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Hereditary angioedema with normal C1 inhibitor gene in a family with affected women and men is associated with the p.Thr328Lys mutation in the F12 gene

2007; Elsevier BV; Volume: 120; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2007.07.002

1097-6825

Ludovic Martin, Nadia Raison‐Peyron, Markus M. Nöthen, Sven Cichon, Christian Drouet,

Vitamin K Research Studies

To the Editor: Hereditary angioedema (HAE) is an autosomal dominant condition with recurrent, potentially life-threatening, swelling attacks in the skin, abdomen, and upper respiratory tract. Edema formation is a result of excessive release of bradykinin. Most cases of HAE are attributable to mutations in the SERPING1 gene, resulting in defective serpin C1 inhibitor (C1Inh; HAE types I and II, Mendelian Inheritance in Man #106100).1Agostoni A. Aygoren-Pursun E. Binkley K.E. Blanch A. Bork K. Bouillet L. et al.Hereditary and acquired angioedema: problems and progress: proceedings of the Third C1 Esterase Inhibitor Deficiency Workshop and beyond.J Allergy Clin Immunol. 2004; 114: S51-S131Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar We and others have described an etiologically distinct form of HAE, with women exhibiting HAE but normal plasma C1Inh function (so-called HAE type III, Mendelian Inheritance in Man #610618).2Bork K. Barnstedt S.E. Koch P. Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women.Lancet. 2000; 356: 213-217Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 3Binkley K.E. Davis A. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema.J Allergy Clin Immunol. 2000; 106: 546-550Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, 4Martin L. Degenne D. Toutain A. Ponard D. Watier H. Hereditary angioedema type 3: an additional French pedigree with autosomal dominant transmission.J Allergy Clin Immunol. 2001; 107: 747-748Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Most affected women experienced angioedema attacks in the setting of estrogen overload, such as pregnancy or contraceptive pill intake. We have recently demonstrated that part of these autosomal dominant HAEs is attributable to a missense mutation in F12 that encodes the Hageman factor protease (FXII).5Cichon S. Martin L. Hennies H.C. Müller F. van Driesche K. Karpushova A. et al.Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III.Am J Hum Genet. 2006; 79: 1098-1104Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar We also showed that some pedigrees with HAE type III are not linked to the F12 locus, strongly suggesting the presence of locus heterogeneity.5Cichon S. Martin L. Hennies H.C. Müller F. van Driesche K. Karpushova A. et al.Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III.Am J Hum Genet. 2006; 79: 1098-1104Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar The mutation p.Thr328Lys results in increased FXII activity in patients' plasma, enhanced kinin production, increased vascular permeability, and edema.5Cichon S. Martin L. Hennies H.C. Müller F. van Driesche K. Karpushova A. et al.Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III.Am J Hum Genet. 2006; 79: 1098-1104Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar Interestingly, HAE type III seemed to affect exclusively women in the families reported to date.2Bork K. Barnstedt S.E. Koch P. Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women.Lancet. 2000; 356: 213-217Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 3Binkley K.E. Davis A. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema.J Allergy Clin Immunol. 2000; 106: 546-550Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, 4Martin L. Degenne D. Toutain A. Ponard D. Watier H. Hereditary angioedema type 3: an additional French pedigree with autosomal dominant transmission.J Allergy Clin Immunol. 2001; 107: 747-748Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar We hypothesized that this sex specificity may be explained by the fact that the expression of FXII is positively regulated by estrogens.6Farsetti A. Misiti S. Citarella F. Felici A. Andreoli M. Fantoni A. et al.Molecular basis of estrogen regulation of the Hageman factor XII gene expression.Endocrinology. 1995; 136: 5076-5083Crossref PubMed Google Scholar Here, we report a novel French pedigree with HAE in which our first diagnosis was idiopathic nonhistaminergic angioedema (INAE) as proposed by Cicardi et al.7Cicardi M. Bergamaschini L. Zingale L.C. Gioffré D. Agostoni A. Idiopathic nonhistaminergic angioedema.Am J Med. 1999; 106: 650-654Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Indeed, attacks were present in both sexes (Fig 1). Attacks in women were most often related to estrogen intake or pregnancy, but sometimes occurred independently and despite prophylactic treatment with tranexamic acid (individual III6). Attacks were clearly present in 1 man, but were less frequent and less severe. This patient had not taken any drug affecting hormonal balance, including testosterone blockers. According to the disease stage, disease severity class8Cicardi M. Zingale L. Clinical manifestations of HAE.J Allergy Clin Immunol. 