Haploinsufficiency due to deletion within the 3'-UTR of C1-INH-gene associated with hereditary angioedema

Purpose: Sequences within the non-coding 3′UTR (untranslated region) of genes were reported to be involved in the regulation of gene expression by modifying pathways of (co)transcription, post-transcriptional processing and RNA transport. However, direct biological evidence (i.e., knock-out models) is sparse. This report intends to correlate the first reported alteration within the 3′UTR of the C1 inhibitor (C1-INH) gene with clinical presentation of hereditary angioedema (HAE). Methods and Results: Direct sequencing of genomic DNA revealed in all affected members of a family suffering from HAE a heterozygous 155 bp deletion 100 bp downstream of the physiological stop-codon in exon 8. A substantial reduction of both mRNA as well as C1-INH protein expression was revealed by RT-PCR and nephelometry, respectively. Conclusion: We suppose that the mutation within the 3′UTR interferes with integral pathways of gene expression leading to pathogenic haploinsufficiency in this family.