Detection of C1 inhibitor mutations in patients with hereditary angioedema

Zuraw, Bruce L.; Herschbach, Jack

doi:10.1067/mai.2000.104780

Cited by 88 publications

(70 citation statements)

References 25 publications

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“…These residues are located between Cys 183 and Cys 406 , and their mutation might also affect stability of the central ␤-sheet. Secondly, mutation of Cys 183 3 Tyr leads to type I HAE (63). The second cysteine in the serpin domain of C1-Inh (Cys 406 ) is located at the same site as the disulfide bridge that links the short N-terminal domain of ATIII to the serpin domain (Cys 21 to Cys 95 ).…”

Section: C1-inh Metastability Depends On Unique N-terminal Domainmentioning

confidence: 99%

“…Several other mutations leading to HAE support the importance of this region for the metastable conformation of C1-Inh. First, mutation of the residues Gly 162 3 Glu/Arg and Thr 169 3 Pro leads to type I HAE (62,63). These residues are located between Cys 183 and Cys 406 , and their mutation might also affect stability of the central ␤-sheet.…”

Section: C1-inh Metastability Depends On Unique N-terminal Domainmentioning

confidence: 99%

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The Functional Integrity of the Serpin Domain of C1-inhibitor Depends on the Unique N-terminal Domain, as Revealed by a Pathological Mutant

Bos

Lubbers

Roem

et al. 2003

Journal of Biological Chemistry

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C1-inhibitor (C1-InhThe autosomal dominant disease hereditary angioedema (HAE) 1 is caused by functional deficiency of C1-inhibitor (C1-Inh) (1). C1-Inh is the major inhibitor of C1s and C1r of the classical pathway of complement and also an inhibitor of the contact system proteases, factor XIIa, kallikrein, and factor XIa (2-9). A lack of this inhibitor may result in recurrent episodes of acute, local, circumscribed edema of the skin or mucosa. The most serious and potentially life-threatening manifestation of the disease is laryngeal edema (10). HAE is inherited as an autosomal dominant trait; affected individuals are heterozygous. Based on the relative levels of functional and antigenic C1-Inh, two types of HAE have traditionally been described. In type I (Ϯ 85% of HAE patients), defective expression of one allele results in low antigenic and functional levels. In type II (Ϯ15% of HAE patients), levels of functional C1-Inh are low, but C1-Inh antigen levels are normal because of the presence of a dysfunctional mutant protein. Although heterozygosity would suggest functional C1-Inh levels of around 50% in HAE, these levels are lower than 50%, typically 5-30%, which is ascribed to increased C1 activation and C1-Inh consumption (10, 11). However, the description of low levels of non-functional C1-Inh mutants in patients with type I HAE has demonstrated that the distinction between types I and II HAE is not absolute (12). For example, low levels of dysfunctional mutant protein may occur in cases where the mutation also leads to defective protein secretion (12, 13). Many different mutations can lead to dysfunctional C1-Inh, as has recently been reviewed (14). C1-Inh is a human plasma glycoprotein and a member of the serine protease inhibitor (serpin) family to which antithrombin III (ATIII), plasminogen activator inhibitor 1, and ␣1-antitrypsin also belong. Serpins are suicide inhibitors that function as a set mousetrap by forming highly stable complexes with their cognate proteases. In its active form, a serpin has a metastable structure with a flexible reactive site loop that protrudes from the core of the molecule, the central ␤-sheet. The key residues P1-P1Ј form the reactive site, a pseudosubstrate for the target protease. Upon proteolytic attack on this bond, the reactive site loop is pulled into the central ␤-sheet, inducing a dramatic conformational change that results in the formation of covalent complexes between inhibitor and protease (15, 16). Recent crystallographic studies support the idea that during complex for- 1 The abbreviations used are: HAE, hereditary angioedema; C1, complement factor 1; C1-Inh, C1 esterase inhibitor, inhibitor of C1, coagulation factors XIIa, XIa, and kallikrein; WT, wild type; C1-Inh 76 , C1-Inh 98 , and C1-Inh 115 , C1-Inh deletion mutants starting at amino acid 76, 98, and 115, respectively; ⌬3 C1-Inh, C1-Inh mutant lacking amino acids 62-116; ATIII, antithrombin III; mAB, monoclonal antibody; RII, mAb reacting with all forms of C1-Inh; Kok-12, mAb reacting with cleaved...

