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

Araya, Kaori; Fukumoto, Seiji; Backenroth, Rebecca; Takeuchi, Yasuhiro; Nakayama, Kounosuke; Ito, Nobuaki; Yoshii, Nozomi; Yamazaki, Y.; Yamashita, Takefumi; Silver, Justin; Igarashi, Takashi; Fujita, Toshiro

doi:10.1210/jc.2005-0301

Cited by 208 publications

(129 citation statements)

References 18 publications

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“…A pathophysiological role of the latter mechanism is indicated by familial tumoral calcinosis (FTC), an autosomal recessive metabolic disorder with clinical manifestations mirroring those of phosphate wasting disorders. Missense mutations in either the UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene (39) or the FGF23 gene (23,40) have been associated with FTC. All FTC patients have abnormally high plasma levels of the C-terminal proteolytic fragment of FGF23 (39,40).…”

Section: Discussionmentioning

confidence: 99%

“…Missense mutations in either the UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene (39) or the FGF23 gene (23,40) have been associated with FTC. All FTC patients have abnormally high plasma levels of the C-terminal proteolytic fragment of FGF23 (39,40). Our findings suggest that excess C-terminal FGF23 fragment may aggravate hyperphosphatemia and the resulting soft tissue calcification, by antagonizing the action of any residual, functional FGF23 ligand in these patients.…”

Section: Discussionmentioning

confidence: 99%

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Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

Goetz

Nakada²,

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

343

335

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Fibroblast growth factor (FGF) 23 inhibits renal phosphate reabsorption by activating FGF receptor (FGFR) 1c in a Klotho-dependent fashion. The phosphaturic activity of FGF23 is abrogated by proteolytic cleavage at the RXXR motif that lies at the boundary between the FGF core homology domain and the 72-residue-long C-terminal tail of FGF23. Here, we show that the soluble ectodomains of FGFR1c and Klotho are sufficient to form a ternary complex with FGF23 in vitro. The C-terminal tail of FGF23 mediates binding of FGF23 to a de novo site generated at the composite FGFR1c-Klotho interface. Consistent with this finding, the isolated 72-residue-long C-terminal tail of FGF23 impairs FGF23 signaling by competing with full-length ligand for binding to the binary FGFR-Klotho complex. Injection of the FGF23 C-terminal tail peptide into healthy rats inhibits renal phosphate excretion and induces hyperphosphatemia. In a mouse model of renal phosphate wasting attributable to high FGF23, the FGF23 C-terminal peptide reduces phosphate excretion, leading to an increase in serum phosphate concentration. Our data indicate that proteolytic cleavage at the RXXR motif abrogates FGF23 activity by a dual mechanism: by removing the binding site for the binary FGFRKlotho complex that resides in the C-terminal region of FGF23, and by generating an endogenous inhibitor of FGF23. We propose that peptides derived from the C-terminal tail of FGF23 or peptidomimetics and small-molecule organomimetics of the C-terminal tail can be used as therapeutics to treat renal phosphate wasting.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

Goetz

Nakada²,

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

343

335

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“…Fibroblast growth factor 23 (FGF23) is a phosphateand vitamin D-regulating hormone (1)(2)(3)(4)(5)(6). FGF23 levels are elevated in patients with CKD and are independently associated with increased mortality in patients receiving hemodialysis (7,8).…”

Section: Introductionmentioning

confidence: 99%

Randomized Trial Assessing the Effects of Ergocalciferol Administration on Circulating FGF23

Burnett-Bowie

Leder

Henao

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Fibroblast growth factor 23 is a phosphate-and vitamin D-regulating hormone. The objective of this study was to determine the effect of ergocalciferol administration on fibroblast growth factor 23 levels in healthy vitamin D-deficient subjects.Design, setting, participants, & measurements In this 12-week trial conducted in a clinical research center, 18-to 45-year-old subjects (n=90) with 25-hydroxyvitamin D levels #20 ng/ml (by chemiluminescent immunoassay) were randomized to weekly ergocalciferol treatment of 50,000 international units or placebo, while consuming a self-selected diet. Changes in fibroblast growth factor 23, 25-hydroxyvitamin D (by liquid chromatography/ tandem mass spectroscopy), 1,25-dihydroxyvitamin D, parathyroid hormone, and serum phosphate were measured.Results Mean 25-hydroxyvitamin D (P,0.0001), 1,25-dihydroxyvitamin D (P=0.01), and fibroblast growth factor 23 (P=0.003) increased in the treatment versus placebo group. In the treatment group, 25-hydroxyvitamin D increased from 1867 to 40612 ng/ml at week 4 (P,0.0001) and remained stable at 43612 ng/ml at week 12 (P,0.0001); 1,25-dihydroxyvitamin D increased from 42617 to 52618 pg/ml at week 4 (P,0.001) and then remained stable, and fibroblast growth factor 23 increased from 43617 to 60633 pg/ml at week 8 (P=0.001) and 74642 pg/ml at week 12 (P,0.0001). Urinary phosphate excretion increased within the treatment group, but parathyroid hormone and serum phosphate were unchanged.Conclusions Ergocalciferol administration increases circulating fibroblast growth factor 23. When measuring fibroblast growth factor 23, concurrent 25-hydroxyvitamin D measurements should be obtained, because vitamin D deficiency may lower circulating fibroblast growth factor 23 levels.

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“…It is often associated with hyperphosphatemia (Smack et al 1996), and is then termed hyperphosphatemic familial tumoral calcinosis (HFTC; MIM211900). HFTC has been shown to result from loss-of-function mutations in at least two genes: GAL-NT3 coding for UDP-N-acetyl-alpha-D-galactosamine: polypeptide n-acetylgalactosaminyltransferase 3 (ppGalNacT3) (Topaz et al 2004;Ichikawa et al 2005), a glycosyltransferase, which initiates O-glycosylation (Ten Hagen et al 2003);and FGF23 (Benet-Page`s et al 2005;Larsson et al 2005;Araya et al 2005;Chefetz et al 2005) coding for fibroblast growth factor 23 (FGF23), a potent phosphaturic protein (Berndt et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred

et al. 2006

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Hyperphosphatemic familial tumoral calcinosis (HFTC) is an autosomal recessive metabolic disorder characterized by extensive phenotypic and genetic heterogeneity. HFTC was shown recently to result from mutations in two genes: GALNT3, coding for a glycosyltransferase responsible for initiating O-glycosylation, and FGF23, coding for a potent phosphaturic protein.All GALNT3 mutations reported so far have been identified in patients of either Middle Eastern or African-American extraction, corroborating numerous historical reports of the disorder in Africa and in the Middle East. In the present study, we describe a patient of Northern European origin displaying typical features of HFTC. Mutation analysis revealed that this patient carries a homozygous novel nonsense mutation in GALNT3 predicted to result in the synthesis of a significantly truncated protein. The present results expand the spectrum of known mutations in GALNT3 and demonstrate the existence of HFTC-causing mutations in this gene outside the Middle Eastern and AfricanAmerican populations.

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

Abstract: 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.

Cited by 208 publications

References 18 publications

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

Randomized Trial Assessing the Effects of Ergocalciferol Administration on Circulating FGF23

Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred

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