FEMORAL ABNORMALITIES AND VITAMIN-D METABOLISM IN X-LINKED HYPOPHOSPHATEMIC (HYP AND GY) MICE

X-linked hypophosphatemia is a genetic bone disease in humans and mice . Two closely linked mutations in mice, Hyp and Gy, cause low plasma p hosphate and a rachitic and osteomalacic bone disease. Because of the controversy as to whether Gy is a good model for X-linked hypophosphat emia, the phenotypic severity of these two mutations was compared in b oth sexes and on two genetic backgrounds. The depression in plasma lev els of phosphate was similar in all 10-week-old mutant mice. Male Hyp mice and heterozygous female Hyp mice were affected with similar sever ity in terms of reduced tail growth, shortened femora, reduced femoral mineral content, and abnormal mineral composition of the femoral matr ix. In contrast, male Gy mice did not survive on the C57BL/6J backgrou nd and were more severely affected than female Gy mice on the B6C3H ba ckground. The hybrid B6C3H background ameliorated the bone disease com pared with the inbred C57BL/6J background for both mutant strains. The re was no evidence of change in the plasma levels of 1,25-dihydroxyvit amin D, duodenal level of vitamin D-dependent calcium-binding protein, or urinary level of calcium in these adult mutant mice. In summary, G y mice have a sexual dimorphism not present in Hyp mice. These two gen es may indicate the presence of multiple gene loci in the human diseas e, with multiple proteins involved in the pathophysiology of the bone disease.