The familial hypophosphatemic rachitic diseases are the most common forms of rickets/osteomalacia in developed countries. The three forms of hereditary rickets/osteomalacia: X-linked hypophosphatemic rickets (XLH), hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and autosomal dominant hypophosphatemic rickets (ADHR) are inherited in an X-linked dominant, autosomal recessive and autosomal dominant mode, respectively. These distinct disorders have different clinical presentations, although in each case abnormal renal phosphate transport disturbs phosphate homeostasis and results in renal phosphate wasting and consequent hypophosphatemia. Thus, these disorders are 'experiments of nature' in which mutations have arisen in genes that play important roles in phosphate homeostasis. The goals of this study are to characterize the phenotypic abnormalities in ADHR, the disorder about which least is known, and to isolate the gene responsible for this disorder. To accomplish these goals we will evaluate affected individuals clinically, biochemically and radiographically and use positional cloning techniques to eventually clone the disease gene. Initially, we will employ linkage analysis in kindreds with ADHR to localize the disease gene to an autosome. Subsequently, we will determine a more detailed genetic map of the area around the ADHR gene. Once a detailed genetic map of the region is determined, we will eventually clone the ADHR gene using fine structure mapping techniques. Successful completion of this study will not only characterize a poorly understood disease, but will allow elucidation of the pathogenesis of the renal phosphate wasting in this disorder and increase our understanding of phosphate homeostasis.
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