Molecular defects of the C1-inhibitor gene in hereditary angioedema

Family studies of hereditary angioedema are discussed with particular emphasis on the molecular basis of the more common form of the disease (type I), characterized by quantitative C1-Inhibitor deficiencies. Results obtained in several laboratories can be interpreted in the light of the restriction maps and of the exon-intron structure of the normal C1-Inhibitor gene that have been published recently. Several partial deletions of either exon 4 or exon 7 or of larger portions of the 5' end of the gene and a duplication of exon 4 have been described. These gene alterations are essentially family-specific and they account for at least fifteen-percent of the defects in type I hereditary angioedema. Detailed sequences analyses of cloned defective genes indicate that clusters of repetitive sequences of the Alu family, located within several introns, are responsible for the relatively high frequency of gross gene alterations observed at the C1-Inhibitor locus. In contrast, most of the defects that lead to production of dysfunctional proteins appear to be point mutations within the P1 residue of the reactive site, whose codon features a hypermutable CpG dinucleotide.