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A novel Phex mutation in a new mouse model of hypophosphatemic rickets.
J Cell Biochem. 2012 Jul; 113(7):2432-41.JC

Abstract

X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disease characterized by renal phosphate wasting, aberrant vitamin D metabolism, and defective bone mineralization. It is known that XLH in humans and in certain mouse models is caused by inactivating mutations in PHEX/Phex (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). By a genome-wide N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a dominant mouse mutation that exhibits the classic clinical manifestations of XLH, including growth retardation, skeletal abnormalities (rickets/osteomalacia), hypophosphatemia, and increased serum alkaline phosphatase (ALP) levels. Mapping and sequencing revealed that these mice carry a point mutation in exon 14 of the Phex gene that introduces a stop codon at amino acid 496 of the coding sequence (Phex(Jrt) also published as Phex(K496X) [Ichikawa et al., 2012]). Fgf23 mRNA expression as well as that of osteocalcin, bone sialoprotein, and matrix extracellular phosphoglycoprotein was upregulated in male mutant long bone, but that of sclerostin was unaffected. Although Phex mRNA is expressed in bone from mutant hemizygous male mice (Phex(Jrt)/Y mice), no Phex protein was detected in immunoblots of femoral bone protein. Stromal cultures from mutant bone marrow were indistinguishable from those of wild-type mice with respect to differentiation and mineralization. The ability of Phex(Jrt)/Y osteoblasts to mineralize and the altered expression levels of matrix proteins compared with the well-studied Hyp mice makes it a unique model with which to further explore the clinical manifestations of XLH and its link to FGF23 as well as to evaluate potential new therapeutic strategies.

Authors+Show Affiliations

Centre For Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22573557

Citation

Owen, Celeste, et al. "A Novel Phex Mutation in a New Mouse Model of Hypophosphatemic Rickets." Journal of Cellular Biochemistry, vol. 113, no. 7, 2012, pp. 2432-41.
Owen C, Chen F, Flenniken AM, et al. A novel Phex mutation in a new mouse model of hypophosphatemic rickets. J Cell Biochem. 2012;113(7):2432-41.
Owen, C., Chen, F., Flenniken, A. M., Osborne, L. R., Ichikawa, S., Adamson, S. L., Rossant, J., & Aubin, J. E. (2012). A novel Phex mutation in a new mouse model of hypophosphatemic rickets. Journal of Cellular Biochemistry, 113(7), 2432-41. https://doi.org/10.1002/jcb.24115
Owen C, et al. A Novel Phex Mutation in a New Mouse Model of Hypophosphatemic Rickets. J Cell Biochem. 2012;113(7):2432-41. PubMed PMID: 22573557.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel Phex mutation in a new mouse model of hypophosphatemic rickets. AU - Owen,Celeste, AU - Chen,Frieda, AU - Flenniken,Ann M, AU - Osborne,Lucy R, AU - Ichikawa,Shoji, AU - Adamson,S Lee, AU - Rossant,Janet, AU - Aubin,Jane E, PY - 2012/5/11/entrez PY - 2012/5/11/pubmed PY - 2012/10/30/medline SP - 2432 EP - 41 JF - Journal of cellular biochemistry JO - J. Cell. Biochem. VL - 113 IS - 7 N2 - X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disease characterized by renal phosphate wasting, aberrant vitamin D metabolism, and defective bone mineralization. It is known that XLH in humans and in certain mouse models is caused by inactivating mutations in PHEX/Phex (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). By a genome-wide N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a dominant mouse mutation that exhibits the classic clinical manifestations of XLH, including growth retardation, skeletal abnormalities (rickets/osteomalacia), hypophosphatemia, and increased serum alkaline phosphatase (ALP) levels. Mapping and sequencing revealed that these mice carry a point mutation in exon 14 of the Phex gene that introduces a stop codon at amino acid 496 of the coding sequence (Phex(Jrt) also published as Phex(K496X) [Ichikawa et al., 2012]). Fgf23 mRNA expression as well as that of osteocalcin, bone sialoprotein, and matrix extracellular phosphoglycoprotein was upregulated in male mutant long bone, but that of sclerostin was unaffected. Although Phex mRNA is expressed in bone from mutant hemizygous male mice (Phex(Jrt)/Y mice), no Phex protein was detected in immunoblots of femoral bone protein. Stromal cultures from mutant bone marrow were indistinguishable from those of wild-type mice with respect to differentiation and mineralization. The ability of Phex(Jrt)/Y osteoblasts to mineralize and the altered expression levels of matrix proteins compared with the well-studied Hyp mice makes it a unique model with which to further explore the clinical manifestations of XLH and its link to FGF23 as well as to evaluate potential new therapeutic strategies. SN - 1097-4644 UR - https://www.unboundmedicine.com/medline/citation/22573557/A_novel_Phex_mutation_in_a_new_mouse_model_of_hypophosphatemic_rickets_ L2 - https://doi.org/10.1002/jcb.24115 DB - PRIME DP - Unbound Medicine ER -