C1 inhibitor gene expression in patients with hereditary angioedema : quantitative evaluation by means of real-time RT-PCR

Background: Hereditary angioedema (HAE) is caused by heterozygous defects in the Cl inhibitor (Cl-INH) gene (SERPINGI/CINH). In patients' plasma Cl-INH levels range between 5% and 30% of normal levels (ie, far from the 50% expected for an autosomal dominant defect). Most patients have antigenic and functional deficiency (type I HAE), and 15% have reduced Cl-INH function but normal to increased antigen because of the presence of a dysfunctional protein (type II HAE). Objective: We sought to contribute to the understanding of the pattern of C1-INH gene expression in patients with HAE. Methods: We used real-time quantitative RT-PCR to measure C1-INH mRNA levels in PBMCs of 57 patients with HAE typed for mutations in the SERPINGI/CINH gene. Results: Thirty-six different mutations were identified in genomic DNA. Compared with healthy control subjects, Cl-INH mRNA was significantly and similarly reduced in patients with type I and type II HAE (40% and 47%, respectively; P <.0001). By means of direct sequencing of cDNAs, we found that 74% of patients with type I HAE carrying small mutations presented significant amounts of mutated transcripts at the mRNA level, suggesting that both allelic mRNA products were reduced to approximately 50%. In 4 patients carrying large deletions expected to fully inactivate expression from the mutant allele, Cl-INH mRNA was 23% on average compared with that seen in control subjects, confirming that normal mRNA was strongly underexpressed. Conclusions: These new findings, combined with previous evidence of increased Cl-INH consumption, might explain the plasma levels of normal Cl-INH that are markedly less than the expected 50%.