2004; 114: S55-S61Google Scholar was 4 or 5 in men versus 1 or 2 in women. Several male carriers younger than 50 years were symptomless (III2, 3, 5). No prophylactic treatment was given in any man. All affected patients had C1Inh antigenic level and function within normal ranges. Plasma C4 levels were always found within the normal range during and in between attacks. After informed consent, DNA was extracted from peripheral blood, and the SERPING1 gene was found normal after exhaustive analysis according to a previously described strategy.9Drouet C. Blanch A. Roche O. Monnier N. Duponchel C. Kalmar L. et al.HAE: genetic investigations.J Allergy Clin Immunol. 2004; 114: S65-S74Google Scholar Because of phenotype similarity between INAE and HAE type III, we sought to investigate whether mutations in F12 might also be associated with INAE. Indeed, we could identify in all affected family members (Fig 1) the same F12 mutation (c.1032C>A resulting in p.Thr328Lys) previously reported by us in families with HAE type III.5Cichon S. Martin L. Hennies H.C. Müller F. van Driesche K. Karpushova A. et al.Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III.Am J Hum Genet. 2006; 79: 1098-1104Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar Kininogenase plasma activity was measured in patient III6 and in her parents by using the para-nitroanilide Arg substrate as previously described,5Cichon S. Martin L. Hennies H.C. Müller F. van Driesche K. Karpushova A. et al.Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III.Am J Hum Genet. 2006; 79: 1098-1104Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar and reported in percentage of both enzyme and proenzyme converted in the presence of 25 μg/mL dextran sulfate on ice. Amidolytic activity was found dramatically increased in the patient sample in comparison with those measured in her father (who only experienced a single facial attack in his life and displayed a discrete increase of the enzymatic activity) and her unaffected mother (Fig 1). Interestingly, only patient III6 displayed a slight decrease in C1Inh function level at the time of attacks. The anti-C1Inh immunoblot performed on 7.5% SDS-PAGE (nonreducing conditions) demonstrated proteolyzed circulating C1Inh (Fig 1). Collectively, these data allowed us to give the diagnosis of HAE type III and provide some comments about the condition. It seems indisputable now that men can be affected with HAE type III. Given that a clinical diagnosis of HAE type III now can be extended to both sexes, it will be interesting to consider to what extent previously reported families may be reclassified. For instance, Cicardi et al7Cicardi M. Bergamaschini L. Zingale L.C. Gioffré D. Agostoni A. Idiopathic nonhistaminergic angioedema.Am J Med. 1999; 106: 650-654Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar first described familial cases of the so-called idiopathic nonhistaminergic angioedema. Among their patients, some were male, including brothers, and male-to-male transmission was present in 1 family. More recently, Bork et al10Bork K. Gül D. Dewald G. Hereditary angioedema with normal C1-inhibitor in a family with affected women and men.Br J Dermatol. 2005; 154: 542-545Crossref Scopus (66) Google Scholar reported a pedigree with 8 affected members in 4 successive generations. Three patients were male, and male-to-male transmission was also noticed. Gupta et al11Gupta S. Yu F. Klaustermeyer W.B. New variant hereditary angioedema in three brothers with normal C1 esterase inhibitor level and function.Allergy. 2004; 59: 557-558Crossref PubMed Scopus (15) Google Scholar reported 3 brothers with angioedema and normal C1Inh function. It is not clear, however, whether the latter patients had HAE type III because the occurrence of their condition was compatible with recessive inheritance, whereas HAE type III is described to have an autosomal dominant mode of inheritance. Autosomal dominant inheritance in this family, however, might still be present assuming reduced penetrance in one of the parents. In addition, we have had the opportunity to observe that the father of the female index case of our first French family with HAE type III4Martin L. Degenne D. Toutain A. Ponard D. Watier H. Hereditary angioedema type 3: an additional French pedigree with autosomal dominant transmission.J Allergy Clin Immunol. 2001; 107: 747-748Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar unequivocally developed attacks of genital and laryngeal angioedema. Interestingly, in all those male cases, attacks were less severe and less frequent. Further, the average age of onset (in the sixth decade) was older than that of females. Strikingly, kininogenase activity was found highly elevated and C1Inh defective to some extent in the female case III6, but not in her affected father, II4. C1Inh function was slightly lower (drop of 10% to 40%) than normal in patient III6, a situation observed in most female patients with HAE type III (C. Drouet, unpublished data, May 2007). This was related to the cleavage of the serpin from 105 to 95 kd without development of serpin-protease association (Fig 1), suggesting that the factor XII mutant escaped control by C1Inh. Whether clinical severity is only or closely related to plasma kininogenase activity in HAE type III is still unknown. In our experience, however, kininogenase activity in male carriers is always far below the female values (C. Drouet, unpublished data, May 2007), and consistent with limited disease expression in male patients. Further studies are needed to shed light on the biological reasons for these findings. The authors are indebted to Dr Denise Ponard for C1Inh analyses and for helpful discussions.