Detection of C1 inhibitor mutations in patients with hereditary angioedema

doi:10.1067/mai.2000.104780

Journal of Allergy and Clinical Immunology

Volume 105, Issue 3, March 2000, Pages 541-546

https://doi.org/10.1067/mai.2000.104780 Get rights and content

Abstract

Background: Hereditary angioedema (HAE) results from a deficiency in the functional level of C1 inhibitor caused by mutations in the C1 inhibitor gene. The mutations responsible for HAE have been shown to be heterogeneous. Objective: Because the identification of C1 inhibitor mutations may depend, in part, on the technique used to screen for mutations, we screened the entire C1 inhibitor coding region to identify mutations in a cohort of patients with HAE. Methods: By using single-stranded conformational polymorphism analysis, 24 subjects with HAE from 16 different kindreds were screened for C1 inhibitor polymorphisms. C1 inhibitor mutations were identified by sequencing the exons containing identified polymorphisms. Results: All 24 subjects with HAE had identifiable polymorphisms, involving exons 2, 3, 4, 5, or 8. Fourteen different C1 inhibitor mutations were identified: 8 missense, 1 nonsense, 4 frameshift, and 1 small deletion mutations. No large deletions or duplications were found. Nine of the 14 mutations represent newly recognized C1 inhibitor mutations, 6 of which involve exon 4. Conclusions: Single-stranded conformational polymorphism is an effective approach for identifying new mutations in HAE. Elucidation of the range of C1 inhibitor mutations causing HAE is important for both defining which residues are required for C1 inhibitor secretion or function and providing the basis for future studies to define the relationship between the C1 inhibitor genotype and disease severity. (J Allergy Clin Immunol 2000;105:541-6.)

Section snippets

Patients and genomic DNA

All subjects gave informed consent, which was approved by the Human Subjects Committee of Scripps Clinic and The Scripps Research Institute. The diagnosis of HAE was made by demonstration of decreased C1 inhibitor antigenic or functional levels with normal C1q levels. All subjects with HAE had a history of recurrent angioedema. High-molecular-weight DNA was extracted from peripheral blood leukocytes by use of the Applied Biosystems (Foster City, Calif) DNA extractor.

Detection of restriction fragment length polymorphisms

Genomic DNA (2 μg) was

Screening for large deletions or transpositions by restriction fragment length polymorphism

The restriction endonuclease Bcl I yields a single 20-kb fragment containing the entire C1 inhibitor gene and has been used to screen for the presence of deletions or transpositions within the gene.¹³ Therefore to detect large deletions or transpositions of the C1 inhibitor gene, genomic DNA from each of the patients with HAE, as well as normal control subjects, was digested with Bcl I and analyzed for evidence of restriction fragment length polymorphisms (RFLPs). No RFLPs were detected.

Detection of C1 inhibitor polymorphisms by means of SSCP analysis

Each of

DISCUSSION

HAE is an autosomal dominant disease that results from structural mutations of the C1 inhibitor gene. C1 inhibitor is a member of the serpin (serine proteinase inhibitor) superfamily, all of which share a similar overall tertiary structure.¹⁹ A variety of different mutations have been found to cause functional deficiencies in several of the serpins, including α₁-antitrypsin, antithrombin, and C1 inhibitor. Most type II HAE mutations involve the reactive center or hinge region of the C1

Acknowledgements

We thank Dr David Lang for providing the DNA sample for kindred 11.

