Coagulation factor XII (Hageman factor): a new angioedema gene

Background:

Hereditary angioedema (HAE) is characterized by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening upper airway obstruction. The classic HAE types (I and II) are caused by mutations in the complement C1 inhibitor gene, resulting in a quantitatve or qualitative deficiency of C1 inhibitor. In contrast, in a novel HAE type, affecting mainly women, C1 inhibitor concentration and activity in plasma are normal (HAE type III, HAE with normal C1 inhibitor); we hypothesized that an abnormal coagulation factor XII molecule may lead to inappropriate activation of the kinin-forming cascade and, therefore, performed a search for mutations in the F12 gene.

Methods:

Twenty unrelated index patients from families with hereditary angioedema and normal C1 inhibitor activity were screened for mutations in the coagulation factor XII gene by sequencing of the 14 exons and splice junctions of the F12 gene; subsequently, beside 235 control individuals, another six such index patients as well as 90 patients with idiopathic angioedema were selectively sequenced for exon 9 of the F12 gene.

Results:

Two different non-conservative missense mutations, both located in exactly the same position within exon 9, namely in the second position of the codon (ACG) encoding Thr309 of the mature protein, were identified. Five of the twenty patients screened showed a heterozygous C→A transversion (1032C→A), predicting a threonine-to-lysine substitution (Thr309Lys); one additional patient showed a heterozygous C→G transversion (1032C→G), resulting in a threonine-to-arginine substitution (Thr309Arg). Sequencing of exon 9 in another six index patients revealed one further patient heterozygous for the Thr309Lys mutation. Thus, in 7 of 26 unrelated patients the wild-type threonine is substituted by a basic amino acid residue. The mutations were not found in healthy control individuals (n=235) and co-segregated with the phenotype in seven families with altogether 23 affected women, providing strong support that they cause disease. Finally, the Thr309Lys mutation was also identified in 2 out of 90 patients with idiopathic angioedema; thus, this mutation may also play a role in a subgroup of these singular angioedema cases with no affected family members.

Conclusion:

These findings provide strong support that the coagulation factor XII gene is a new angioedema gene.