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

2005 ◽  
Vol 90 (10) ◽  
pp. 5523-5527 ◽  
Author(s):  
Kaori Araya ◽  
Seiji Fukumoto ◽  
Rebecca Backenroth ◽  
Yasuhiro Takeuchi ◽  
Kounosuke Nakayama ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Western Blotting ◽  
Mammalian Cells ◽  
Fibroblast Growth Factor 23 ◽  
Full Length ◽  
Tumoral Calcinosis ◽  
Fibroblast Growth ◽  
Wild Type ◽  
Terminal Fragment

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.

scholarly journals Regulation of serum 1,25(OH)2Vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4

2011 ◽  
Vol 301 (2) ◽  
pp. F371-F377 ◽  
Author(s):  
Jyothsna Gattineni ◽  
Katherine Twombley ◽  
Regina Goetz ◽  
Moosa Mohammadi ◽  
Michel Baum
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Serum Levels ◽  
Phosphate Transport ◽  
Fibroblast Growth ◽  
Wild Type ◽  
Baseline Serum ◽  
Renal Phosphate Reabsorption

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in the pathogenesis of several hypophosphatemic disorders. FGF23 causes hypophosphatemia by decreasing the expression of sodium phosphate cotransporters (NaPi-2a and NaPi-2c) and decreasing serum 1,25(OH)2Vitamin D3 levels. We previously showed that FGFR1 is the predominant receptor for the hypophosphatemic actions of FGF23 by decreasing renal NaPi-2a and 2c expression while the receptors regulating 1,25(OH)2Vitamin D3 levels remained elusive. To determine the FGFRs regulating 1,25(OH)2Vitamin D3 levels, we studied FGFR3−/−FGFR4−/− mice as these mice have shortened life span and are growth retarded similar to FGF23−/− and Klotho−/− mice. Baseline serum 1,25(OH)2Vitamin D3 levels were elevated in the FGFR3−/−FGFR4−/− mice compared with wild-type mice (102.2 ± 14.8 vs. 266.0 ± 34.0 pmol/l; P = 0.001) as were the serum levels of FGF23. Administration of recombinant FGF23 had no effect on serum 1,25(OH)2Vitamin D3 in the FGFR3−/−FGFR4−/− mice (173.4 ± 32.7 vs. 219.7 ± 56.5 pmol/l; vehicle vs. FGF23) while it reduced serum 1,25(OH)2Vitamin D3 levels in wild-type mice. Administration of FGF23 to FGFR3−/−FGFR4−/− mice resulted in a decrease in serum parathyroid hormone (PTH) levels and an increase in serum phosphorus levels mediated by increased renal phosphate reabsorption. These data indicate that FGFR3 and 4 are the receptors that regulate serum 1,25(OH)2Vitamin D3 levels in response to FGF23. In addition, when 1,25(OH)2Vitamin D3 levels are not affected by FGF23, as in FGFR3−/−FGFR4−/− mice, a reduction in PTH can override the effects of FGF23 on renal phosphate transport.

scholarly journals A Novel Recessive Mutation in Fibroblast Growth Factor-23 Causes Familial Tumoral Calcinosis

2005 ◽  
Vol 90 (4) ◽  
pp. 2424-2427 ◽  
Author(s):  
Tobias Larsson ◽  
Xijie Yu ◽  
Siobhan I. Davis ◽  
Mohamad S. Draman ◽  
Sean D. Mooney ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Tumoral Calcinosis ◽  
Recessive Mutation ◽  
Fibroblast Growth

scholarly journals Carboxy-terminal fragment of fibroblast growth factor 23 induces heart hypertrophy in sickle cell disease

Haematologica ◽  
2016 ◽  
Vol 102 (2) ◽  
pp. e33-e35 ◽  
Author(s):  
Marie Courbebaisse ◽  
Hind Mehel ◽  
Camille Petit-Hoang ◽  
Jean-Antoine Ribeil ◽  
Laurent Sabbah ◽  
...  
Keyword(s):  
Growth Factor ◽  
Sickle Cell Disease ◽  
Fibroblast Growth Factor ◽  
Sickle Cell ◽  
Fibroblast Growth Factor 23 ◽  
Heart Hypertrophy ◽  
Fibroblast Growth ◽  
Cell Disease ◽  
Terminal Fragment ◽  
Carboxy Terminal

scholarly journals The Role of Mutant UDP-N-Acetyl-α-d-Galactosamine-Polypeptide N-Acetylgalactosaminyltransferase 3 in Regulating Serum Intact Fibroblast Growth Factor 23 and Matrix Extracellular Phosphoglycoprotein in Heritable Tumoral Calcinosis

2006 ◽  
Vol 91 (10) ◽  
pp. 4037-4042 ◽  
Author(s):  
Holly J. Garringer ◽  
Corinne Fisher ◽  
Tobias E. Larsson ◽  
Siobhan I. Davis ◽  
Daniel L. Koller ◽  
...  
Keyword(s):  
Growth Factor ◽  
Combination Therapy ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
High Serum ◽  
Biologically Active ◽  
Tumoral Calcinosis ◽  
Fibroblast Growth ◽  
Loss Of Function ◽  
Matrix Extracellular Phosphoglycoprotein

