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

BACKGROUND

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.

OBJECTIVE

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

METHODS

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.

RESULTS

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.

CONCLUSION

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.