A gene (PEX) with homologies to endopeptidases is mutated in patients with X–linked hypophosphatemic rickets

Francis, Fiona; Hennig, Steffen; Korn, Bernd; Reinhardt, Richard; Jong, Pieter J. de; Poustka, Albert J.; Lehrach, Hans; Rowe, Peter; Goulding, J.; Summerfield, Tina C.; Mountford, Roger; Read, Andrew P.; Popowska, Ewa; Pronicka, Ewa; Davies, Kay E.; O’Riordan, J. L. H.; Econs, Michael J.; Nesbitt, Teresa; Drezner, Marc K.; Oudet, C.; Pannetier, Solange; Hanauer, André; Strom, Tim M.; Meindl, Alfons; Lorenz, Bettina; Cagnoli, B.; Mohnike, Klaus; Murken, Jan; Meitinger, Thomas

doi:10.1038/ng1095-130

Cited by 1,025 publications

(293 citation statements)

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“…Soon after the identification by positional cloning in 1995 by the Hyp Consortium (1) of an inactivating PHEX mutation in XLH patients, whose phenotypic bone deformities result from defective skeletal mineralization (hypomineralization, osteomalacia) caused in part by renal phosphate wasting, a search began for circulating phosphaturic factors (phosphatonins) induced by the absence of PHEX and for PHEX substrate proteins/peptides. Such a phosphaturic factor decreased expression levels of the renal sodium phosphate co-transporter type 2a (NPT2a) essential for inorganic phosphate (Pi) homeostasis by promoting the renal epithelial cell reabsorption of Pi from the urinary filtrate that is required for normal skeletal development and mineraliza- tion.…”

Section: Discussionmentioning

confidence: 99%

“…(1)(2)(3) In humans, inactivating mutations in PHEX cause X-linked hypophosphatemia (XLH), with similar phenotypic features occurring in the hypophosphatemic (Hyp) mouse model of this disease. XLH is the most frequent inherited formin mineral ion metabolism and local changes within the bone tissue, resulting in the clinical and biochemical features of XLH, are still not completely known.…”

Section: Introductionmentioning

confidence: 99%

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Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia

Barros

Hoac

Neves

et al. 2012

Journal of Bone and Mineral Research

125

111

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X-linked hypophosphatemia (XLH/HYP)-with renal phosphate wasting, hypophosphatemia, osteomalacia, and tooth abscesses-is caused by mutations in the zinc-metallopeptidase PHEX gene (phosphate-regulating gene with homologies to endopeptidase on the X chromosome). PHEX is highly expressed by mineralized tissue cells. Inactivating mutations in PHEX lead to distal renal effects (implying accumulation of a secreted, circulating phosphaturic factor) and accumulation in bone and teeth of mineralization-inhibiting, acidic serine-and aspartate-rich motif (ASARM)-containing peptides, which are proteolytically derived from the mineral-binding matrix proteins of the SIBLING family (small, integrin-binding ligand N-linked glycoproteins). Although the latter observation suggests a local, direct matrix effect for PHEX, its physiologically relevant substrate protein(s) have not been identified. Here, we investigated two SIBLING proteins containing the ASARM motif-osteopontin (OPN) and bone sialoprotein (BSP)-as potential substrates for PHEX. Using cleavage assays, gel electrophoresis, and mass spectrometry, we report that OPN is a full-length protein substrate for PHEX. Degradation of OPN was essentially complete, including hydrolysis of the ASARM motif, resulting in only very small residual fragments. Western blotting of Hyp (the murine homolog of human XLH) mouse bone extracts having no PHEX activity clearly showed accumulation of an $35 kDa OPN fragment that was not present in wild-type mouse bone. Immunohistochemistry and immunogold labeling (electron microscopy) for OPN in Hyp bone likewise showed an accumulation of OPN and/or its fragments compared with normal wild-type bone. Incubation of Hyp mouse bone extracts with PHEX resulted in the complete degradation of these fragments. In conclusion, these results identify full-length OPN and its fragments as novel, physiologically relevant substrates for PHEX, suggesting that accumulation of mineralization-inhibiting OPN fragments may contribute to the mineralization defect seen in the osteomalacic bone characteristic of XLH/HYP. ß

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia

Barros

Hoac

Neves

et al. 2012

Journal of Bone and Mineral Research

125

111

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“…The hypothesis that a single common humoral factor may explain both HYP and oncogenic osteomalacia has now been challenged by the identification of PEX as the candidate gene for human HYP (Francis et al, 1995). The PEX gene has strong homology to a family of neutral, membrane-bound endopeptidases.…”

Section: Implications Of the Identification Of Pex As The Candidate Gmentioning

confidence: 99%

Oncogenic osteomalacia: is there a new phosphate regulating hormone?

Nelson

Robinson

Mason

1997

Clinical Endocrinology

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SummaryOncogenic osteomalacia is a syndrome associated with rare, usually mesenchymal tumours, which is characterized by hypophosphataemia, phosphaturia and low concentrations of 1,25-dihydroxyvitamin D. The reversal of clinical and biochemical abnormalities following removal of the tumour, indicates it is the source of a humoral factor that is responsible for these abnormalities. It has been demonstrated that the humoral factor inhibits renal phosphate uptake and reduces 1,25-dihydroxyvitamin D production. Although there is evidence that it may act via parathyroid hormone/parathyroid hormone-related peptide receptors and may be a peptide, the factor has not yet been identified, nor has its relationship to factors involved in X-linked hypophosphataemic rickets been established. We propose unifying hypotheses for the pathogenesis of oncogenic osteomalacia and X-linked hypophosphataemic rickets which involve defects in the PEX gene. These hypotheses do not fully explain all the available data and it remains possible that hormone(s) with little or no role in X-linked hypophosphataemic rickets may be responsible for oncogenic osteomalacia.

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“…In this disease, females are more affected than males. 9,10 Phosphatemia in blood, along with low level of vitamin 1,25(OH)2D and normal serum calcium levels associated with increased alkaline phosphatase activity, accompanied with normal or mild elevation of parathyroid hormone (PTH) levels can be used to differentiate XLH patients from other sorts of hypohphsphatemia. Based on the latest research, inactivating mutation of the PHEX leads to XLH and increases the FGF23 levels.…”

Section: Methodsmentioning

confidence: 99%

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

Manjili¹,

Aliabad²,

Kalantar³

et al. 2017

Int J Basic Sci Med

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A gene (PEX) with homologies to endopeptidases is mutated in patients with X–linked hypophosphatemic rickets

Cited by 1,025 publications

References 40 publications

Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia

Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia

Oncogenic osteomalacia: is there a new phosphate regulating hormone?

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

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