Mutation screening of C1 inhibitor gene in 108 unrelated families with hereditary angioedema: functional and structural correlates.

Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by the deficiency of the inhibitor of the first component of complement system (C1-INH), which is due to mutations in its structural gene. There are two phenotypic variants: HAE type I, with reduced plasma antigen levels and HAE type II with normal antigen levels and reduced functional C1 inhibitor activity. The aim of this study was to determine the disease-causing mutations in 108 unrelated HAE families, followed at a single center in Italy, and in 50 normal controls by a genetic screening strategy of the C1-INH gene (SERPIN1G). To detect small mutations we either used fluorescence assisted mismatch analysis, followed by sequencing, or direct sequencing. Patients negative for mutations at this screening were further analyzed by long-range PCR to detect the presence of large deletions or insertions. Overall we identified 81 different mutations possibly responsible for the disease in 102 families, in the remaining 6 families no mutation was detected except for a synonymous substitution in a single probant. Sixty-seven of these mutations (23 missense, 22 frameshift, 8 splicing defects, 8 nonsense and 6 large insertion/deletions) had not been previously published. In addition, 4 rare variants, 2 synonymous alterations and 1 new polymorphism in the 3'UTR of the C1-INH gene were found. Mutations were distributed over all exons, at splice sites and in introns. Our study identified a large number of new mutations related to HAE providing additional evidence of the genetic heterogeneity of this disease. Our results also point toward particular amino acid residues important for protein function that may represent mutation hot spots.