using 2 monoclonal antibodies to FGF23. The results indicated that biologically active uncleaved FGF23 is present in normal circulation. In addition, the circulatory level of FGF23 was increased in a patient with tumor-induced rickets/osteomalacia and returned to normal soon after resection of the tumor. The serum level of FGF23 was high in patients with X-linked hypophosphatemic rickets/osteomalacia (307800). The authors suggested that hypophosphatemic rickets/osteomalacia may be caused by excess activity of full-length FGF23.
Jonsson et al. (2003) showed that FGF23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis.
Kato et al. (2006) identified GALNT3 (601756) as an enzyme that protects intact FGF23 from proteolytic processing. FGF23 is a phosphaturic protein whose secretion as an intact active form requires O-glycosylation by GALNT3. GALNT3 selectively directs O-glycosylation of FGF23 in a subtilisin-like proprotein convertase (SPC) recognition sequence motif at thr178, which blocks proteolytic processing of FGF23. The findings suggested a novel posttranslational regulatory model of FGF23 involving competing O-glycosylation by GALNT3 and protease processing to produce intact FGF23. Mutations in GALNT3 result in a cleavage of intact FGF23 before secretion, leading to an accumulation of fragmented FGF23 and reduced intact active FGF23.
Urakawa et al. (2006) demonstrated that a previously undescribed receptor conversion by Klotho (604824) generates the FGF23 receptor. Using a renal homogenate, Urakawa et al. (2006) found that Klotho binds to FGF23. Forced expression of Klotho enabled the high affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wildtype mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signaling, Urakawa et al. (2006) searched for other components of the FGF23 receptor and found FGFR1(IIIc) (see 136350), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor.
Hypophosphatemic Rickets, Autosomal Dominant
The ADHR Consortium (2000) identified 3 missense mutations in the FGF23 (see, e.g., 605380.0001-605380.0002) in affected members of 4 unrelated families with autosomal dominant hypophosphatemic rickets (193100). These mutations, which represented the first found in a human FGF gene causing disease, affected 2 arginines that lie only 3 amino acids apart. This finding supported the speculation that the ADHR phenotype is caused by a gain-of-function mechanism.
Hyperphosphatemic Familial Tumoral Calcinosis 2
In an individual with familial hyperphosphatemic tumoral calcinosis (HFTC2; 617933), an autosomal recessive disorder characterized by ectopic calcifications and elevated serum phosphate levels, Benet-Pages et al. (2005) identified a homozygous ser71-to-gly (S71G) substitution in the FGF23 gene (605380.0003). Whereas wildtype FGF23 is secreted as an intact protein as well as processed N-terminal and C-terminal fragments, transfection experiments revealed that the mutated protein was only secreted as the C-terminal fragment; the intact protein was retained in the Golgi complex. Benet-Pages et al. (2005) suggested that FGF23 function is decreased by absent or extremely reduced secretion of intact FGF23 and that FGF23 mutations in hypophosphatemic rickets and familial tumoral calcinosis have opposite effects on phosphate homeostasis.
In a patient with hyperphosphatemic tumoral calcinosis, Chefetz et al. (2005) identified a homozygous missense mutation (M6T; 605380.0004) in the FGF23 gene.
In 2 affected members of a consanguineous Arabian family with hyperphosphatemic tumoral calcinosis, Araya et al. (2005) identified a homozygous missense mutation (S129F; 605380.0005) in the FGF23 gene. Two other members of the family were affected, but were unavailable for testing.
Shimada et al. (2004) generated Fgf23 -/- mice which exhibited severe growth retardation with an abnormal bone phenotype and markedly short life span, as well as severe hyperphosphatemia, enhanced renal phosphate reabsorption. They also showed high serum 1,25-dihydroxyvitamin D due to increased expression of renal 25-hydroxyvitamin D-1-alpha-hydroxylase. Heterozygotes showed no abnormality in any of the parameters examined, including serum FGF23. Because these phenotypes could not be explained by known regulators of mineral homeostasis, Shimada et al. (2004) concluded that FGF23 is essential for normal phosphate and vitamin D metabolism.
