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

作者：Xiong Xiwen; Qi Xin; Ge Xiaomei; Gu Pengyu; Zhao Jing; Zhao Qingshun; Gao Xiang^*

来源：Journal of Biomedical Science, 2008, 15(1): 47-59.

DOI：10.1007/s11373-007-9199-6

• ENU mutagenesis
• Phex
• hypophosphatemia
• bone mineral density
• glycosylation

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.

• 出版日期2008-1
• 单位南京大学; 上海大学