title: A novel Phex mutation with defective glycosylation causes hypophosphatemia and rickets in mice.
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 PHEX(pug) 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.
authors: Model Animal Research Center, Nanjing University, 12 Xuefu Road, Pukou District, Nanjing, 210061, PR China.
authors: Xiwen
authors: X
authors: Xiong
authors: Xin
authors: X
authors: Qi
authors: Xiaomei
authors: X
authors: Ge
authors: Pengyu
authors: P
authors: Gu
authors: Jing
authors: J
authors: Zhao
authors: Qingshun
authors: Q
authors: Zhao
authors: Xiang
authors: X
authors: Gao
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D053098:Familial Hypophosphatemic Rickets / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D040181:Genetic Diseases, X-Linked; D006031:Glycosylation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014960:X Chromosome / Q000235:genetics
chemical_list: D017931:DNA Primers; D011994:Recombinant Proteins; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse