Genotype‐phenotype correlations in Brazilian patients with hereditary angioedema due to C1 inhibitor deficiency

Maia, Luana S.M.; Moreno, Adriana S.; Ferriani, Mariana Paes Leme; Nunes, Fernanda Leonel; Ferraro, Marcelo Rosanova; Dias, Marina M.; Roxo-Junior, Persio; Dias, Fabrício C.; Valle, Solange Oliveira Rodrigues; Levy, Soloni Afra Pires; Alonso, Maria Luiza Oliva; França, Alfeu Tavares; Serpa, Faradiba Sarquis; Motta, Antônio Abílio; Maia, Felipe Gonçalves Motta; Aragon, Davi Casale; Sarti, Willy; Silva, Wilson A.; Cichon, Sven; Bork, Konrad; Arruda, L. Karla

doi:10.1111/all.13699

Cited by 16 publications

(17 citation statements)

References 9 publications

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“…Several reasons for SERPING1 allelic heterogeneity have been developed by Germenis and Speletas (). A deeper knowledge of transcriptome signatures (López‐Lera, Cabo, Garrido, Dopazo, & López‐Trascasa, ) is expected to be gained in the coming years, with a contribution of epigenetic elements, gene–gene or gene–environment that regulate gene expression and biological processes, as recently suggested by Maia et al (). This important issue will lead to a better understanding of C1‐INH‐HAE pathophysiology and interpretation of genetics of C1‐INH‐HAE.…”

Section: Discussionmentioning

confidence: 92%

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

Ponard¹,

Gaboriaud

Charignon

et al. 2019

Human Mutation

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C1 inhibitor (C1Inh) deficiency is responsible for hereditary angioedema (C1‐INH‐HAE) and caused by variants of the SERPING1/C1INH/C1NH gene. C1Inh is the major control of kallikrein–kinin system. C1Inh deficiency leads to its uncontrolled activation, with subsequent generation of the vasoactive peptide bradykinin. This update documents 748 different SERPING1 variants, including published variants and additional 120 unpublished ones. They were identified as heterozygous variants (n = 729), as homozygous variants in 10 probands and as compound heterozygous variants (nine combinations). Six probands with heterozygous variants exhibited gonadal mosaicism. Probands with heterozygous (n = 72) and homozygous (n = 1) variants were identified as de novo cases. Overall, 58 variants were found at positions showing high residue conservation among serpins, and have been referred to as a mousetrap function of C1Inh: reactive center loop, gate, shutter, breach, and hinge. C1Inh phenotype analysis identified dysfunctional serpin variants with failed serpin–protease association and a residual 105‐kDa species after incubation with target protease. Regarding this characteristic, in conditions with low antigenic C1Inh, 74 C1‐INH‐HAE probands presented with an additional so‐called intermediate C1‐INH‐HAE phenotype. The present update addresses a comprehensive SERPING1 variant spectrum that facilitates genotype–phenotype correlations, highlighting residues of strategic importance for serpin function and for identification of C1Inh deficiency as serpinopathy.

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Section: Discussionmentioning

confidence: 92%

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

Ponard¹,

Gaboriaud

Charignon

et al. 2019

Human Mutation

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“…PCR was conducted using specific SERPING1 primers to amplify the 8 exons and intronic boundaries. Primer sequences and PCR conditions were as described by Maia et al [10]. DNA sequences were analyzed using Seqman software TM (Lasergene; DNAStar, Inc., Madison, WI, USA), with the SERPING1 gene sequence obtained from GenBank as a reference [10].…”

Section: Genetic Analysismentioning

confidence: 99%

“…Other important clues to differentiate them include the later onset of symptoms in AAE-C1-INH in the fourth or fifth decade of life, although symptoms of AAE-C1-INH have been reported in patients younger than 40 years [8], and the onset of symptoms in HAE-C1-INH that may occur in patients older than 40 years [10,11]. A family history of the disease is present in most patients with HAE-C1-INH, although up to 25% of cases of HAE-C1-INH could result from de novo mutations in SERPING1 [10]. Low C1q levels were found in 70-80% of AAE-C1-INH patients, while they were normal in those with HAE-C1-INH [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice

