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Gene Review

PHEX  -  phosphate regulating endopeptidase homolog...

Homo sapiens

Synonyms: HPDR, HPDR1, HYP, HYP1, LXHR, ...


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Disease relevance of PHEX


Psychiatry related information on PHEX


High impact information on PHEX


Chemical compound and disease context of PHEX


Biological context of PHEX

  • Mutations in PHEX, a phosphate-regulating gene with homology to endopeptidases on the X chromosome, are responsible for X-linked hypophosphatemia (XLH) [22].
  • The aim of this study was, therefore, to examine whether transgenic overexpression of PHEX under the human beta-actin promoter would rescue the Hyp phenotype [23].
  • X-linked hypophosphatemia (XLH) is phenotypically similar to OHO and results from mutations in PHEX, a putative metallopeptidase believed to process a factor(s) regulating bone mineralization and renal phosphate reabsorption [24].
  • FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization [25].
  • Seven different PHEX mutations were detected in 8 patients: 2 missense mutations, 2 nonsense mutations, and 3 short deletions [26].

Anatomical context of PHEX

  • We also present two other patients whose parathyroid glands were analyzed for PHEX mRNA expression following parathyroidectomy [2].
  • The abundance of PHEX mRNA, relative to beta-actin mRNA, in parathyroid glands from patients 2 and 3 was several-fold greater than that in human fetal calvaria, as estimated by ribonuclease protection assay [2].
  • Human recombinant endopeptidase PHEX has a strict S1' specificity for acidic residues and cleaves peptides derived from fibroblast growth factor-23 and matrix extracellular phosphoglycoprotein [27].
  • These studies indicate that mutations in the PHEX gene are unlikely to be responsible for OOM and suggest that the tumor-derived factor that inhibits phosphate uptake is a small protein that does not downregulate type II NaPi mRNA, and requires an intact cytoskeleton and protein synthesis for activity [28].
  • Altered cathepsin D metabolism in PHEX antisense human osteoblast cells [29].

Associations of PHEX with chemical compounds

  • We found that affected individuals have a missense mutation in PHEX exon 16 that results in an amino acid change from leucine to proline in residue 555 [30].
  • The peptide Abz-GFSDYK(Dnp)-OH, which contains the most favourable residues in the P(2) to P(2)' positions, was hydrolysed by PHEX at the N-terminus of aspartate with a k(cat)/ K(m) of 167 mM(-1) x s(-1) [27].
  • In order to study PHEX substrate specificity, combinatorial fluorescent-quenched peptide libraries containing o -aminobenzoic acid (Abz) and 2,4-dinitrophenyl (Dnp) as the donor-acceptor pair were synthesized and tested as PHEX substrates [27].
  • We hypothesized that the processing of DMP1 and DSPP is catalyzed by the PHEX enzyme, since this protein, an endopeptidase that is predominantly expressed in bone and tooth, has a strong preference for cleavage at the NH2-terminus of aspartyl residue [31].
  • Of the three mutant PHEX proteins, the S711R was the least stable and the only one that could be rescued from the ER to the plasma membrane in cells grown at 26 degrees C. The chemical chaperone glycerol failed to correct defective targeting of all three mutant proteins [32].

Physical interactions of PHEX

  • Our aims were to determine (1) whether PHEX binds specifically to MEPE, (2) whether the binding involves the ASARM motif region, and (3) whether free ASARM peptide affects mineralization in vivo in mice [33].

Enzymatic interactions of PHEX

  • We found that both recombinant MEPE and synthetic phosphorylated ASARM peptide (ASARM-PO(4)) inhibit PHEX enzyme activities in an in vitro fluorescent-quenched PHEX enzyme activity assay [34].
  • PHEX cleaves ASARM peptides from MEPE [35] and OPN [36], and full-length OPN [16].

Regulatory relationships of PHEX

  • Recombinant MEPE also inhibits PHEX activity (K(i) = 2 nM and V(max-i) = 26%) [34].
  • FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate [37].
  • MATERIALS AND METHODS: We tested this hypothesis by generating two mouse lines expressing human PHEX under the control of a human beta-actin promoter (PHEX-tg) [23].
  • It is unclear whether the mutant PHEX gene can induce hyperparathyroidism by abnormal regulation of peptidases [38].
  • 24,25(OH)2 D3 improves skeletal lesions in a murine model of XLH and suppresses PTH secretion in animals [39].

