Altered vitamin D, cyclic nucleotide and trace mineral metabolism in the X-linked hypophosphatemic mouse.

Hyp mice have a defective control system for the synthesis of 1,25-(OH)2-vitamin D that does not respond to a low phosphate stimulus. While the plasma levels of 25-OH-vitamin D are reduced somewhat, this seems to be not a serious defect since plasma 1,25-(OH)2-vitamin D levels are normal. Hyp kidneys synthesize and excrete elevated levels of cyclic AMP and cyclic GMP. The elevated tissue levels of trace minerals suggests increased food intake with normal intestinal absorption of the minerals. In addition there is the reduced renal tubular reabsorption of phosphate caused by a change in the brush border transport of phosphate. This leads to hypophosphatemia, osteomalacic bone disease and altered Mg metabolism. There is intestinal resistance to 1,25-(OH)2-vitamin D stimulation. Many of these defects seem unrelated to the reduced renal tubular reabsorption of phosphate. Yet all are derived from one mutation in the Hyp gene. The underlying explanation must account for all abnormalities by a single mutation in a single gene product. The near normal phosphate levels in soft tissues and the multiple defects argue against a genetic change in the phosphate pump as an ultimate explanation. Still to be explored are possible changes in a phosphate recognition site on a cell membrane or a change in an as yet unknown phosphate regulating system.

Increased urinary excretion of cyclic nucleotides in X-linked hypophosphatemic (Hyp) mice.

Hyp mice, a model for human X-linked hypophosphatemia, had elevated urinary cyclic AMP, cyclic GMP, and magnesium excretion compared to normal mice. The data suggest a renal origin of the urinary cyclic nucleotides. No significant differences in plasma cyclic AMP and cyclic GMP were observed between genotypes.