CLINICAL & GENETIC STUDIES OF AUTOSOMAL DOMINANT OSTEOPETROSIS

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Type 2 autosomal dominant osteopetrosis (ADO2) is an inherited disorder that results from a failure in osteoclast mediated bone resorption. Although ADO2 patients have increased bone mineral density, the bone is of poor quality and they are at increased risk for fracture. The disease has a 75% penetrance, thus "carriers" exist that do not have the typical radiographic manifestations of the disorder. However, sensitive methods have not been used to determine if carriers have subtle defects in osteoclast function. Although ADO2 is due to a failure of osteoclast mediated bone resorption, the pathogenesis of the disorder is poorly understood and there are no animal models of the disorder. The goals of the present study are to further characterize the clinical manifestations of the disorder and to identify the gene responsible for the disorder using positional cloning techniques. To accomplish our goal we will 1) phenotypically characterize and obtain blood for biochemical and DNA studies from ADO2 family members; 2) map the disease gene with high resolution and 3) isolate and clone the gene. Identification of the gene will provide insight into the pathophysiology of ADO2 as well as provide insight into osteoclast regulation and function.