Other interactions of PHEX


Analytical, diagnostic and therapeutic context of PHEX


  1. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. Jonsson, K.B., Zahradnik, R., Larsson, T., White, K.E., Sugimoto, T., Imanishi, Y., Yamamoto, T., Hampson, G., Koshiyama, H., Ljunggren, O., Oba, K., Yang, I.M., Miyauchi, A., Econs, M.J., Lavigne, J., Jüppner, H. N. Engl. J. Med. (2003) [Pubmed]
  2. PHEX expression in parathyroid gland and parathyroid hormone dysregulation in X-linked hypophosphatemia. Blydt-Hansen, T.D., Tenenhouse, H.S., Goodyer, P. Pediatr. Nephrol. (1999) [Pubmed]
  3. Serum FGF23 levels in normal and disordered phosphorus homeostasis. Weber, T.J., Liu, S., Indridason, O.S., Quarles, L.D. J. Bone Miner. Res. (2003) [Pubmed]
  4. PHEX gene and hypophosphatemia. Drezner, M.K. Kidney Int. (2000) [Pubmed]
  5. Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia. McKee, M.D., Hoac, B., Addison, W.N., Barros, N.M., Millán, J.L., Chaussain, C. Periodontol. 2000. (2013) [Pubmed]
  6. A case of neuroendocrine oncogenic osteomalacia associated with a PHEX and fibroblast growth factor-23 expressing sinusidal malignant schwannoma. John, M.R., Wickert, H., Zaar, K., Jonsson, K.B., Grauer, A., Ruppersberger, P., Schmidt-Gayk, H., Murer, H., Ziegler, R., Blind, E. Bone (2001) [Pubmed]
  7. A longitudinal study of high scorers on the hypomanic personality scale. Kwapil, T.R., Miller, M.B., Zinser, M.C., Chapman, L.J., Chapman, J., Eckblad, M. Journal of abnormal psychology. (2000) [Pubmed]
  8. St. John's Wort for depressive disorders: results of an outpatient study with the Hypericum preparation HYP 811. Mueller, B.M. Advances in therapy. (1998) [Pubmed]
  9. The pachygyria-polymicrogyria spectrum of cortical dysplasia in X-linked hydrocephalus. Graf, W.D., Born, D.E., Sarnat, H.B. European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift für Kinderchirurgie. (1998) [Pubmed]
  10. Components involved in peroxisome import, biogenesis, proliferation, turnover, and movement. Subramani, S. Physiol. Rev. (1998) [Pubmed]
  11. Human PEX1 is mutated in complementation group 1 of the peroxisome biogenesis disorders. Portsteffen, H., Beyer, A., Becker, E., Epplen, C., Pawlak, A., Kunau, W.H., Dodt, G. Nat. Genet. (1997) [Pubmed]
  12. Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease. Scriver, C.R., Reade, T.M., DeLuca, H.F., Hamstra, A.J. N. Engl. J. Med. (1978) [Pubmed]
  13. Peroxisome biogenesis. Purdue, P.E., Lazarow, P.B. Annu. Rev. Cell Dev. Biol. (2001) [Pubmed]
  14. Orthophosphate transport in the erythrocyte of normal subjects and of patients with X-linked hypophosphatemia. Tenenhouse, H.S., Scriver, C.R. J. Clin. Invest. (1975) [Pubmed]
  15. Osteopontin. Sodek, J., Ganss, B., McKee, M.D. Crit. Rev. Oral. Biol. Med. (2000) [Pubmed]
  16. Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia. Barros, N.M., Hoac, B., Neves, R.L., Addison, W.N., Assis, D.M., Murshed, M., Carmona, A.K., McKee, M.D. J. Bone. Miner. Res. (2013) [Pubmed]
  17. Cloning and characterization of three PHEX homologues in Drosophila. Ito, M., Akai, E., Izuka, M., Segawa, H., Kuwahata, M., Miyamoto, K. J. Bone Miner. Metab. (2004) [Pubmed]
  18. A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo. Hayashibara, T., Hiraga, T., Yi, B., Nomizu, M., Kumagai, Y., Nishimura, R., Yoneda, T. J. Bone Miner. Res. (2004) [Pubmed]
  19. Parathyroid hormone effects on serum 1,25-dihydroxyvitamin D levels in patients with X-linked hypophosphatemic rickets: evidence for abnormal 25-hydroxyvitamin D-1-hydroxylase activity. Lyles, K.W., Drezner, M.K. J. Clin. Endocrinol. Metab. (1982) [Pubmed]
  20. Biochemical markers of bone turnover for the clinical assessment of bone metabolism. Taylor, A.K., Lueken, S.A., Libanati, C., Baylink, D.J. Rheum. Dis. Clin. North Am. (1994) [Pubmed]
  21. Effect of dipyridamole on serum and urinary phosphate in X-linked hypophosphatemia. Seikaly, M.G., Quigley, R., Baum, M. Pediatr. Nephrol. (2000) [Pubmed]
  22. Developmental expression and tissue distribution of Phex protein: effect of the Hyp mutation and relationship to bone markers. Ruchon, A.F., Tenenhouse, H.S., Marcinkiewicz, M., Siegfried, G., Aubin, J.E., DesGroseillers, L., Crine, P., Boileau, G. J. Bone Miner. Res. (2000) [Pubmed]
  23. Overexpression of human PHEX under the human beta-actin promoter does not fully rescue the Hyp mouse phenotype. Erben, R.G., Mayer, D., Weber, K., Jonsson, K., Jüppner, H., Lanske, B. J. Bone Miner. Res. (2005) [Pubmed]
