SERPING1 mutations in 59 families with hereditary angioedema

Hereditary angioedema due to C1 Inhibitor (C1Inh) deficiency (HAE types I and II) is a rare, life-threatening disease causing spontaneous edema of the submucosal layers.A cohort of 127 individuals with symptoms of recurrent familial angioedema from 59 non-related families was studied. All the patients included fulfilled the diagnostic and biochemical criteria of HAE, including low C1Inh function and/or concentration. Genetic studies were carried out by PCR and sequencing of the C1NH locus followed, in the negative cases, by MLPA, long-range PCR and restriction enzyme analysis of genomic DNA to detect potential large rearrangements. Mutations located in consensus splicing sequences or nearby positions were studied by RT-PCR.The study identified 52 different mutations (25 missense, 15 frameshift, 7 splicing defects and 5 large deletions) responsible for the disease in 56 HAE families. In the remaining three families no molecular alteration could be detected. Twenty-seven of the mutations in this cohort are novel and 10 are confirmed de novo cases. The pathologic effect of the 5 splicing defects first reported here was assessed at the RNA and protein levels. Large deletions affecting exons 4 and 7, ranging from approximately 1500 to 2500 bp, were partially characterized by their altered restriction patterns upon long-range amplification.These results highlight the heterogeneity of mutations in the C1NH gene causing C1Inh deficiency and HAE. An approach to the molecular effects associated to each of the mutations reported here was made when possible based on the available data of pathological variants of serpins.

► We found 52 different disease-causing mutations in 56 out of 59 HAE families studied, reporting 27 novel alterations. ► Characterization of novel splicing defects and large deletions by RT-PCR, Western blot and genomic XL-PCR analysis. ► High heterogeneity of mutations in the C1NH gene causing C1Inh deficiency and HAE.