A review of the reported defects in the human C1 esterase inhibitor gene producing hereditary angioedema including four new mutations

C1 esterase inhibitor (C1INH) is an important regulatory protein of the cla ssical pathway of complement. Mutations in the gene for this protein cause the autosomal dominant disorder hereditary angioedema (HAE). Approximately 85% of patients with HAE have a Type I defect, characterized by a diminishe d level of antigenic and functional C1INH. Patients with Type II defects ha ve sufficient protein, but one allele produces dysfunctional protein. We ha ve sequenced the DNA from HAE: patients and have discovered four previously unreported mutations. The first mutation is a splice site error at nucleot ide 8721, which changes the 3' acceptor splice site AG to GG at the end of intron 5 at nucleotide 8721-8722. The second mutation is a single base inse rtion in exon 3 between nucleotides 2467 and 2468. The third mutation is a missense error present in the eighth exon of the C1INH; at nucleotide 16867 (amino acid 470), a T to A mutation transforms a Met to a Lys. The fourth mutation closely resembles the third mutation in that it is a missense erro r occurring in exon 8 in the distal hinge region; a T16827C substitution ch anges the Phe at amino acid 457 to Leu. This report compiles a list of 97 d istinct defects in the C1INH gene that cause hereditary angioedema. (C) 200 1 Academic Press.