The ultimate goals of these studies are to precisely define the genetic defects, at the molecular level, in hereditary angioneurotic edema. In addition, knowledge of the complete structure of normal and dysfunctional C1 inhibitor proteins will help to understand the function of this protease inhibitor. These studies may lead to the development of more specific therapy for hereditary angioneurotic edema, to its prenatal detection and ultimately to gene therapy for the disease. Toward these ends, C1 inhibitor cDNA clones have been isolated, and their sequence is being determined. This will be used to define the complete sequence of the protein. Restriction fragment length polymorphism of the C1 inhibitor gene will be analyzed, and possible linkage to Alport's syndrome will be investigated. Genomic clones for C1 inhibitor have been isolated and the structure of the gene will be determined. Both genomic and cDNA libraries will be constructed from patients with type I and type II hereditary angioedemia; C1 inhibitor clones will be isolated and their structure determined and compared with the normal. Synthesis studies of C1 inhibitor by monocytes in vitro will help to define the level of the defects, and eventually transfection studies with genes coding for the normal and dysfunctional proteins will define possible control regions in the gene.
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