Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III

被引:272
作者
Cichon, Sven
Martin, Ludovic
Hennies, Hans Christian
Mueller, Felicitas
Van Driessche, Karen
Karpushova, Anna
Stevens, Wim
Colombo, Roberto
Renne, Thomas
Drouet, Christian
Bork, Konrad
Noethen, Markus M.
机构
[1] Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany
[2] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany
[3] Hop Porte Madeleine, Dept Dermatol, Orleans, France
[4] Univ Cologne, Cologne Ctr Genom, D-5000 Cologne, Germany
[5] Univ Cologne, Ctr Mol Med Cologne, D-5000 Cologne 41, Germany
[6] Univ Wurzburg, Inst Clin Chem & Pathobiochem, D-97070 Wurzburg, Germany
[7] Univ Antwerp, Dept Immunol, B-2020 Antwerp, Belgium
[8] Univ Sacred Heart, Lab Human Mol Biol & Genet, I-20123 Milan, Italy
[9] Univ Grenoble 1, Immunol Lab, Grenoble, France
[10] CHU Grenoble, F-38043 Grenoble, France
[11] Univ Mainz, Dept Dermatol, D-6500 Mainz, Germany
关键词
D O I
10.1086/509899
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Hereditary angioedema (HAE) is characterized clinically by recurrent acute skin swelling, abdominal pain, and potentially life-threatening laryngeal edema. Three forms of HAE have been described. The classic forms, HAE types I and II, occur as a consequence of mutations in the C1-inhibitor gene. In contrast to HAE types I and II, HAE type III has been observed exclusively in women, where it appears to be correlated with conditions of high estrogen levels - for example, pregnancy or the use of oral contraceptives. A recent report proposed two missense mutations (c.1032C -> A and c. 1032C -> G) in F12, the gene encoding human coagulation factor XII (FXII, or Hageman factor) as a possible cause of HAE type III. Here, we report the occurrence of the c.1032C -> A (p.Thr328Lys) mutation in an HAE type III - affected family of French origin. Investigation of the F12 gene in a large German family did not reveal a coding mutation. Haplotype analysis with use of microsatellite markers is compatible with locus heterogeneity in HAE type III. To shed more light on the pathogenic relevance of the HAE type III-associated p. Thr328Lys mutation, we compared FXII activity and plasma levels in patients carrying the mutation with that of healthy control individuals. Our data strongly suggest that p. Thr328Lys is a gain-of-function mutation that markedly increases FXII amidolytic activity but that does not alter FXII plasma levels. We conclude that enhanced FXII enzymatic plasma activity in female mutation carriers leads to enhanced kinin production, which results in angioedema. Transcription of F12 is positively regulated by estrogens, which may explain why only women are affected with HAE type III. The results of our study represent an important step toward an understanding of the molecular processes involved in HAE type III and provide diagnostic and possibly new therapeutic opportunities.
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页码:1098 / 1104
页数:7
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