The goal of our investigation is to determine the pathophysiological basis for the vitamin D resistant rachitic and osteomalacic disorders and to define optimal therapeutic regimens for these diseases. Over the past year we have highlighted study of the archetypal vitamin D resistant disease in man, X-linked hypophosphatemic rickets and osteomalacia (XLH). Characters of XLH include abnormal renal phosphate (Pi) handling, vitamin D metabolism and bone mineralization, and an X-linked dominant mode of inheritance. Although investigators generally agree that the primary inborn error in this disease results in an expressed abnormality of the renal proximal tubule that impairs Pi reabsorption, whether this defect is primary or secondary to the elaboration of a humoral factor has been controversial. Recently, however, we concentrated efforts on establishing that XLH is, in fact, due to a humoral abnormality. During the upcoming years we plan further studies to enhance our knowledge regarding XLH. Efforts to further knowledge about the pathophysiological basis of this disorder will focus on attempts: 1) to identify and localize mutations in the PEX gene and thereby determine crucial epitopes in the coded protein; 2) to clone the murine counterpart of the PEX cDNA and define the tissue expression pattern and physiologic regulation of the gene in mice; 3) to further investigate the putative phosphaturic factor which apparently serves as a substrate for the PEX gene product and underlies the abnormal phosphate transport in XLH; and 4) to study the sodium-dependent phosphate cotransporter (NPT-2) gene knockout mouse in order to determine those elements of the hyp-phenotype that are secondary to renal phosphate wasting (and hypophosphatemia) and those that are more directly PEX dependent. In complementary studies we will continue to evaluate the therapeutic effects of calcitriol and phosphorus in XLH and the ancillary actions of growth hormone. We will pay particular attention to the long-term benefits of growth hormone with the intent of discovering if treatment positive affects final adult height.
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