Molecular genetic diagnosis of hereditary angioedema

Hereditary angioedema (HAE) is a rare genetic condition currently subdivided into two groups: HAE due to C1-inhibitor deficiency (Type I) or dysfunction (Type II) (C1-INH-HAE) and HAE with normal activity of C1‐INH (nC1- INH-HAE). C1-INH-HAE is estimated to occur in approximately 99 % of cases HAE and is caused by sequence variants in the SERPING1 gene. The prevalence of nC1-INH-HAE is extremely low and accounts for about 1 % of all cases of HAE. nC1-INH-HAE currently subdivided on HAE, due to mutations in factor XII (FXII-HAE), plasminogen (PLG-HAE), angiopoietin 1 (ANGPT1-HAE), kininogen 1 gene (KNG1-HAE), or angioedema of unknown origin (U-HAE).The amplicons of the entire coding regions and splice-sites of 18 genes from 24 patients (18 female) belonging to 17 families were analyzed by Next Generation Sequencing (NGS). The median age of patients was 33.5, of onset ‒ 16 years. 15 patients had a family history of edema.We identified seven C1-INH-HAE patients and variants were detected in the SERPING1 gene. For three patients (members of the same family), a heterozygous variant was found deep in the intron of the SERPING1 gene, which is likely to affect protein synthesis. We identified two patients with changes in the PLAUR gene, which may be associated with the manifestation of symptoms angioedema. Six patients showed abnormalities in the genes AGT and KNG1, which can probably explain their early hypertension, which could provoke the appearance of edema.

Download Full-text

Mutational spectrum of the SERPING1 gene in patients with hereditary angioedema

Proceedings of the National Academy of Sciences of Belarus Medical series ◽

10.29235/1814-6023-2019-16-3-349-356 ◽

2019 ◽

Vol 16 (3) ◽

pp. 349-356

Author(s):

I. E. Guryanova ◽

K. A. Paliakova ◽

M. V. Belevtsev ◽

O. V. Aleynikova

Keyword(s):

Hereditary Angioedema ◽

De Novo ◽

Type I ◽

C1 Inhibitor ◽

De Novo Mutations ◽

Genetic Condition ◽

C1 Inhibitor Deficiency ◽

Serping1 Gene ◽

Deficiency Type ◽

Global Population

Hereditary angioedema due to the C1-inhibitor deficiency (Type I) or the dysfunction (Type II) is a rare genetic condition characterized by recurrent episodes of edema with an estimated frequency of 1:10 000 and 1:50 000 in the global population without racial or gender differences. HAE Type III is even less common, and unlike Types I and II, it does not appear to be connected with the levels of the C1-inhibitor. For 45 patients (64.44% female; 35.56% male) from 19 unrelated families C1-INH-HAE was confirmed. A series of 19 different mutations in the SERPING1 gene was identified: 17 splicing (37.7%), 15 missense (33.3%), 8 frameshift (17.8%), 3 large del (6.7%), 2 nonsense (4.5%) mutations were found. De novo mutations were detected in 8 patients (17.78%). For 6 patients, the HAE diagnosis was determined at the pre-symptom stage. 9 C1NH mutations had not been previously described. The number of different mutations identified highlights the heterogeneity of the C1 inhibitor deficiency.

Download Full-text

Screening for Plasminogen Mutations in Hereditary Angioedema Patients

Genes ◽

10.3390/genes12030402 ◽

2021 ◽

Vol 12 (3) ◽

pp. 402

Author(s):

Henriette Farkas ◽

Anna Dóczy ◽

Edina Szabó ◽

Lilian Varga ◽

Dorottya Csuka

Keyword(s):

Gene Mutation ◽

Hereditary Angioedema ◽

Unknown Origin ◽

Factor Xii ◽

Gene Encoding ◽

New Techniques ◽

Ex Post ◽

Appropriate Therapy ◽

Exon 9 ◽

Serping1 Gene

Hereditary angioedema (HAE) is a rare disease belonging to the group of bradykinin-mediated angioedemas, characterized by recurring edematous episodes involving the subcutaneous and/or submucosal tissues. Most cases of HAE are caused by mutations in the SERPING1 gene encoding C1-inhibitor (C1-INH-HAE); however, mutation analysis identified seven further types of HAE: HAE with Factor XII mutation (FXII-HAE), with plasminogen gene mutation (PLG-HAE), with angiopoietin-1 gene mutation (ANGPT1-HAE), with kininogen-1 gene mutation (KNG1-HAE), with a myoferlin gene mutation (MYOF-HAE), with a heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6) mutation, and hereditary angioedema of unknown origin (U-HAE). We sequenced DNA samples stored from 124 U-HAE patients in the biorepository for exon 9 of the PLG gene. One of the 124 subjects carried the mutation causing a lysine to glutamic acid amino acid exchange at position 330 (K330E). Later, the same PLG mutation was identified in the patient’s son. The introduction of new techniques into genetic testing has increased the number of genes identified. As shown by this study, a biorepository creates the means for the ex-post analysis of recently identified genes in stored DNA samples of the patients. This makes the diagnosis more accurate with the possibility of subsequent family screening and the introduction of appropriate therapy.

