New mutations in C1 esterase inhibitor (SERPING1) in a German family with hereditary angioedema

Hereditary angioedema (HAE) is a genetically dominant clinical disorder characterized by recurrent, acute oedema of the skin or mucosa, usually involving the extremities, face, larynx and gastrointestinal tract. C1 inhibitor (C1inh) deficiency is linked to the development of HAE, either by decrease of its plasma level or presence of a dysfunctional protein. The purpose of this study was to identify the genetic abnormality of C1inh in three patients with HAE (mother and her two children). Analysis was carried out using PCR, and direct sequencing of genomic DNA obtained from whole peripheral blood. DNA sequencing of the eight exons of the C1 esterase inhibitor gene (SERPING1) revealed one mutation and one polymorphism in the mother and the two children. The polymorphism was a heterozygous GTG 458 ATG (Val 458 Met) in exon 8 and the mutation was a one-nucleotide deletion in codon 456 in Exon 8. This frameshift mutation (CTC456(power)TC) leads to a 45 amino acid larger protein with altered protein sequence and should be regarded as the causative defect in the patients. It is concluded, that heterozygous frameshift mutation at exon 8 alters the protein sequence of the C1 esterase inhibitor, leading to inactive protein in all three patients analyzed.