Our proposed studies are designed to investigate the role of abnormal vitamin D-metabolism in the pathogenesis of X-linked hypophosphatemic rickets and to determine the mechanism for the impaired renal tubular reabsorption of phosphate, characteristic of this disorder. Studies of potential abnormalities in vitamin D metabolism and efficacy of therapy with 1,25-dihydroxycholecalciferol will be conducted in both affected human subjects and in a mouse animal model with x-linked dominant inheritance of hypophosphatemia and rickets. These investigations will be directed at determining the circulating concentration of vitamin D metabolites in these hypophosphatemic states and determining whether hormonal and metabolic regulation of 25-hydroxycholecalciferol-1 alpha-hydroxylase activity remains intact. Further, therapeutic efficacy of drug regimens (particularly, 1,25-dihydroxycholecalciferol) will be assessed, with emphasis on the potential benfits on bone histomorphology. Investigation of the mechanism(s) of impaired renal tubular phosphate reabsorption will be performed on the Hyp-mouse kidney in a series of in vitro experiments. In these studies specific emphasis will be directed at determining whether abnormalities in cyclic AMP binding to renal cortical cell apical membrane bound protein kinase, alterations in apical membrane bound cyclic AMP dependent protein kinase activity, or abnormalities of the cyclic AMP-phosphorylatable substrates in the apical membrane underlie the defect in phosphate transport. These investigations will be accomplished employing renal brush-border membranes from normal and mutant mice, in which the activities or functions aforementioned will be compared.