DMP1 C-terminal Mutant Mice Recapture the Human ARHR Phenotype

OBJECTIVES: Identification of DMP1 mutations in autosomal recessive hypophosphatemic rickets (ARHR) patients suggests that inactivating mutations of DMP1 are the likely cause of ARHR. In parallel, mice lacking Dmp1 have an overlapping pathophysiology, such as hypophosphatemia. However, minor differences exist between the mouse model and the human ARHR patients. These differences could be due to a species-specificity of human versus mouse, or that the mutant DMP1 in humans may maintain a partial function of DMP1. Thus, generation of DMP1 mutant mouse models based on the human mutations will be critical for distinguishing these differences, as well as for pathophysiological studies of this disorder. The goals of this study were to determine the molecular genetics and pathophysiology of DMP1 mutations through generation and analyses of a mouse model harboring these DMP1 mutations. METHODS: 1) Generating transgenic mice harboring a full-length of Dmp1 cDNA with the same C-terminal mutations as observed in ARHR patients under control of the 3.6 kb Col1a1 promoter; 2) Crossing these transgenic lines to Dmp1-null mice for generation of mice that have no endogenous Dmp1 but contain the Dmp1-mutant; and 3) Comparing both phenotypes using a combinations of techniques including calcein/alizarin red labeling, SEM, histology and radiography. RESULTS: Three independent mutant transgenic lines were generated and fully characterized. These mutant transgenic mice showed no apparent phenotype in WT background, but mice with the transgene in Dmp1-null background displayed ricketic phenotypes similar to those observed in Dmp1-KO mice. However, the phenotype is mild, and identical to that in human ARHR patients, suggesting that the mutant Dmp1 has a partial function and this animal model recaptures human ARHR phenotype. CONCLUSION: Successful generation/characterization of ARHR animal model provides a powerful tool for studies of the pathophysiological process of this disease in future.(Work supported by NIH grant: AR51587)