CREATION OF THE AD02 MOUSE

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DESCRIPTION (provided by applicant): Autosomal dominant osteopetrosis, type 2 (ADO2) is an osteosclerotic disorder that results from impaired osteoclastic bone resorption. The disorder usually results from missense mutations in the Chloride Channel 7 gene (CLCN7). Disease severity varies widely, even among members of the same family, and one third of individuals with mutations are asymptomatic carriers. In vitro studies in our laboratory indicate that osteoclasts from asymptomatic carriers resorb bone normally, while those from affected individuals have markedly defective bone resorption. Thus, the difference between affected individuals and carriers is due to osteoclast specific properties. Our preliminary data, are consistent with there being more than one modifier gene that is responsible for this difference. This proposal focuses on the creation of an ADO2 mouse model. This animal model will allow us to test potential therapies and find genes that control disease severity. Lay abstract: Autosomal dominant osteopetrosis (ADO2) is a disease in which there is dense, but fragile bone. The severity of the disease varies between carriers (who are disease free) and severely affected individuals, who have multiple fractures, bone infections and, occasionally, blindness. This proposal focuses on the creation of an ADO2 mouse model. This animal model will allow us to test potential therapies and find genes that control disease severity.