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Section: C1-inh Metastability Depends On Unique N-terminal Domainmentioning

confidence: 99%

Section: C1-inh Metastability Depends On Unique N-terminal Domainmentioning

confidence: 99%

The Functional Integrity of the Serpin Domain of C1-inhibitor Depends on the Unique N-terminal Domain, as Revealed by a Pathological Mutant

Bos

Lubbers

Roem

et al. 2003

Journal of Biological Chemistry

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“…11. koromozom (11q12-q13,1) üzerinde lokalize olan C1 inhibitör genindeki (SERPING1) mutasyonla ilişkili verilere bakıldığında HAE'lı olgularda 200'ü aşkın farklı mutasyon bildirilmiştir.Klasik HAE'nın tip 1 (%85) ve tip 2 (%15) olmak üzere iki ana formu bulunmaktadır. Her iki HAE tipinin klinik görünümleri birbirinden farksız olmakla birlikte farklı mutasyonlarla ortaya çıkmaktadır 15 . Tip 1 HAE'ya neden olan C1 inhibitör mutasyonları tüm gen boyunca meydana gelerek etkili olarak salgılanamayan kesik veya yanlış katlanmış proteinlerin oluşumuna neden olur ve C1 inhibitör düzeylerinin hem antijenik hem de fonksiyonel olarak azalmasıyla sonuçlanır.…”

Section: Herediter Anjiyoödemunclassified

“…Tip 1 HAE'ya neden olan C1 inhibitör mutasyonları tüm gen boyunca meydana gelerek etkili olarak salgılanamayan kesik veya yanlış katlanmış proteinlerin oluşumuna neden olur ve C1 inhibitör düzeylerinin hem antijenik hem de fonksiyonel olarak azalmasıyla sonuçlanır. Tip 2 HAE'ya neden olan mutasyonlar ise genellikle aktif alan veya komşuluğundaki ekson 8'i etkiler ve fonksiyonu kusurlu olan mutant proteinin salgılanmasına yol açarak antijenik C1 inhibitör düzeylerinin normal ancak fonksiyonel C1 inhibitör düzeylerinin düşük olmasına neden olur [14][15][16][17][18] . Klasik HAE dışında son zamanlarda antijenik ve fonksiyonel C1 inhibitör düzeyleri normal olgularla karakterize olan tip 3 HAE formu tanımlanmıştır.…”

Section: Herediter Anjiyoödemunclassified

“…Takiben istenen antijenik ve fonksiyonel C1 inhibitör düzeylerinin ölçümleri HAE tanısını doğrularken aynı zamanda tip 1 (düşük antijenik ve fonksiyonel C1 inhibitör düzeyleri) ve tip 2 (normal antijenik C1 inhibitör düzeyi, ancak düşük fonksiyonel C1 inhibitör aktivitesi) HAE'nın ayırtedilmesine olanak sağlar. Nadiren HAE'lı olguların normal fonksiyonel C1 inhibitör düzeylerine sahip olduğu ve bu olguların bazılarında faktör 12 mutasyonu bulunduğu bildirilmiştir [14][15][16][17] . Klasik HAE'nın optimal tedavisinde akut atakların tedavisi, kısa süreli pro laksi ve tekrarlayan atakları önlemek için uzun süreli pro laksi uygulaması gibi çeşitli yaklaşımlar bulunmaktadır 14,[16][17][18] .…”

Section: Herediter Anjiyoödemunclassified

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Angioedema: Diagnosis and treatment approaches