Download Full-text

Hereditary angioedema: Pathophysiology (HAE type I, HAE type II, and HAE nC1-INH)

Allergy and Asthma Proceedings ◽

10.2500/aap.2020.41.200081 ◽

2020 ◽

Vol 41 (6) ◽

pp. S14-S17 ◽

Cited By ~ 4

Author(s):

H. James Wedner

Keyword(s):

Serine Protease ◽

Hereditary Angioedema ◽

Normal Activity ◽

Genetic Alterations ◽

Type I ◽

Factor Xii ◽

Kinin System ◽

Major Pathway ◽

Major Mechanism ◽

Kallikrein Kinin System

The pathophysiology of hereditary angioedema (HAE) in virtually all cases is the result of the uncontrolled production of the vasoactive peptide bradykinin. C1 inhibitor (C1-INH) is a serine protease inhibitor, which, under normal circumstances, is the regulator of critical enzymes that are active in the cascades that result in bradykinin generation. In the classic forms of HAE, C1-INH is not produced in sufficient quantities (<40% of normal) or the function is <40% of normal activity. The major pathway for the production of bradykinin is the “contact system,” also known as the kallikrein-kinin system. This system begins with the activation of factor XII (FXII) to FXIIa, by a variety of physiologic and pathologic stimuli. FXIIa is a serine protease that binds to surfaces and cleaves prekallikrein to the active serine protease kallikrein. Kallikrein then cleaves high-molecular-weight kininogen to release the nonapeptide bradykinin. Bradykinin binds to the bradykinin β2 receptor, which increases vascular permeability and allows the flow of fluids into the extracellular space and results in angioedema. The two major enzymes generated in this cascade FXIIa and kallikrein are inhibited by C1-INH, which is the major regulator of this cascade. Failure to adequately control the production of bradykinin is thus the major mechanism for HAE. Several other types of HAE in which C1-INH is not decreased (HAE nlC1-INH) have been described. The alterations in FXII and plasminogen (also a serine protease inhibited by C1-INH) like with classic HAE are the result of dysregulation of bradykinin generation. Only genetic alterations in angiopoietin-1 may not be related to bradykinin generation, rather related to the control of the effect of bradykinin on the vascular endothelium.

Download Full-text

Pathophysiology of Hereditary Angioedema

American Journal of Rhinology and Allergy ◽

10.2500/ajra.2011.25.3661 ◽

2011 ◽

Vol 25 (6) ◽

pp. 373-378 ◽

Cited By ~ 17

Author(s):

Bruce L. Zuraw ◽

Sandra C. Christiansen

Keyword(s):

Hereditary Angioedema ◽

Clinical Characteristics ◽

Ace Inhibitor ◽

Vascular Endothelial Cells ◽

Type I ◽

Factor Xii ◽

Type Iii ◽

C1inh Deficiency ◽

Serping1 Gene ◽

High Index Of Suspicion

Background Laryngeal angioedema may be associated with significant morbidity and even mortality. Because of the potential severity of attacks, both allergists and otolaryngologists must be knowledgeable about the recognition and treatment of laryngeal angioedema. This study describes the clinical characteristics and pathophysiology of bradykinin-mediated angioedema. Methods A literature review was conducted concerning the clinical characteristics and pathophysiology of types I and II hereditary angioedema (HAE), type III HAE, acquired C1 inhibitor (C1INH) deficiency, and angiotensin-converting enzyme (ACE) inhibitor–associated angioedema. Results The diagnosis of type I/II HAE is relatively straightforward as long as the clinician maintains a high index of suspicion. Mutations in the SERPING1 gene result in decreased secretion of functional C1INH and episodic activation of plasma kallikrein and Hageman factor (FXII) of the plasma contact system with cleavage of high molecular weight kininogen and generation of bradykinin. In contrast, there are no unequivocal criteria for making a diagnosis of type III HAE, although a minority of these patients may have a mutation in the factor XII gene. Angioedema attacks and mediator of swelling in acquired C1INH deficiency are similar to those in type I or II HAE; however, it occurs on a sporadic basis because of excessive consumption of C1INH in patients who are middle aged or older. ACE inhibitor–associated angioedema should always be considered in any patient taking an ACE inhibitor who experiences angioedema. ACE is a kininase, which when inhibited is thought to result in increased bradykinin levels. Bradykinin acts on vascular endothelial cells to enhance vascular permeability. Conclusion Laryngeal swelling is not infrequently encountered in bradykinin-mediated angioedema. Novel therapies are becoming available that for the first time provide effective treatment for bradykinin-mediated angioedema. Because the characteristics and treatment of these angioedemas are quite distinct from each other and from histamine-mediated angioedema, it is crucial that the physician be able to recognize and distinguish these swelling disorders.