In affected members of 2 unrelated families with autosomal dominant hypophosphatemic rickets (193100), the ADHR Consortium (2000) identified a heterozygous 527G-A transition in the FGF23 gene, resulting in an arg176-to-gln (R176Q) substitution. The families had been reported by Bianchine et al. (1971) and Econs and McEnery (1997).
In affected members of a family with autosomal dominant hypophosphatemic rickets (193100) reported by Rowe et al. (1992), the ADHR Consortium (2000) identified a 535C-T transition in the FGF23 gene, resulting in an arg179-to-trp (R179W) substitution.
In an individual with tumoral calcinosis with hyperphosphatemia (HFTC2; 617993), Benet-Pages et al. (2005) identified a homozygous 211A-G transition in the FGF23 gene, resulting in a ser71-to-gly (S71G) substitution at an evolutionarily conserved residue. Expression of the mutated protein in HEK293 cells showed that only the C-terminal fragment was secreted, whereas the intact protein was retained in the Golgi complex. Circulating FGF23 in the patient showed a marked increase in the C-terminal fragment. Benet-Pages et al. (2005) suggested that FGF23 function is decreased by absent or extremely reduced secretion of intact FGF23.
In a severe case of tumoral calcinosis (HFTC2; 617993) displaying calcifications of cutaneous and numerous extracutaneous tissues, Chefetz et al. (2005) identified a homozygous T-to-C transition at position 287 of the FGF23 gene that resulted in a met96-to-thr (M96T) amino acid substitution. The M96T mutation affected a highly conserved methionine residue. No direct familial relationship between the parents of the index patient could be established, although they both originated from the same Greek village located near the Turkish border. The patient was first seen at 5 years of age for surgical removal of calcified foci from the oral mucosa. Subsequently, he developed large subcutaneous tumors around his wrists, knees, and ankles. Small calcified deposits were visible at the external border of the lower eyelids. He showed persistent hyperphosphatemia at the age of 13 years. There was sonographic evidence of calcinosis of the renal medullae, and disseminated foci of vascular calcifications including aortic valve and arch. Eruption of permanent teeth was delayed, with 8 primary teeth still in place at the age of 12 years and 4 months. The patient suffered a left-sided facial nerve palsy at 13 years of age that was thought possibly to be caused by bony compression. Hearing was not impaired.
In the proband of a consanguineous Arabian family with hyperphosphatemic tumoral calcinosis (HFTC2; 617993), Araya et al. (2005) detected homozygosity for a C-to-T transition at codon 129 of FGF23 that resulted in substitution of phenylalanine for serine (S129F). The same mutation was found in the proband's brother; 2 other members of the family who were unavailable for analysis were also affected. Serum FGF23 in the proband was extremely high when measured by C-terminal assay. In contrast, it was low normal by full-length assay. When the mutant FGF23 was expressed in vitro, full-length and N-terminal fragments were barely detectable by Western blotting, whereas a C-terminal fragment with the same molecular weight as that from wildtype FGF23 could be detected.
