A novel Phex mutation in a new mouse model of hypophosphatemic rickets

Celeste Owen, Frieda Chen, Ann M. Flenniken, Lucy R. Osborne, Shoji Ichikawa, S. Lee Adamson, Janet Rossant, Jane E. Aubin

Research output: Contribution to journalArticle

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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 (PhexJrt also published as PhexK496X [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 (PhexJrt/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 PhexJrt/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.

Original languageEnglish
Pages (from-to)2432-2441
Number of pages10
JournalJournal of Cellular Biochemistry
Volume113
Issue number7
DOIs
StatePublished - Jul 2012

Fingerprint

Hypophosphatemic Rickets
Familial Hypophosphatemic Rickets
Bone
Mutation
Genes
Phosphates
Integrin-Binding Sialoprotein
Bone and Bones
Ethylnitrosourea
Endopeptidases
Mutagenesis
Messenger RNA
Proteins
Osteocalcin
Osteoblasts
Chromosomes
Metabolism
Vitamin D
Hypophosphatemia
Physiologic Calcification

Keywords

  • bone
  • endopeptidase
  • mineralization
  • N-Ethyl-N-nitrosourea mutagenesis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Owen, C., Chen, F., Flenniken, A. M., Osborne, L. R., Ichikawa, S., Adamson, S. L., ... Aubin, J. E. (2012). A novel Phex mutation in a new mouse model of hypophosphatemic rickets. Journal of Cellular Biochemistry, 113(7), 2432-2441. https://doi.org/10.1002/jcb.24115

A novel Phex mutation in a new mouse model of hypophosphatemic rickets. / Owen, Celeste; Chen, Frieda; Flenniken, Ann M.; Osborne, Lucy R.; Ichikawa, Shoji; Adamson, S. Lee; Rossant, Janet; Aubin, Jane E.

In: Journal of Cellular Biochemistry, Vol. 113, No. 7, 07.2012, p. 2432-2441.

Research output: Contribution to journalArticle

Owen, C, Chen, F, Flenniken, AM, Osborne, LR, Ichikawa, S, Adamson, SL, Rossant, J & Aubin, JE 2012, 'A novel Phex mutation in a new mouse model of hypophosphatemic rickets', Journal of Cellular Biochemistry, vol. 113, no. 7, pp. 2432-2441. https://doi.org/10.1002/jcb.24115
Owen C, Chen F, Flenniken AM, Osborne LR, Ichikawa S, Adamson SL et al. A novel Phex mutation in a new mouse model of hypophosphatemic rickets. Journal of Cellular Biochemistry. 2012 Jul;113(7):2432-2441. https://doi.org/10.1002/jcb.24115
Owen, Celeste ; Chen, Frieda ; Flenniken, Ann M. ; Osborne, Lucy R. ; Ichikawa, Shoji ; Adamson, S. Lee ; Rossant, Janet ; Aubin, Jane E. / A novel Phex mutation in a new mouse model of hypophosphatemic rickets. In: Journal of Cellular Biochemistry. 2012 ; Vol. 113, No. 7. pp. 2432-2441.
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