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Complex analysis of the national Hereditary angioedema cohort in Slovakia – Identification of 12 novel variants in SERPING1 gene
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Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterised by acute episodes of non-pruritic skin and submucosal swelling caused by increase in vascular permeability.
Here we present the first complex analysis of the National HAE Slovakian cohort with the detection of 12 previously un-published genetic variants in SERPING1 gene.
In patients diagnosed with hereditary angioedema caused by deficiency or dysfunction of C1 inhibitor (C1–INH-HAE) based on clinical manifestation and complement measurements, SERPING1 gene was tested by DNA sequencing (Sanger sequencing/massive parallel sequencing) and/or multiplex ligation-dependent probe amplification for detection of large rearrangements.
The Slovakian national cohort consisted of 132 living patients with confirmed HAE. We identified 51 index cases (32 families, 19 sporadic patients/112 adults, 20 children). One hundred seventeen patients had HAE caused by deficiency of C1 inhibitor (C1–INH-HAE-1) and 15 patients had HAE caused by dysfunction of C1 inhibitor (C1–INH-HAE-2). The prevalence of HAE in Slovakia has recently been calculated to 1:41 280 which is higher than average calculated prevalence. The estimated incidence was 1:1360 000. Molecular-genetic testing of the SERPING1 gene found 22 unique causal variants in 26 index cases, including 12 previously undescribed and unreported.
The first complex report about epidemiology and genetics of the Slovakian national HAE cohort expands the knowledge of the C1–INH-HAE genetics. Twelve novel causal variants were present in the half of the index cases. A higher percentage of inframe variants comparing to other studies was observed. Heterozygous deletion of exon 3 found in a large C1–INH-HAE-1 family probably causes the dysregulation of the splicing isoforms balance and leads to the decrease of full-length C1–INH level.
Restriction of C1-inhibitor activity in hereditary angioedema by dominant-negative effects of disease-associated SERPING1 gene variants
2023, Journal of Allergy and Clinical Immunology
Patients with hereditary angioedema experience recurrent, sometimes life-threatening, attacks of edema. It is a rare genetic disorder characterized by genetic and clinical heterogenicity. Most cases are caused by genetic variants in the SERPING1 gene leading to plasma deficiency of the encoded protein C1 inhibitor (C1INH). More than 500 different hereditary angioedema–causing variants have been identified in the SERPING1 gene, but the disease mechanisms by which they result in pathologically low C1INH plasma levels remain largely unknown.
The aim was to describe trans-inhibitory effects of full-length or near full-length C1INH encoded by 28 disease-associated SERPING1 variants.
HeLa cells were transfected with expression constructs encoding the studied SERPING1 variants. Extensive and comparative studies of C1INH expression, secretion, functionality, and intracellular localization were carried out.
Our findings characterized functional properties of a subset of SERPING1 variants allowing the examined variants to be subdivided into 5 different clusters, each containing variants sharing specific molecular characteristics. For all variants except 2, we found that coexpression of mutant and normal C1INH negatively affected the overall capacity to target proteases. Strikingly, for a subset of variants, intracellular formation of C1INH foci was detectable only in heterozygous configurations enabling simultaneous expression of normal and mutant C1INH.
We provide a functional classification of SERPING1 gene variants suggesting that different SERPING1 variants drive the pathogenicity through different and in some cases overlapping molecular disease mechanisms. For a subset of gene variants, our data define some types of hereditary angioedema with C1INH deficiency as serpinopathies driven by dominant-negative disease mechanisms.
Hereditary angioedema and its new treatments: An update
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Les angiœdèmes héréditaires, avec ou sans déficit en C1-inhibiteur, sont des maladies rares caractérisées par des crises récurrentes d’œdème non inflammatoire sous-cutané et/ou sous-muqueux. Elles peuvent menacer le pronostic vital et impacter substantiellement la qualité de vie. Les crises peuvent être spontanées ou provoquées, dans un contexte de stress émotionnel, par les infections ou les traumatismes physiques en particulier. Le médiateur-clé étant la bradykinine, ces angiœdèmes ne répondent pas aux thérapeutiques usuelles des angiœdèmes mastocytaires (antihistaminiques, corticoïdes, adrénaline), beaucoup plus fréquents. La prise en charge thérapeutique des angiœdèmes héréditaires consiste d’abord à traiter les crises sévères par un antagoniste sélectif du récepteur B2 de la bradykinine ou un concentré de C1-inhibiteur. Les concentrés de C1-inhibiteur ou un androgène atténué (danazol) peuvent être utilisés en prophylaxie à court terme. Les options thérapeutiques classiquement proposées pour la prévention des crises à long terme (danazol, antifibrinolytiques [acide tranexamique], concentré de C1-inhibiteur) sont d’efficacité variable et/ou posent des problèmes de tolérance ou de facilité d’emploi. La mise à disposition récente de molécules innovantes de la classe des inhibiteurs de la kallicréine comme traitement de fond (lanadelumab sous-cutané, bérotralstat oral) constitue une avancée thérapeutique importante dans la prophylaxie à long terme des crises d’angiœdème héréditaire. L’arrivée de ces nouvelles molécules s’accompagne d’une nouvelle ambition pour les patients : obtenir le contrôle optimal de la maladie pour limiter au maximum son retentissement sur la qualité de vie du patient.
Hereditary angioedema, with or without deficient C1 inhibitor level or function, is a rare disease characterized by recurrent attacks of noninflammatory subcutaneous and/or submucosal edema. It may be life-threatening and substantially affects quality of life. Attacks may be spontaneous or induced, in a setting of emotional stress, by infections or physical trauma, in particular. As the key mediator is bradykinin, this angioedema does not respond to the usual treatments of mast cell-mediated angioedema (antihistamines, corticosteroids, adrenaline), which is much more frequent. Therapeutic management of hereditary angioedema first consists in treating severe attacks with a selective B2 bradykinin receptor antagonist or a C1 inhibitor concentrate. The latter or an attenuated androgen (danazol) can be used for short-term prophylaxis. Therapeutic solutions conventionally proposed for long-term prophylaxis (danazol, antifibrinolytics [tranexamic acid], C1 inhibitor concentrate) vary in efficacy and/or pose problems of safety or ease of use. Kallikrein inhibitors (subcutaneous lanadelumab, oral berotralstat) recently made available as disease-modifying treatment constitute an important advance in long-term prophylaxis of hereditary angioedema attacks. The advent of these new drugs is accompanied by a new ambition for patients: optimize control of the disease and thereby minimize its impact on quality of life.
Unusual presentation of linear wrist blisters associated with hereditary angioedema: The first case report in Taiwan
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Hereditary angioedema (HAE) is an autosomal dominant disease characterized clinically by recurrent episodes of swelling in the tissues of the extremities, face, abdomen, and respiratory tract. It is most often caused by C1 esterase inhibitor (C1 INH) gene mutation. This swelling may lead to bradykinin release, resulting in recurrent, paroxysmal, painful angioedema. Blister formation is an uncommon cutaneous manifestation of HAE. Herein, we report a case of a patient with HAE who developed linear wrist blisters on her skin, with swelling, as a rare complication of HAE. She was treated with attenuated androgens (Danazol) for two weeks at our clinic, after which the blisters showed dramatic improvement. To date, only a few HAE cases have been reported across the world. Therefore, it is important to focus on and recognize the development of edema blisters as a flare of HAE, which could consequently avoid unnecessary dermatological diagnostic workup and treatment.
The Panorama of Primary Angioedema in the Brazilian Population
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Primary angioedema (PA) is a complex disorder, presenting multiple hereditary (hereditary angioedema) and acquired subtypes (acquired angioedema). Despite a very similar clinical presentation among subtypes, the differential diagnosis is limited by the difficulty to identify bradykinin-mediated PA and the lack of specific biomarkers.
To report the clinical and genetic features of Brazilian patients with PA.
Brazilian patients referred from 50 centers were diagnosed on the basis of clinical symptoms, C1 inhibitor (C1-INH) and C4 plasma measurements, and DNA sequencing of genes associated with hereditary angioedema.
We characterized 92 patients with acquired angioedema and 425 with HAE: 125 with C1-INH deficiency, 180 with F12 mutations, and 120 of unknown cause. Thirty-one different mutations were identified in SERPING1 and 2 in F12, in addition to 2 mutations of uncertain significance in the ANGPT1 gene. The molecular diagnosis was decisive for 34 patients with HAE without family history, and for 39% of patients with inconsistent biochemical measurements. The median delay in diagnosis was 10 years, with a maximum of 18 years for HAE with C1-INH deficiency. Androgens and tranexamic acid were the most used drugs for long-term prophylaxis in all the PA subtypes, and they were used on demand by 15% of patients. Only 10% of patients reported the use of specific medication for HAE during attacks.
Our analysis exposes a broad picture of PA diagnosis and management in a developing country. Complement measurements presented considerable inconsistencies, increasing the diagnosis delay, while patients with PA with normal C1-INH remain with an inaccurate diagnosis and unspecific treatment.
Brazilian guidelines for hereditary angioedema management - 2017 update part 1: Definition, classification and diagnosis
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Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the “Associação Brasileira de Alergia e Imunologia (ASBAI)” and the “Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)” has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