Download Full-text

The Genetics of Hereditary Angioedema: A Review

Journal of Clinical Medicine ◽

10.3390/jcm10092023 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2023

Author(s):

Rosa Santacroce ◽

Giovanna D'Andrea ◽

Angela Bruna Maffione ◽

Maurizio Margaglione ◽

Maria d'Apolito

Keyword(s):

Hereditary Angioedema ◽

Factor Xii ◽

Inherited Disease ◽

C1 Inhibitor Deficiency ◽

C1 Esterase Inhibitor ◽

New Type ◽

Diagnostic Applications ◽

Serping1 Gene ◽

Esterase Inhibitor

Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Mutations in SERPING1, the gene that encodes C1-INH (C1 esterase inhibitor), are responsible for the majority of cases of hereditary angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes that are implicated in the cascades of bradykinin generation, which increases the vascular permeability and allows the flow of fluids into the extracellular space and results in angioedema. Moreover, a dominantly inherited disease has been described that has a similar clinical picture to C1-INH-HAE (Hereditary angioedema due to C1 inhibitor deficiency), but with normal C1-INH level and activity. This new type of HAE has no mutation in the SERPING1 gene and it is classified as nC1-INH-HAE (HAE with normal C1-INH). Currently mutations in six different genes have been identified as causing nC1-INH-HAE: factor XII (F12), plasminogen (PLG), angiopoietin 1 (ANGPT1), Kininogen 1 (KNG1), Myoferlin (MYOF), and heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6). In this review we aim to summarize the recent advances in genetic characterization of angioedema and possible future prospects in the identification of new genetic defects in HAE. We also provide an overview of diagnostic applications of genetic biomarkers using NGS technologies (Next Generation Sequencing).

Download Full-text

Evidence for a dominant‐negative effect of a missense mutation in the SERPING1 gene responsible for hereditary angioedema type I

The Journal of Dermatology ◽

10.1111/1346-8138.15930 ◽

2021 ◽

Author(s):

Shuichiro Yasuno ◽

Osamu Ansai ◽

Ryota Hayashi ◽

Sawako Nakamura ◽

Yutaka Shimomura

Keyword(s):

Missense Mutation ◽

Hereditary Angioedema ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Type I ◽

Negative Effect ◽

Serping1 Gene

Download Full-text

Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

Acta Endocrinologica ◽

10.1530/eje.0.1390096 ◽

1998 ◽

pp. 96-100 ◽

Cited By ~ 14

Author(s):

M Peter ◽

K Bunger ◽

SL Drop ◽

WG Sippell

Keyword(s):

Genetic Study ◽

Stop Codon ◽

Molecular Genetic ◽

Premature Stop Codon ◽

Type I ◽

Type Ii ◽

Loss Of Function ◽

Molecular Genetic Study ◽

Base Exchange ◽

Deficiency Type

We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2). presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

Download Full-text

CLINICAL AND MOLECULAR GENETIC DIAGNOSIS OF GLUCOSE TRANSPORTER DEFICIENCY SYNDROME TYPE I IN PATIENTS OF NEUROPSYCHIATRIC DEPARTMENT

PEDIATRIA Journal named after G N SPERANSKY ◽

10.24110/0031-403x-2017-96-1-156-164 ◽

2017 ◽

Vol 96 (1) ◽

pp. 156-164

Author(s):

T. V. Kozhanova ◽

S. S. Zhilina ◽

T. I. Mescheryakova ◽

S. O. Ayvazyan ◽

K. V. Osipova ◽

...

Keyword(s):

Glucose Transporter ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Deficiency Syndrome ◽

Type I ◽

Syndrome Type ◽

Molecular Genetic Diagnosis ◽

Transporter Deficiency

Download Full-text

Hereditary Angioedema due to C1 Inhibitor Deficiency: C1-INH Replacement Therapy

Reviews in Health Care ◽

10.7175/rhc.v5i2.913 ◽

2014 ◽

Vol 5 (2) ◽

pp. 55-66

Author(s):

Mauro Cancian

Keyword(s):

Replacement Therapy ◽

Hereditary Angioedema ◽

Rare Condition ◽

Type I ◽

Therapeutic Approaches ◽

C1 Inhibitor Deficiency ◽

Deep Tissue ◽

Gene Encoding ◽

The Face

Hereditary angioedema (HAE) is a rare condition affecting about 1 in 50.000 individuals and caused by a mutation in the gene encoding the C1-esterase inhibitor (C1-INH), which is involved in the control of complement, clotting, fibrinolytic and kinin pathways. HAE is characterized by plasma outflow from blood vessels, leading to fluid collecting (edema) in the deep tissue layers of the face, larynx, abdomen, and extremities. Three different types of HAE have been identified: in type I the mutation leads to the lack of production of C1-INH, in type II the mutation leads to the production of dysfunctional C1-INH, while type III is extremely rare and still not fully understood. Therapeutic approaches for HAE include on-demand treatments to stop angioedema attacks and prophylactic treatment to prevent attacks both by pre-procedural (short-term) and routine (long-term) prophylaxis. Aim of the present review is to present an overview of C1-INH replacement therapy with the plasma-derived concentrate of C1-INH Berinert® (CSL Behring GmbH) in the treatment of type I and II HAE.

Download Full-text