Missense Mutations in the Proline-Rich Region of Coagulation Factor XII in Hereditary and Idiopathic Angioedema.

Hereditary angioedema (HAE) is characterized by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening upper airway obstruction. The two classic HAE types (I and II) are caused by mutations in the complement C1 inhibitor gene, resulting in a functional deficiency of C1 inhibitor. Recently, a novel type of hereditary angioedema has been described, these patients showing normal C1 inhibitor concentration and activity in plasma (HAE with normal C1 inhibitor, HAE type III). With few exceptions, all reported patients have been women, and exposition to estrogens appears to be an important precipitating factor. Screening of twenty unrelated female patients with this new type of HAE for mutations in the coagulation factor XII gene revealed two different 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. Five patients showed a C→A transversion (1032C→A), predicting a threonine-to-lysine substitution (Thr309Lys); one additional patient showed a C→G transversion (1032C→G), resulting in a threonine-to-arginine substitution (Thr309Arg). Thus, in 6 of 20 unrelated patients the wild-type threonine residue is substituted by a basic amino acid residue. The mutations are located in the proline-rich region of factor XII which may play some role in the binding of factor XII to negatively charged surfaces, and, thus, may eventually influence mechanisms of contact activation. The predicted structural and functional impact of the mutations, their absence in healthy control individuals (n=145), and their co-segregation with the phenotype in five families with altogether 20 affected women provide strong support that they cause disease (