Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23

White, Kenneth E.; Carn, Gwénaëlle; Lorenz‐Depiereux, Bettina; Benet‐Pagès, Anna; Strom, Tim M.; Econs, Michael J.

doi:10.1046/j.1523-1755.2001.00064.x

Cited by 453 publications

(337 citation statements)

References 30 publications

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“…Recent discoveries have confirmed that autosomal dominant hypophosphatemic rickets (ADHR) is caused by activating mutations in FGF23 [4,82,97,98]. The specific ADHR mutations increase the stability of mutated FGF23 and the uncleaved mutated molecule is phosphaturic and elicits osteomalacia/rickets [4,77,81,98].…”

Section: Introductionmentioning

confidence: 99%

MEPE has the properties of an osteoblastic phosphatonin and minhibin

Rowe

Kumagai²,

Gutiérrez³

et al. 2004

Bone

245

277

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Matrix extracellular phosphoglycoprotein (MEPE) is expressed exclusively in osteoblasts, osteocytes and odontoblasts with markedly elevated expression found in X-linked hypophosphatemic rickets (Hyp) osteoblasts and in oncogenic hypophosphatemic osteomalacia (OHO) tumors. Because these syndromes are associated with abnormalities in mineralization and renal phosphate excretion, we examined the effects of insect-expressed full-length human-MEPE (Hu-MEPE) on serum and urinary phosphate in vivo, 33 PO 4 uptake in renal proximal tubule cultures and mineralization of osteoblast cultures. Dose-dependent hypophosphatemia and hyperphosphaturia occurred in mice following intraperitoneal (IP) administration of Hu-MEPE (up to 400 μg kg -1 31 h -1 ), similar to mice given the phosphaturic hormone PTH (80 μg kg -1 31 h -1 ). Also the fractional excretion of phosphate (FEP) was stimulated by MEPE [65.0% (P < 0.001)] and PTH groups [53.3% (P < 0.001)] relative to the vehicle group [28.7% (SEM 3.97)]. In addition, Hu-MEPE significantly inhibited 33 PO 4 uptake in primary human proximal tubule renal cells (RPTEC) and a human renal cell line (Hu-CL8) in vitro (V max 53.4% inhibition; K m 27.4 ng/ ml, and V max 9.1% inhibition; K m 23.8 ng/ml, respectively). Moreover, Hu-MEPE dose dependently (50-800 ng/ml) inhibited BMP2-mediated mineralization of a murine osteoblast cell line (2T3) in vitro. Inhibition of mineralization was localized to a small (2 kDa) cathepsin B released carboxy-terminal MEPE peptide (protease-resistant) containing the acidic serineaspartate-rich motif (ASARM peptide). We conclude that MEPE promotes renal phosphate excretion and modulates mineralization.

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Section: Introductionmentioning

confidence: 99%

MEPE has the properties of an osteoblastic phosphatonin and minhibin

Rowe

Kumagai²,

Gutiérrez³

et al. 2004

Bone

245

277

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“…The mutant FGF-23 has a prolonged half-life [6,7,9,11,28]. Our studies suggest that although furin cleavage between residues 176 and 179 results in a reduction of bioactivity of FGF-23, significant bioactivity persists with fragments that extend from carboxyl terminal amino acid residue 180 up to residue 206.…”

Section: Discussionmentioning

confidence: 93%

“…The role of FGF-23 in the pathogenesis of ADHR has been shown to be due to mutations in the FGF-23 gene that result in the production of a mutant protein in which the amino acid sequence of a furin proconvertase cleavage site (176RHTR179) is altered (R176Q, R179Q, R179W), rendering the mutant FGF-23 resistant to proteolysis [6,7,9]. The mutant FGF-23 has a prolonged half-life [6,7,9,11,28].…”

Section: Discussionmentioning

confidence: 99%

“…The twenty three FGFs and the four known plasma membrane associated receptors, the fibroblast growth receptors (FGFRs) transduce a variety of biochemical changes in developing and adult tissues [3][4][5]. The recently identified fibroblast growth factor, FGF-23, inhibits renal phosphate reabsorption and 1 ,25-dihydroxyvitamin D (1 ,25(OH) 2 D) synthesis [6][7][8][9][10][11][12][13]. FGF-23 plays a role in the pathogenesis of a variety of hypophosphatemic disorders including autosomal dominant hypophosphatameic rickets, tumor-induced osteomalacia and X-linked hypophosphatemic rickets [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…In autosomal dominant hypophosphatemic rickets (ADHR), a disease associated with low serum phosphorus and 1 ,25(OH) 2 D concentrations and rickets, mutations in FGF-23 gene result in the expression of a protein that is resistant to proteolysis and with an increased half life [7,9,11,14,28]. Mutations in the gene alter the furin proconvertase recognition site (176RHTR179) in the protein such that the arginine residue at 176 is replaced by glutamine (R176Q) or the arginine residue at amino acid 179 is replaced by a glutamine (R179Q) or tryptophan residue (R179W).…”

Section: Introductionmentioning

confidence: 99%

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Biological activity of FGF-23 fragments

Berndt

Craig

McCormick

et al. 2007

Pflugers Arch - Eur J Physiol

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SUMMARYThe phosphaturic activity of intact, full-length, fibroblast growth factor-23 (FGF-23) is well documented. FGF-23 circulates as the intact protein, and as fragments generated as the result of proteolysis of the full-length protein. To assess whether short fragments of FGF-23 are phosphaturic, we compared the effect of acute, equimolar infusions of full-length FGF-23 and various FGF-23 fragments carboxyl-terminal to amino acid 176. In rats, intravenous infusions of full-length FGF-23, and FGF-23 176-251, significantly and equivalently increased fractional phosphate excretion (FE Pi)) from 14±3 to 32±5% and 15±2 to 33±2% (p <0.001), respectively. reduced Na + -dependent Pi uptake and enhanced internalization of the Na + -Pi IIa co-transporter. We conclude that carboxyl terminal fragments of FGF-23 are phosphaturic, and that a short, 26 amino acid fragment of FGF-23 retains significant phosphaturic activity.

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Tumor-Induced Osteomalacia

Beur¹

2005

JAMA

219

196

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Tumor-induced osteomalacia (TIO) is a rare paraneoplastic form of renal phosphate wasting that results in severe hypophosphatemia, a defect in vitamin D metabolism, and osteomalacia. This debilitating disorder is illustrated by the clinical presentation of a 55-year-old woman with progressive fatigue, weakness, and muscle and bone pain with fractures. After a protracted clinical course and extensive laboratory evaluation, tumor-induced osteomalacia was identified as the basis of her clinical presentation. In this article, the distinctive clinical characteristics of this syndrome, the advances in diagnosis of TIO, and new insights into the pathophysiology of this disorder are discussed.

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Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23

Cited by 453 publications

References 30 publications

MEPE has the properties of an osteoblastic phosphatonin and minhibin

MEPE has the properties of an osteoblastic phosphatonin and minhibin

Biological activity of FGF-23 fragments

Tumor-Induced Osteomalacia

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