title: Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III.
abstract: 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.
authors.affiliation: Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. sven.cichon@uni-bonn.de
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Ludovic
authors.initials: L
authors.lastname: Martin
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Hennies
authors.forename: Felicitas
authors.initials: F
authors.lastname: Müller
authors.forename: Karen
authors.initials: K
authors.lastname: Van Driessche
authors.forename: Anna
authors.initials: A
authors.lastname: Karpushova
authors.forename: Wim
authors.initials: W
authors.lastname: Stevens
authors.forename: Roberto
authors.initials: R
authors.lastname: Colombo
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.forename: Christian
authors.initials: C
authors.lastname: Drouet
authors.forename: Konrad
authors.initials: K
authors.lastname: Bork
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
mesh_terms: D000799:Angioedema / Q000235:genetics*; D001499:Bayes Theorem; D005174:Factor XII / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D018703:Founder Effect; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007705:Kinins / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008390:Markov Chains; D018895:Microsatellite Repeats; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree; D013997:Time Factors
chemical_list: D007705:Kinins; D005174:Factor XII