Characterization of a unique pathogenic variant in the SERPING1 gene of a patient with hereditary angioedema type I

Hereditary angioedema (HAE) is a rare genetic disease characterized by sudden onset of edema involving various organs. Among the three subtypes of the disease, HAE types I and II are caused by heterozygous variants in SERPING1 gene encoding C1 inhibitor (C1INH). The pathogenicity of each variant, however, has not fully been revealed.

To assess the mechanism how a SERPING1 gene-variant identified in a patient with HAE type I caused the disease.

Genetic analysis was conducted for a Japanese patient with HAE type I. The consequences resulting from the SERPING1 gene-variant were analyzed at mRNA levels. Overexpression studies in cultured cells were performed to analyze behavior of the mutant C1INH proteins. Effect of a small interfering RNA specific to the mutant SERPING1-mRNA on expression of wild-type C1INH was also tested.

We identified a recurrent heterozygous variant c.820 A>G (p.Ile274Val) in the patient's SERPING1 gene. While we did not find any abnormalities in C1INH with the p.Ile274Val-variant, we found that the variant c.820 A>G caused an aberrant splicing event leading to a frameshift and a premature termination codon. This truncated protein clearly showed a dominant-negative effect against the wild-type C1INH. Finally, we showed that knock-down of the mutant SERPING1-mRNA recovered expression of the wild-type C1INH.

A unique pathogenic mechanism for the SERPING1 gene-variant c.820 A>G has been disclosed. Furthermore, our findings have raised the possibility that RNA interference could be a new therapeutic tool for the disease.