  24. Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone. Argiro, L., Desbarats, M., Glorieux, F.H., Ecarot, B. Genomics (2001) [Pubmed]
  25. FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Quarles, L.D. Am. J. Physiol. Endocrinol. Metab. (2003) [Pubmed]
  26. A clinical and molecular genetic study of hypophosphatemic rickets in children. Cho, H.Y., Lee, B.H., Kang, J.H., Ha, I.S., Cheong, H.I., Choi, Y. Pediatr. Res. (2005) [Pubmed]
  27. Human recombinant endopeptidase PHEX has a strict S1' specificity for acidic residues and cleaves peptides derived from fibroblast growth factor-23 and matrix extracellular phosphoglycoprotein. Campos, M., Couture, C., Hirata, I.Y., Juliano, M.A., Loisel, T.P., Crine, P., Juliano, L., Boileau, G., Carmona, A.K. Biochem. J. (2003) [Pubmed]
  28. Phosphate wasting in oncogenic osteomalacia: PHEX is normal and the tumor-derived factor has unique properties. Nelson, A.E., Hogan, J.J., Holm, I.A., Robinson, B.G., Mason, R.S. Bone (2001) [Pubmed]
  29. Altered cathepsin D metabolism in PHEX antisense human osteoblast cells. Matsumoto, N., Jo, O.D., Shih, R.N., Yanagawa, N. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  30. A PHEX gene mutation is responsible for adult-onset vitamin D-resistant hypophosphatemic osteomalacia: evidence that the disorder is not a distinct entity from X-linked hypophosphatemic rickets. Econs, M.J., Friedman, N.E., Rowe, P.S., Speer, M.C., Francis, F., Strom, T.M., Oudet, C., Smith, J.A., Ninomiya, J.T., Lee, B.E., Bergen, H. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  31. Post-translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis. Qin, C., Baba, O., Butler, W.T. Crit. Rev. Oral Biol. Med. (2004) [Pubmed]
  32. Disease-causing missense mutations in the PHEX gene interfere with membrane targeting of the recombinant protein. Sabbagh, Y., Boileau, G., DesGroseillers, L., Tenenhouse, H.S. Hum. Mol. Genet. (2001) [Pubmed]
  33. Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the MEPE-ASARM motif: a model for impaired mineralization in X-linked rickets (HYP). Rowe, P.S., Garrett, I.R., Schwarz, P.M., Carnes, D.L., Lafer, E.M., Mundy, G.R., Gutierrez, G.E. Bone (2005) [Pubmed]
  34. Phosphorylated acidic serine-aspartate-rich MEPE-associated motif peptide from matrix extracellular phosphoglycoprotein inhibits phosphate regulating gene with homologies to endopeptidases on the X-chromosome enzyme activity. Liu, S., Rowe, P.S., Vierthaler, L., Zhou, J., Quarles, L.D. J. Endocrinol. (2007) [Pubmed]
  35. MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. Addison, W.N., Nakano, Y., Loisel, T., Crine, P., McKee, M.D. J. Bone. Miner. Res. (2008) [Pubmed]
  36. Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. Addison, W.N., Masica, D.L., Gray, J.J., McKee, M.D. J. Bone. Miner. Res. (2010) [Pubmed]
  37. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Bowe, A.E., Finnegan, R., Jan de Beur, S.M., Cho, J., Levine, M.A., Kumar, R., Schiavi, S.C. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  38. The enigma of hyperparathyroidism in hypophosphatemic rickets. Schmitt, C.P., Mehls, O. Pediatr. Nephrol. (2004) [Pubmed]
  39. 24,25 Dihydroxyvitamin D supplementation corrects hyperparathyroidism and improves skeletal abnormalities in X-linked hypophosphatemic rickets--a clinical research center study. Carpenter, T.O., Keller, M., Schwartz, D., Mitnick, M., Smith, C., Ellison, A., Carey, D., Comite, F., Horst, R., Travers, R., Glorieux, F.H., Gundberg, C.M., Poole, A.R., Insogna, K.L. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  40. FGF23 is processed by proprotein convertases but not by PHEX. Benet-Pagès, A., Lorenz-Depiereux, B., Zischka, H., White, K.E., Econs, M.J., Strom, T.M. Bone (2004) [Pubmed]
  41. New insights into the pathogenesis of inherited phosphate wasting disorders. Econs, M.J. Bone (1999) [Pubmed]
  42. Resolution of severe, adolescent-onset hypophosphatemic rickets following resection of an FGF-23-producing tumour of the distal ulna. Ward, L.M., Rauch, F., White, K.E., Filler, G., Matzinger, M.A., Letts, M., Travers, R., Econs, M.J., Glorieux, F.H. Bone (2004) [Pubmed]
  43. Bone as a source of FGF23: regulation by phosphate? Mirams, M., Robinson, B.G., Mason, R.S., Nelson, A.E. Bone (2004) [Pubmed]
  44. Two novel PHEX mutations in Taiwanese patients with X-linked hypophosphatemic rickets. Lo, F.S., Kuo, M.T., Wang, C.J., Chang, C.H., Lee, Z.L., Van, Y.H. Nephron. Physiology [electronic resource]. (2006) [Pubmed]
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