Ferriani

Trevisan-Neto

Costa

et al. 2020

Int Arch Allergy Immunol

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Background: Acquired angioedema due to C1 inhibitor deficiency (AAE-C1-INH) is a very rare disease. In clinical practice, it may be difficult to differentiate AAE-C1-INH from hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). In both conditions, patients are at an increased risk of death from asphyxiation due to upper airway obstruction. The association of AAE-C1-INH with lymphoproliferative and autoimmune diseases, and with presence of anti-C1-INH antibodies has been well documented, and treatment of the underlying condition may result in complete remission of angioedema. Objectives: To discuss the clinical evaluation, diagnosis, and treatment outcomes of AAE-C1-INH in the context of the care of 2 patients with recurrent isolated angioedema. Methods: Two patients were followed up prospectively at our clinic. Measurements of C3, C4, C1-INH, and C1q levels were carried out by nephelometry, and the functional activity of C1-INH was determined by a chromogenic assay. Hematological investigation included morphological and immunophenotyping analysis of peripheral blood, bone marrow, and spleen histopathology. Sequencing of the 8 exons and adjacent intronic regions of the SERPING1 gene was performed using the Sanger method. Results: Two patients were diagnosed with AAE-C1-INH associated with splenic marginal zone lymphoma during follow-up. Conclusions: Close follow-up, including detailed clinical history, physical examination, and laboratory tests, of our patients with AAE-C1-INH was essential for the early diagnosis and successful treatment of the lymphoproliferative disease, leading to the resolution of the angioedema attacks.

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“…New mutations are being defined every day, original research is reported from around the world, and new techniques are applied, providing improved understanding of the disease. [34,37,38] Next-generation sequencing has been used to study the genotype in C1-INH-HAE, and it has revealed that most [34] Relevant studies from our country [39] have been conducted and heterozygous mutations have been described in the 7 th exon (p.Leu416X [c.1247T> A]) by Akoglu et al [40] and by Büyüköztürk et al [41] in the promoter region (CAAT box, c.−101A>G). Ozkars et al [42] reported c. 601A>T nonsense variant mutation in the SERPING1 gene in C1-INH HAE patients.…”

Section: Serping1 Genementioning

confidence: 99%

“…[43,44] Genotype-phenotype correlations in C1-INH-HAE disease are currently being extensively investigated. [38,45,46] Speletas et al [45] conducted research in various European countries (Greece, Germany, Romania, and Hungary) and found that abdominal attacks were less common in Hungarians, and that the onset of the C1-INH-HAE type of the disease was delayed in Romanian patients.…”

Section: Serping1 Genementioning

confidence: 99%

Novelties in Hereditary Angioedema Patho-physiology

Özdemir¹

2019

South Clin Ist Euras

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Hereditary angioedema (HAE) is a rare, inherited disease mostly associated with mutations in the SERPING1 gene (serpin family G member 1), which encodes the C1 inhibitor (C1-INH) protein. Regulation can lead to plasma deficiency and ensuing repeated attacks of severe angioedema. This disease was first described clinically and genetically in 1888 by William Osler, who named it "hereditary angioneurotic edema (HANE)." It took 75 years until Donaldson and Evans identified the fundamental role of C1-INH in the pathophysiology of so-called HANE by Osler. Significant progress has been made in the research of this genetic disease when the role of neural factors was documented as being too small to lead to edema, the name was changed as HAE. Therefore, the name of more than 490 different mutations have been reported in the region of the C1-INH gene (SERPING1) until mid-2018. It is now known that C1-INH deficiency overstimulates the plasma contact (kallikrein-kinin) system, which eventually results in the overproduction of bradykinin. By binding to the bradykinin B2 receptor, bradykinin increases vascular permeability (vasodilation) and causes contraction of nonvascular smooth muscle, and acts as a main/major mediator in the pathophysiology of HAE. Reports since 2000 have described a new type of HAE with "normal" CI-INH levels, primarily in Caucasians. A number of abnormalities in the genes encoding for factor XII, angiopoietin-1, and plasminogen have been identified in this novel disease entity. The establishment of treatment modalities for HAE with normal C1-INH is also expected.

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Genotype‐phenotype correlations in Brazilian patients with hereditary angioedema due to C1 inhibitor deficiency

Abstract: et al. A new approach to the isolation and characterization of wheat flour allergens. Clin Exp Allergy.

Cited by 16 publications

References 9 publications

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice

Novelties in Hereditary Angioedema Patho-physiology

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