Analysis of SERPING1 expression on hereditary angioedema patients: quantitative analysis of full-length and exon 3 splicing variants.

Hereditary angioedema (HAE) due to C1-inhibitor (C1-Inh) deficiency is an autosomal dominant disease caused by mutations in the SERPING1 locus. According to protein levels in plasma, two HAE phenotypes have been described: Type I, with low circulating protein levels in plasma, and Type II, where the protein is present but dysfunctional. Although more than 200 mutations have been described to date, studies on the molecular basis of this autosomic dominant trait are scarce. Previous studies demonstrated that C1-Inh mRNA expression was decreased in HAE patients. Herein, we have confirmed these findings in a large series of Spanish patients. Moreover, when our data were analyzed taking into account the type of mutation carried by the patient (i.e., missense, frameshift,…), significant differences were amongst the control, nonsense and splicing mutations groups (P<0.05). By opposite, no differences in C1-Inh mRNA expression were found between the control and HAE Type II groups, nor between treated and untreated patients groups, although a significant difference was observed between controls and untreated HAE Type I patients. An alternative splicing event has been described in the SERPING1 locus resulting in two different transcripts: the full-length and a shorter variant with skipping of exon 3. In order to investigate a possible role for this splicing in HAE, we quantified both mRNA variants in a series of 28 patients. No statistical differences were found in the expression of both variants between controls and patients when compared. However, a separate analysis considering each type of mutation evidenced a significant decrease (P: 0.0156) in the expression of the exon 3 skipping variant in those HAE Type I patients carrying nonsense mutations. Besides, median of the full variant's copy number was statistically decreased on the splicing group when compared with either stop and/or missense groups. The results of these studies provide new data about C1 inhibitor expression in HAE patients and shed more light on the transcriptional regulation of the SERPING1 locus. Quantitative analysis of splicing variants could help to determine the eventual variations of these two transcripts and their possible role under inflammatory stimuli.