Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor

doi:10.1016/j.bbrc.2006.03.092

Biochemical and Biophysical Research Communications

Volume 343, Issue 4, 19 May 2006, Pages 1286-1289

https://doi.org/10.1016/j.bbrc.2006.03.092 Get rights and content

Abstract

Hereditary angioedema is characterized by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening upper airway obstruction. The two classic types are both caused by mutations within the complement C1 inhibitor gene. A recently described new type does not show a deficiency of C1 inhibitor and affects almost exclusively women. We screened twenty unrelated index patients with this new type of hereditary angioedema for mutations in the coagulation factor XII gene. Two different missense mutations were identified in exactly the same position within exon 9 of the F12 gene. ‘Mutation 1’ (1032C → A), encountered in five patients, predicts a threonine-to-lysine substitution (Thr309Lys). ‘Mutation 2’ (1032C → G), observed in one patient, results in a threonine-to-arginine substitution (Thr309Arg). The predicted structural and functional impact of the mutations, their absence in 145 healthy controls, and their co-segregation with the phenotype in five families provide strong support that they cause disease.

Section snippets

Materials and methods

Study subjects. Twenty unrelated patients, all female and of German origin, were studied. All patients had experienced recurrent angioedema attacks, had one or more affected relatives (also exclusively women), and showed normal C1 inhibitor measurements. For several of these index patients, various numbers of family members could be included in the study. One hundred and forty-five healthy blood donors of German origin served as controls. Informed consent was provided by all subjects, and

Results and discussion

The 14 exons and splice junctions of the F12 gene [11] were screened in 20 unrelated patients by PCR amplification and bidirectional sequencing. Aside from several known polymorphic variants, two different non-conservative missense mutations were identified in exon 9 (Fig. 1). Both mutations are located in exactly the same position, namely in the second position of the codon (ACG) encoding amino acid residue 309 of the mature protein, a threonine residue. ‘Mutation 1’ (1032C → A), encountered in

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Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterised by acute episodes of non-pruritic skin and submucosal swelling caused by increase in vascular permeability.
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Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor

Abstract

Section snippets

Materials and methods

Results and discussion

J. Am. Acad. Dermatol.

Immunobiology

J. Allergy Clin. Immunol.

Clin. Immunol.

Lancet

J. Allergy Clin. Immunol.

Am. J. Med.