Abstract Context: Familial tumoral calcinosis (TC) results from disruptions in phosphate metabolism and is characterized by high serum phosphate with normal or elevated 1,25 dihydroxyvitamin vitamin D concentrations and ectopic and vascular calcifications. Recessive loss-of-function mutations in UDP-N-acetyl-α-d-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) and fibroblast growth factor-23 (FGF23) result in TC. Objective: The objective of the study was to determine the relationship between GALNT3 and FGF23 in familial TC. Design, Setting, and Patients: We assessed the major biochemical defects and potential genes involved in patients with TC. Intervention: Combination therapy consisted of the phosphate binder Sevelamer and the carbonic anhydrase inhibitor acetazolamide. Results: We report a patient homozygous for a GALNT3 exon 1 deletion, which is predicted to truncate the encoded protein. This patient had high serum FGF23 concentrations when assessed with a C-terminal FGF23 ELISA but low-normal FGF23 levels when tested with an ELISA for intact FGF23 concentrations. Matrix extracellular phosphoglycoprotein has been identified as a possible regulator of phosphate homeostasis. Serum matrix extracellular phosphoglycoprotein levels, however, were normal in the family with GALNT3-TC and a kindred with TC carrying the FGF23 S71G mutation. The tumoral masses of the patient with GALNT3-TC completely resolved after combination therapy. Conclusions: Our findings demonstrate that GALNT3 inactivation in patients with TC leads to inadequate production of biologically active FGF23 as the most likely cause of the hyperphosphatemic phenotype. Furthermore, combination therapy may be effective for reducing the tumoral burden associated with familial TC.

scholarly journals Effects of erythropoietin on fibroblast growth factor 23 in mice and humans

2018 ◽  
Vol 34 (12) ◽  
pp. 2057-2065 ◽  
Author(s):  
Mark R Hanudel ◽  
Michele F Eisenga ◽  
Maxime Rappaport ◽  
Kristine Chua ◽  
Bo Qiao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Chronic Exposure ◽  
Fibroblast Growth Factor 23 ◽  
Renal Transplant Recipients ◽  
Fibroblast Growth ◽  
Murine Models ◽  
Normal Kidney ◽  
Transplant Recipients ◽  
Wild Type

Abstract Background Erythropoietin (EPO) has been reported as a novel determinant of fibroblast growth factor 23 (FGF23) production; however, it is unknown whether FGF23 is stimulated by chronic exposure to EPO or by EPO administration in nonpolycystic chronic kidney disease (CKD) models. Methods We analyzed the effects of chronic EPO on FGF23 in murine models with chronically high EPO levels and normal kidney function. We studied the effects of exogenous EPO on FGF23 in wild-type mice, with and without CKD, injected with EPO. Also, in four independent human CKD cohorts, we evaluated associations between FGF23 and serum EPO levels or exogenous EPO dose. Results Mice with high endogenous EPO have elevated circulating total FGF23, increased disproportionately to intact FGF23, suggesting coupling of increased FGF23 production with increased proteolytic cleavage. Similarly, in wild-type mice with and without CKD, a single exogenous EPO dose acutely increases circulating total FGF23 out of proportion to intact FGF23. In these murine models, the bone marrow is shown to be a novel source of EPO-stimulated FGF23 production. In humans, serum EPO levels and recombinant human EPO dose are positively and independently associated with total FGF23 levels across the spectrum of CKD and after kidney transplantation. In our largest cohort of 680 renal transplant recipients, serum EPO levels are associated with total FGF23, but not intact FGF23, consistent with the effects of EPO on FGF23 production and metabolism observed in our murine models. Conclusion EPO affects FGF23 production and metabolism, which may have important implications for CKD patients.

scholarly journals Ubiquitin COOH-terminal hydrolase L1 deletion is associated with urinary α-klotho deficiency and perturbed phosphate homeostasis

2018 ◽  
Vol 315 (2) ◽  
pp. F353-F363 ◽  
Author(s):  
Naomi C. Boisvert ◽  
Chet E. Holterman ◽  
Alexey Gutsol ◽  
Josée Coulombe ◽  
Wanling Pan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Sodium Phosphate ◽  
Fibroblast Growth Factor 23 ◽  
Fractional Excretion ◽  
Mrna Levels ◽  
Fibroblast Growth ◽  
Wild Type ◽  
Phosphate Homeostasis ◽  
Renal Brush Border Membrane

Loss of ubiquitin COOH-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme required for neuronal function, led to hyperphosphatemia accompanied by phosphaturia in mice, while calcium homeostasis remained intact. We therefore investigated the mechanisms underlying the phosphate imbalance in Uchl1−/− mice. Interestingly, phosphaturia was not a result of lower renal brush border membrane sodium-phosphate cotransporter expression as sodium-phosphate cotransporter 2a and 2c expression levels was similar to wild-type levels. Plasma parathyroid hormone and fibroblast growth factor 23 levels were not different; however, fibroblast growth factor 23 mRNA levels were significantly increased in femur homogenates from Uchl1−/− mice. Full-length and soluble α-klotho levels were comparable in kidneys from wild-type and Uchl1−/− mice; however, soluble α-klotho was reduced in Uchl1−/− mice urine. Consistent with unchanged components of 1,25(OH)2D3 metabolism (i.e., CYP27B1 and CYP24A1), sodium-phosphate cotransporter 2b protein levels were not different in ileum brush borders from Uchl1−/− mice, suggesting that the intestine is not the source of hyperphosphatemia. Nonetheless, when Uchl1−/− mice were fed a low-phosphate diet, plasma phosphate, urinary phosphate, and fractional excretion of phosphate were significantly attenuated and comparable to levels of low-phosphate diet-fed wild-type mice. Our findings demonstrate that Uchl1-deleted mice exhibit perturbed phosphate homeostasis, likely consequent to decreased urinary soluble α-klotho, which can be rescued with a low-phosphate diet. Uchl1−/− mice may provide a useful mouse model to study mild perturbations in phosphate homeostasis.

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