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Araya, K., Fukumoto, S., Backenroth, R., Takeuchi, Y., Nakayama, K., Ito, N., Yoshii, N., Yamazaki, Y., Yamashita, T., Silver, J., Igarashi, T., Fujita, T. A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J. Clin. Endocr. Metab. 90: 5523-5527, 2005. [PubMed: 16030159] [Full Text: https://doi.org/10.1210/jc.2005-0301]
Benet-Pages, A., Orlik, P., Strom, T. M., Lorenz-Depiereux, B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum. Molec. Genet. 14: 385-390, 2005. [PubMed: 15590700] [Full Text: https://doi.org/10.1093/hmg/ddi034]
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Chefetz, I., Heller, R., Galli-Tsinopoulou, A., Richard, G., Wollnik, B., Indelman, M., Koerber, F., Topaz, O., Bergman, R., Sprecher, E., Schoenau, E. A novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification. Hum. Genet. 118: 261-266, 2005. [PubMed: 16151858] [Full Text: https://doi.org/10.1007/s00439-005-0026-8]
Chen, G., Liu, Y., Goetz, R., Fu, L., Jayaraman, S., Hu, MC., Moe, O. W., Liang, G., Li, X., Mohammadi, M. Alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 553: 461-466, 2018. [PubMed: 29342138] [Full Text: https://doi.org/10.1038/nature25451]
Econs, M. J., McEnery, P. T. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J. Clin. Endocr. Metab. 82: 674-681, 1997. [PubMed: 9024275] [Full Text: https://doi.org/10.1210/jcem.82.2.3765]
Jonsson, K. B., Zahradnik, R., Larsson, T., White, K. E., Sugimoto, T., Imanishi, Y., Yamamoto, T., Hampson, G., Koshiyama, H., Ljunggren, O., Oba, K., Yang, I. M., Miyauchi, A., Econs, M. J., Lavigne, J., Juppner, H. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. New Eng. J. Med. 348: 1656-1663, 2003. [PubMed: 12711740] [Full Text: https://doi.org/10.1056/NEJMoa020881]
Kato, K., Jeanneau, C., Tarp, M. A., Benet-Pages, A., Lorenz-Depiereux, B., Bennett, E. P., Mandel, U., Strom, T. M., Clausen, H. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J. Biol. Chem. 281: 18370-18377, 2006. [PubMed: 16638743] [Full Text: https://doi.org/10.1074/jbc.M602469200]
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Shimada, T., Kakitani, M., Yamazaki, Y., Hasegawa, H., Takeuchi, Y., Fujita, T., Fukumoto, S., Tomizuka, K., Yamashita, T. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J. Clin. Invest. 113: 561-568, 2004. [PubMed: 14966565] [Full Text: https://doi.org/10.1172/JCI19081]
Shimada, T., Mizutani, S., Muto, T., Yoneya, T., Hino, R., Takeda, S., Takeuchi, Y., Fujita, T., Fukumoto, S., Yamashita, T. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc. Nat. Acad. Sci. 98: 6500-6505, 2001. [PubMed: 11344269] [Full Text: https://doi.org/10.1073/pnas.101545198]
Shimada, T., Muto, T., Urakawa, I., Yoneya, T., Yamazaki, Y., Okawa, K., Takeuchi, Y., Fujita, T., Fukumoto, S., Yamashita, T. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143: 3179-3182, 2002. [PubMed: 12130585] [Full Text: https://doi.org/10.1210/endo.143.8.8795]
Strewler, G. J. FGF23, hypophosphatemia, and rickets: has phosphorylation been found? (Commentary) Proc. Nat. Acad. Sci. 98: 5945-5946, 2001. [PubMed: 11371627] [Full Text: https://doi.org/10.1073/pnas.111154898]
Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., Yamashita, T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770-774, 2006. [PubMed: 17086194] [Full Text: https://doi.org/10.1038/nature05315]
White, K. E., Jonsson, K. B., Carn, G., Hampson, G., Spector, T. D., Mannstadt, M., Lorenz-Depiereux, B., Miyauchi, A., Yang, I. M., Ljunggren, O., Meitinger, T., Strom, T. M., Juppner, H., Econs, M. J. The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J. Clin. Endocr. Metab. 86: 497-500, 2001. [PubMed: 11157998] [Full Text: https://doi.org/10.1210/jcem.86.2.7408]
Yamashita, T., Yoshioka, M., Itoh, N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem. Biophys. Res. Commun. 277: 494-498, 2000. [PubMed: 11032749] [Full Text: https://doi.org/10.1006/bbrc.2000.3696]
Yamazaki, Y., Okazaki, R., Shibata, M., Hasegawa, Y., Satoh, K., Tajima, T., Takeuchi, Y., Fujita, T., Nakahara, K., Yamashita, T., Fukumoto, S. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J. Clin. Endocr. Metab. 87: 4957-4960, 2002. [PubMed: 12414858] [Full Text: https://doi.org/10.1210/jc.2002-021105]