Femoral abnormalities and vitamin D metabolism in X‐linked hypophosphatemic ( Hyp and Gy ) mice

Abstract X‐linked hypophosphatemia is a genetic bone disease in humans and mice. Two closely linked mutations in mice. Hyp and Gy . cause low plasma phosphate and a rachitic and osteomalacic bone disease. Because of the controversy as to whether Gy is a good model for X‐linked hypophosphatemia, the phenotypic severity of these two mutations was compared in both sexes and on two genetic backgrounds. The depression in plasma levels of phosphate was similar in all 10‐week‐old mutant mice. Male Hyp mice and heterozygous female Hyp mice were affected with similar severity in terms of reduced tail growth, shortened femora, reduced femoral mineral content, and abnormal mineral composition of the femoral matrix. In contrast, male Gy mice did not survive on the C57BL/6J background and were more severely affected than female Gy mice on the B6C3H background. The hybrid B6C3H background ameliorated the bone disease compared with the inbred C57BL/6J background for both mutant strains. There was no evidence of change in the plasma levels of 1.25‐dihydroxyvitamin D, duodenal level of vitamin D‐dependent calcium‐binding protein, or urinary level of calcium in these adult mutant mice. In summary, Gy mice have a sexual dimorphism not present in Hyp mice. These two genes may indicate the presence of multiple gene loci in the human disease, with multiple proteins involved in the pathophysiology of the bone disease.