A CLUSTER OF MUTATIONS WITHIN A SHORT TRIPLET REPEAT IN THE C1 INHIBITOR GENE

Mutations in the C1 inhibitor gene that result in low functional level s of C1 inhibitor protein cause hereditary angioneurotic edema. This d isease is characterized by episodic edema leading to considerable morb idity and death. Among 60 unreported kindred with the disease, four pa tients were discovered to have mutations clustered within a 12-bp segm ent of exon 5 from nucleotide 8449 to nucleotide 8460. This short segm ent of DNA contains three direct repeats of the triplet CAA and is imm ediately preceded by a similar adenosine-rich sequence (CAAGAACAC). Th ese triplet repeats make this region susceptible to mutation by a slip ped mispairing mechanism. There are two other short triplet repeat ele ments in the coding region for this gene, but they have not become mut ated in any kindred examined. This suggests that the apparent enhanced mutation rate in this region of exon 5 may be influenced by DNA struc tural characteristics.