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Dosage Effect of a Phex Mutation in a Murine Model of X-Linked Hypophosphatemia

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Abstract

X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene, which increase circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Because XLH is a dominant disease, one mutant allele is sufficient for manifestation of the disease. However, the dosage effect of a PHEX mutation in XLH is not completely understood. To examine the effect of Phex genotypes, we compared serum biochemistries and skeletal measures between all five possible genotypes of a new murine model of XLH (Phex K496X or Phex Jrt). Compared to sex-matched littermate controls, all Phex mutant mice had hypophosphatemia, mild hypocalcemia, and increased parathyroid hormone and alkaline phosphatase levels. Furthermore, mutant mice had markedly elevated serum Fgf23 levels due to increased Fgf23 expression and reduced cleavage of Fgf23. Although females with a homozygous Phex mutation were slightly more hypocalcemic and hypophosphatemic than heterozygous females, the two groups had comparable intact Fgf23 levels. Similarly, there was no difference in intact Fgf23 or phosphorus concentrations between hemizygous males and heterozygous females. Compared to heterozygous females, homozygous counterparts were significantly smaller and had shorter femurs with reduced bone mineral density, suggesting the existence of dosage effect in the skeletal phenotype of XLH. However, overall phenotypic trends in regards to mineral ion homeostasis were mostly unaffected by the presence of one or two mutant Phex allele(s). The lack of a gene dosage effect on circulating Fgf23 (and thus phosphorus) levels suggests that a Phex mutation may create the lower set point for extracellular phosphate concentrations.

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Acknowledgments

This study was supported by Indiana University-Purdue University Indianapolis Undergraduate Research Opportunities Program (UROP) grant (to EB), National Institutes of Health grant R01 AR042228 (to MJE), Indiana University School of Medicine Biomedical Research grant (to SI), Showalter Research Trust Fund (to SI), and KL2 career development award (to SI) from the Indiana Clinical and Translational Sciences Institute funded in part by the National Institutes of Health grant RR025760.

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Authors and Affiliations

  1. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Shoji Ichikawa, Amie K. Gray, Emmanuel Bikorimana & Michael J. Econs

  2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Michael J. Econs

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  1. Shoji Ichikawa
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  2. Amie K. Gray
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Correspondence to Shoji Ichikawa.

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Ichikawa, S., Gray, A.K., Bikorimana, E. et al. Dosage Effect of a Phex Mutation in a Murine Model of X-Linked Hypophosphatemia. Calcif Tissue Int 93, 155–162 (2013). https://doi.org/10.1007/s00223-013-9736-4

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