Genetically defective mice aiding investigations into vitamin-D-resistant rickets

The genetically hypophosphatemic (Hyp) mouse, has become a powerful tool for investigation into the pathogenesis of human X-linked hypophosphatemia (XLH), an inherited disorder of phosphate homeostasis commonly known as vitamin-D-resistant rickets. Both Hyp mice and patients with XLH exhibit increased urinary excretion of phosphorus, which accounts for the hypophosphatemia, as well as rachitic and osteomalacic bone lesions and dwarfism. The Hyp gene in the mouse is located on the X chromosome and seems to be a true homologue for the disease process in human XLH. Treatment of XLH, particularly in growing children, is difficult for both the patient and the physician. The hypophosphatemia can usually be reversed by administration of large doses of phosphate, but this often leads to hypocalcemia and secondary hyperparathyroidism, which further complicate the disease. Hypocalcemia can be prevented by giving very large daily doses (50000 to 100000 IU [1.25 to 2.5 mg]) of vitamin D, but at these doses toxicity is common and patient compliance generally poor. In addition, this treatment does not correct the defect in renal phosphate reabsorption. An alternative method of treatment involves the biologically active form of vitamin D - calcitriol, also known as 1,25-dihydroxycholecalciferol and as 1,25-dihydroxyvitamin D₃. With the help of the Hyp mouse model, investigations that would be impossible in patients with XLH can now be conducted to further define this complex disorder. And although researchers may not totally agree on the interpretation of the clinical and biochemical disturbances in XLH, all concede that identification of the abnormal gene product or the specific cellular mechanisms under the control of the X-linked gene is of primary importance.