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

Larsson, Tobias E.; Yu, Xijie; Davis, Siobhan I.; Draman, Mohd Shazli; Mooney, Sean D.; Cullen, Michael J.; White, Kenneth E.

doi:10.1210/jc.2004-2238

Cited by 206 publications

(150 citation statements)

References 16 publications

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“…(11) Conversely, low levels of iFGF23 and elevated levels of cFGF23 are found in familial tumoral calcinosis (FTC) and hyperphosphatemic hyperostosis syndrome (HHS). (12) FTC and HHS can result from homozygous mutations in the O-linked glycosyl transferase N-acetylgalactosaminyltransferase 3 (ppGalNAcT3), a member of the galactosaminyl transferase family that is known to transfer N-acetylgalactomine residues to specific serine/threonine residues. (13) It has been shown that mutations in ppGalNAcT3 lead to a loss of FGF23 glycosylation and enhanced cleavage of FGF23, resulting in very low levels of iFGF23 and correspondingly high cFGF23 levels.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of FGF23 processing in fibrous dysplasia

Bhattacharyya

Wiench

Dumitrescu

et al. 2012

Journal of Bone and Mineral Research

107

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Fibroblast growth factor-23 (FGF23) is a phosphate-and vitamin D-regulating hormone derived from osteoblasts/osteocytes that circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by O-glycosyl transferase Nacetylgalactosaminyltransferase 3 (ppGalNAcT3) and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. Elevated iFGF23 levels are observed in a number of hypophosphatemic disorders, such as X-linked, autosomal recessive, and autosomal dominant hypophosphatemic rickets, whereas low iFGF23 levels are found in the hyperphosphatemic disorder familial tumoral calcinosis/hyperphosphatemic hyperostosis syndrome. Fibrous dysplasia of bone (FD) is associated with increased total FGF23 levels (cFGF23 þ iFGF23); however, classic hypophosphatemic rickets is uncommon. Our results suggest that it can be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in the small G-protein G s a that results in increased cyclic adenosine monophosphate (cAMP) levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels and ppGalNacT3 and furin activities. Analysis of blood specimens from patients with FD confirmed that the elevated total FGF23 levels are the result of proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells (BMSCs) from patients with FD demonstrated that BMSCs harboring the causative G s a mutation had higher cAMP levels, lower ppGalNAcT3, and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients. ß

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Section: Introductionmentioning

confidence: 99%

Mechanism of FGF23 processing in fibrous dysplasia

Bhattacharyya

Wiench

Dumitrescu

et al. 2012

Journal of Bone and Mineral Research

107

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“…Its physiological importance is exemplified by numerous activating and inactivating mutations in the human FGF23 gene, causing two clinical disorders of disturbed Pi homeostasis: autosomal dominant hypophosphatemic rickets (ADHR, OMIM#193100; ADHR-Consortium 2000) and hyperphosphatemic familial tumoral calcinosis (HFTC, OMIM#211900; Benet-Pages et al 2005, Larsson et al 2005. Elevated FGF23 levels are also associated with several other disorders of hypophosphatemia or dysfunctional regulation of vitamin D, such as autosomal recessive hypophosphatemic rickets (ARHR; Feng et al 2006, Lorenz-Depiereux et al 2006, X-linked hypophosphatemic rickets (XLH; Liu et al 2003, Riminucci et al 2003, tumor-induced osteomalacia (TIO; Shimada et al 2001, White et al 2001b, fibrous dysplasia (FD; Riminucci et al 2003), and linear nevus sebaceous syndrome (LNSS; Hoffman et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells

Krajisnik¹,

Björklund

Marsell

et al. 2007

Journal of Endocrinology

428

268

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Fibroblast growth factor-23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate (Pi) as well as 1,25-dihydroxyvitamin D 3 . Recent studies also suggest a correlation between serum levels of FGF23 and parathyroid hormone (PTH) in patients with chronic kidney disease. It is, however, unknown whether FGF23 directly modulates PTH expression, or whether the correlation is secondary to abnormalities in Pi and vitamin D metabolism. The objective of the current study was therefore to elucidate possible direct effects of FGF23 on bovine parathyroid cells in vitro. Treatment of parathyroid cells with a stabilized form of recombinant FGF23 (FGF23(R176Q)) induced a rise in early response gene-1 mRNA transcripts, a marker of FGF23 signaling. FGF23(R176Q) potently and dose-dependently decreased the PTH mRNA level within 12 h. In agreement, FGF23(R176Q) also decreased PTH secretion into conditioned media. In contrast, FGF23(R176Q) dose-dependently increased 1a-hydroxylase expression within 3 h. FGF23 (R176Q) did not affect cell viability nor induce apoptosis, whereas a small but significant increase in cell proliferation was found. We conclude that FGF23 is a negative regulator of PTH mRNA expression and secretion in vitro. Our data suggest that FGF23 may be a physiologically relevant regulator of PTH. This defines a novel function of FGF23 in addition to the previously established roles in controlling vitamin D and Pi metabolism.

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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 Recessive Mutation in Fibroblast Growth Factor-23 Causes Familial Tumoral Calcinosis

Cited by 206 publications

References 16 publications

Mechanism of FGF23 processing in fibrous dysplasia

Mechanism of FGF23 processing in fibrous dysplasia

Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells

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

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