Güneş¹,

Akarsu²

2013

TURKDERM

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ÖzetAnjiyoödem (AE) deri ve/veya mukozaların ani başlangıçlı geçici lokalize ödemi olarak tanımlanır. Bu şişme tablosu subkutan ve submukozal dokulardaki postkapiller venüllerin geçirgenliğini arttıran çeşitli vazoaktif mediyatörlerin aracılığıyla oluşan interstisyal ödem sonucunda meydana gelir. Deriye lokalize olduğunda asimetrik, gode bırakmayan, yer çekimiyle yer değiştirmeyen ve bazen ağrılı olabilen şişme ile karakterizedir. Bununla birlikte laringeal ödem ve barsak tutulumu gibi mukozal ataklar şiddetli rahatsızlığa ve hayati tehlike oluşturan semptomlara yol açabilir. Çeşitli AE formları arasında C1 inhibitör geninin disfonksiyonu veya eksikliği ile ilişkili AE (klasik herediter AE tipleri ve edinsel AE), allerjik AE, ilaçlarla ilişkili AE (steroid dışı antiinflamatif ilaçlara bağlı AE, anjiyotensin dönüştürücü enzim inhibitörlerine bağlı AE), idiyopatik AE ve yakın zamanda tanımlanan tip 3 herediter AE bulunmaktadır. Bu değişik AE formlarında örtüşen semptomlar olabilmekle birlikte bazı özgün klinik ve öykü özellikleri yanında eşlik eden ürtikaryanın varlığı ayırıcı tanıda yardımcı olabilir. AE benzeri tabloları dışlamak, tetikleyici faktörleri saptamak ve uzaklaştırmak, atakları erken farketmek ve gerekli olduğunda agresif solunum yolu açıklığını sağlamak başarılı tedavinin temelini oluşturur. Bu makalede AE'nın sık ve nadir görülen formları yanında klinik semptomları, ayırıcı tanıları ve tedavi yaklaşımları derlenmiştir. (Türk derm 2013; 47: 7-18) Anah tar Ke li me ler: Anjiyoödem, tanı, ayırıcı tanı, tedavi Sum maryAngioedema (AE) is defined as sudden, localized and transient swelling of the skin and/or mucous membranes. This swelling condition is a result of interstitial edema from vasoactive mediators increasing the permeability of postcapillary venules of the subcutaneous and submucosal tissues. When localized to the skin, it presents as asymmetric, nonpitting, nondependent, and occasionally painful edema. However, mucosal attacks, such as laryngeal edema and bowel involvement can produce severe discomfort and life-threatening symptoms. There are several forms including those involving dysfunction or depletion of the C1-inhibitor gene (classical hereditary AE types and acquired AE), allergic AE, drug-induced AE (nonsteroidal anti-inflammatory drug-induced AE, angiotensin converting enzyme inhibitor-induced AE), idiopathic and a recently described form, HAE type 3. These various forms of AE have overlapping symptoms, but some unique clinical and historical features as well as presence of accompanying urticaria can aid in the differential diagnosis. The key to successful management is to rule out conditions that masquerade as AE, detection and avoidance of triggers, early recognition of attacks, and aggressive airway management when warranted. In this article, common and rare forms as well as clinical symptoms, differential diagnosis, and treatment approaches for AE are reviewed. (Turkderm 2013; 47: 7-18

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Hereditary Angioedema

Nzeako¹

2001

Arch Intern Med

295

148

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Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10,000 to 1 in 150,000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named "type 3" HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain.

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Detection of C1 inhibitor mutations in patients with hereditary angioedema

Cited by 88 publications

References 25 publications

The Functional Integrity of the Serpin Domain of C1-inhibitor Depends on the Unique N-terminal Domain, as Revealed by a Pathological Mutant

The Functional Integrity of the Serpin Domain of C1-inhibitor Depends on the Unique N-terminal Domain, as Revealed by a Pathological Mutant

Angioedema: Diagnosis and treatment approaches

Hereditary Angioedema

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