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^☆: Supported in part by National Institutes of Health grants AI36220 and RR00833 and the Sam and Rose Stein Charitable Trust Fund.

^☆☆: Reprint requests: Bruce L. Zuraw, MD, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037.

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Basic and clinical immunologyDetection of C1 inhibitor mutations in patients with hereditary angioedema☆,☆☆

Abstract

Section snippets

Patients and genomic DNA

Detection of restriction fragment length polymorphisms

Screening for large deletions or transpositions by restriction fragment length polymorphism

Detection of C1 inhibitor polymorphisms by means of SSCP analysis

DISCUSSION

Acknowledgements

J Biol Chem

FEBS Lett

Genomics

J Mol Biol

Immunobiology

J Mol Graph

C1 inhibitor and hereditary angioneurotic edema

Annu Rev Immunol

Hereditary angioneurotic edema: two genetic variants

Science

Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema

J Clin Invest

Dysfunctional C1-inhibitor(At), isolated from a type II hereditary-angio-oedema plasma, contains a P1 ‘reactive centre’ (Arg444-→His) mutation

Biochem J

Variability in purified dysfunctional C1-inhibitor proteins from patients with hereditary angioneurotic edema. Functional and analytical gel studies

JCI

C1 inhibitors and their genes: an update

J Lab Clin Med

Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site

Proc Natl Acad Sci USA

Clusters of intragenic Alu repeats predispose the human C1 inhibitor locus to deleterious rearrangements

Proc Natl Acad Sci USA

Restriction fragment length polymorphism of the C1 inhibitor gene in hereditary angioneurotic edema

JCI

Basic and clinical immunology
Detection of C1 inhibitor mutations in patients with hereditary angioedema☆,☆☆

Dysfunctional C1-inhibitor(At), isolated from a type II hereditary-angio-oedema plasma, contains a P1 ‘reactive centre’ (Arg⁴⁴⁴-→His) mutation