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A novel Phex mutation with defective glycosylation causes hypophosphatemia and rickets in mice

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Journal of Biomedical Science

Abstract

N-ethyl-N-nitrosourea (ENU) mutagenesis is a phenotype-driven approach with potential to assign function to every locus in the mouse genome. In this article, we describe a new mutation, Pug, as a mouse model for X-linked hypophosphatemic rickets (XLH) in human. Mice carrying the Pug mutation exhibit abnormal phenotypes including growth retardation, hypophosphatemia and decreased bone mineral density (BMD). The new mutation was mapped to X-chromosome between 65.4 cM and 66.6 cM, where Phex gene resides. Sequence analysis revealed a unique T-to-C transition mutation resulting in Phe-to-Ser substitution at amino acid 80 of PHEX protein. In vitro studies of Pug mutation demonstrated that PHEXpug was incompletely glycosylated and sequestrated in the endoplasmic reticulum region of cell, whereas wild-type PHEX could be fully glycosylated and transported to the plasma membrane to exert its function as an endopeptidase. Taken together, the Pug mutant directly confirms the role of Phex in phosphate homeostasis and normal skeletal development and may serves as a new disease model of human hypophosphatemic rickets.

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Acknowledgements

We thank Jishuai Zhang of the Institute of Biotechnology for technical assistance, as well as Chen Liu of the Gulou Hospital for serum assays. We also thank Drs. Wen Ning and Jiong Chen for their careful review of this manuscript. This work was supported in part by E-Institutes of Shanghai Municipal Education Commission (E03003), Program for Changjiang Scholars and Innovative Research Team in University (IRT0430), and National 973 Projects (2005CB522501 and 2006CB943500) to Xiang Gao.

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  1. Model Animal Research Center, Nanjing University, 12 Xuefu Road, Pukou District, Nanjing, 210061, P. R. China

    Xiwen Xiong, Xin Qi, Xiaomei Ge, Pengyu Gu, Jing Zhao, Qingshun Zhao & Xiang Gao

  2. Model Organism Division, E-Institutes of Shanghai Universities, Shanghai, 200234, P. R. China

    Xiang Gao

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  1. Xiwen Xiong
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  2. Xin Qi
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  3. Xiaomei Ge
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Correspondence to Xiang Gao.

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Xiong, X., Qi, X., Ge, X. et al. A novel Phex mutation with defective glycosylation causes hypophosphatemia and rickets in mice. J Biomed Sci 15, 47–59 (2008). https://doi.org/10.1007/s11373-007-9199-6

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  • DOI: https://doi.org/10.1007/s11373-007-9199-6

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