Factor XII mutations, estrogen-dependent inherited angioedema, and related conditions.
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ABSTRACT:
SUBMITTER: Binkley KE
PROVIDER: S-EPMC2920236 | biostudies-literature | 2010 Jul
REPOSITORIES: biostudies-literature
Publications
Factor XII mutations, estrogen-dependent inherited angioedema, and related conditions.
Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 20100728 1
The clinical, biochemical and genetic features of the conditions known as estrogen-dependent inherited angioedema, estrogen-associated angioedema, hereditary angioedema with normal C-1 inhibitor, type III angioedema, or factor XII angioedema are reviewed. Discussion emphasizes pathogenesis, diagnosis, and management. ...[more]
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Project description: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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Project description:Early onset urticarial rash with systemic inflammatory symptoms are hallmarks of hereditary autoinflammatory diseases caused by gene mutations of the innate immune pathway, e.g. nucleotide receptor protein 3 (NLRP3). However, in many cases genetic tests are negative, suggesting the existence of unrecognized genetic variants. Here, we report a four-generation family with cold-induced urticarial rash, arthralgia, chills, headache and malaise associated with an autosomal-dominant inheritance. Genetic studies identified a novel substitution mutation in gene F12 (T859A, resulting in p.W268R) which encodes coagulation factor XII (FXII). Occurrence of the mutation segregated with disease status. Functional studies revealed fragmentation and spontaneous activation of FXII in patient plasma and supernatant of HEK293 cells transfected with recombinant W268R-mutated proteins. Furthermore, we observed contact system activation with reduced plasma prekallikrein and profound cleavage of high molecular weight kininogen, representing bradykinin production. As a local source of FXII, skin and blood neutrophils were identified. Interleukin-1ß (IL-1ß) was upregulated in lesional skin and in mononuclear donor cells exposed to recombinant mutant proteins. In accordance with these findings, treatment with icatibant (bradykinin-B2-antagonist) or anakinra (interleukin-1-antagonist) reduced disease activity in patients. Thus, we identified anovel autoinflammatory syndrome characterized by a substitution in the F12 gene resulting in activation of the contact system and cytokine-mediated inflammation.
2010-01-10 | PXD016341 | Pride