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

A Novel Recessive Mutation of Fibroblast Growth Factor-23 in Tumoral Calcinosis

2009 ◽  
Vol 91 (5) ◽  
pp. 1190-1198 ◽  
Author(s):  
L Masi ◽  
A Gozzini ◽  
A Franchi ◽  
D Campanacci ◽  
A Amedei ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Tumoral Calcinosis ◽  
Recessive Mutation ◽  
Fibroblast Growth

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 Ablation of the Galnt3 Gene Leads to Low-Circulating Intact Fibroblast Growth Factor 23 (Fgf23) Concentrations and Hyperphosphatemia Despite Increased Fgf23 Expression

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2543-2550 ◽  
Author(s):  
Shoji Ichikawa ◽  
Andrea H. Sorenson ◽  
Anthony M. Austin ◽  
Donald S. Mackenzie ◽  
Timothy A. Fritz ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Proteolytic Processing ◽  
Tumoral Calcinosis ◽  
Uridine Diphosphate ◽  
Fibroblast Growth ◽  
Mineral Density ◽  
Deficient Mice

Familial tumoral calcinosis is characterized by ectopic calcifications and hyperphosphatemia. The disease is caused by inactivating mutations in fibroblast growth factor 23 (FGF23), Klotho (KL), and uridine diphosphate-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). In vitro studies indicate that GALNT3 O-glycosylates a phosphaturic hormone, FGF23, and prevents its proteolytic processing, thereby allowing secretion of intact FGF23. In this study we generated mice lacking the Galnt3 gene, which developed hyperphosphatemia without apparent calcifications. In response to hyperphosphatemia, Galnt3-deficient mice had markedly increased Fgf23 expression in bone. However, compared with wild-type and heterozygous littermates, homozygous mice had only about half of circulating intact Fgf23 levels and higher levels of C-terminal Fgf23 fragments in bone. Galnt3-deficient mice also exhibited an inappropriately normal 1,25-dihydroxyvitamin D level and decreased alkaline phosphatase activity. Furthermore, renal expression of sodium-phosphate cotransporters and Kl were elevated in Galnt3-deficient mice. Interestingly, there were sex-specific phenotypes; only Galnt3-deficient males showed growth retardation, infertility, and significantly increased bone mineral density. In summary, ablation of Galnt3 impaired secretion of intact Fgf23, leading to decreased circulating Fgf23 and hyperphosphatemia, despite increased Fgf23 expression. Our findings indicate that Galnt3-deficient mice have a biochemical phenotype of tumoral calcinosis and provide in vivo evidence that Galnt3 plays an essential role in proper secretion of Fgf23 in mice.

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 Fibroblast Growth Factor-23 Mutants Causing Familial Tumoral Calcinosis Are Differentially Processed

Endocrinology ◽  
2005 ◽  
Vol 146 (9) ◽  
pp. 3883-3891 ◽  
Author(s):  
Tobias Larsson ◽  
Siobhan I. Davis ◽  
Holly J. Garringer ◽  
Sean D. Mooney ◽  
Mohamad S. Draman ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Conformational Changes ◽  
Fibroblast Growth Factor 23 ◽  
Elevated Serum ◽  
Tumoral Calcinosis ◽  
Intact Protein ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism ◽  
Physiological Importance

Abstract Familial tumoral calcinosis (TC, OMIM 211900) is a heritable disorder characterized by hyperphosphatemia, normal or elevated serum 1,25-dihydroxyvitamin D, and often severe ectopic calcifications. Two recessive mutations in fibroblast growth factor-23 (FGF23), serine 71/glycine (S71G) and serine 129/phenylalanine (S129F), were identified as causing TC. Herein, we undertook comprehensive biochemical analyses of an extended TC family carrying the S71G FGF23 mutation, which revealed that heterozygous (serine/glycine, S/G) individuals had elevated serum FGF23 C-terminal fragments compared with wild-type (serine/serine, S/S) family members (P < 0.025). To understand the differential processing of FGF23 in TC patients, we transiently expressed S71G as well as S129F FGF23. FGF23 ELISA in tandem with Western analyses revealed increased proteolytic cleavage of mutant FGF23 and a limited secretion of intact protein. Furthermore, S71G and S129F FGF23 carrying mutations that disrupt the furin-like protease RXXR motif in FGF23 rescued the secretion of the intact protein, and both TC mutant proteins harboring the R176Q mutation revealed no altered sensitivity to trypsin compared with the native (R176Q)FGF23. Finally, S71G, but not S129F mutant FGF23, is rescued by temperature. In summary, FGF23 mutations causing TC lead to increased intracellular proteolysis of FGF23, most likely by furin-like proteases, due to conformational changes of the mutant protein. The destabilizing nature of these mutations provides new insight into the pathophysiology of TC and exemplifies the physiological importance of FGF23 in phosphate and vitamin D metabolism.

Sex and iron modify fibroblast growth factor 23 concentrations in 1-year-old children

2017 ◽  
Author(s):  
Elisa Holmlund-Suila ◽  
Maria Enlund-Cerullo ◽  
Saara Valkama ◽  
Helena Hauta-alus ◽  
Jenni Rosendahl ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth
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