ArticleThe Journal of clinical investigation2019
Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed, 66 citations in OpenAlex.
- Characterization of missense variants in the signal peptide of C1 esterase inhibitor.The Journal of allergy and clinical immunology · 2026Article
- Family Tree Mapping of Genetic and Phenotypic Codes of Hereditary Angioedema.Medicina (Kaunas, Lithuania) · 2026Article
- Article
- Integrative analysis via bioinformatics and machine learning identifies SERPING1 as a biomarker candidate for major depressive disorder.BMC psychiatry · 2026Article
- Multi-omics identify hallmark protein and lipid features of small extracellular vesicles circulating in human plasma.Nature cell biology · 2025Article
- Therapeutic Advances in Hereditary Angioedema: A Focus on Present and Future Options.Advances in therapy · 2025Review
- Multiparametric Optimization of Human Primary B-Cell Cultures Using Design of Experiments.Scandinavian journal of immunology · 2025Article
- Complement Proteins Identify Rapidly Progressive Diabetic Kidney Disease.Kidney international reports · 2025Article
- Hereditary Angioedema and Venous Thromboembolism: Where There's Smoke, There's Fire.Seminars in thrombosis and hemostasis · 2025Review
- Article
- The roles of serine protease inhibitors in dermatoses.Frontiers in genetics · 2025Review
- Integrated Analysis of Bulk RNA Sequencing, eQTL, GWAS, and Single-Cell RNA Sequencing Reveals Key Genes in Hepatocellular Carcinoma.Journal of cellular and molecular medicine · 2025Article
- Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Hereditary Angioedema: The Clinical Picture of Excessive Contact Activation.Seminars in thrombosis and hemostasis · 2024Review
- Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema.Orphanet journal of rare diseases · 2024Article
- The double whammy of ER-retention and dominant-negative effects in numerous autosomal dominant diseases: significance in disease mechanisms and therapy.Journal of biomedical science · 2024Review
- The biological function of Serpinb9 and Serpinb9-based therapy.Frontiers in immunology · 2024Review
- Phenotypic and molecular characterization of the largest worldwide cluster of hereditary angioedema type 1.PloS one · 2024Article
- RecessiveJournal of clinical medicine · 2023Article
- Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort.Journal of clinical immunology · 2023Article
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14 authors at 3 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent edema attacks associated with morbidity and mortality. HAE results from variations in the SERPING1 gene that encodes the C1 inhibitor (C1INH), a serine protease inhibitor (serpin). Reduced plasma levels of C1INH lead to enhanced activation of the contact system, triggering high levels of bradykinin and increased vascular permeability, but the cellular mechanisms leading to low C1INH levels (20%-30% of normal) in heterozygous HAE type I patients remain obscure. Here, we showed that C1INH encoded by a subset of HAE-causing SERPING1 alleles affected secretion of normal C1INH protein in a dominant-negative fashion by triggering formation of protein-protein interactions between normal and mutant C1INH, leading to the creation of larger intracellular C1INH aggregates that were trapped in the endoplasmic reticulum (ER). Notably, intracellular aggregation of C1INH and ER abnormality were observed in fibroblasts from a heterozygous carrier of a dominant-negative SERPING1 gene variant, but the condition was ameliorated by viral delivery of the SERPING1 gene. Collectively, our data link abnormal accumulation of serpins, a hallmark of serpinopathies, with dominant-negative disease mechanisms affecting C1INH plasma levels in HAE type I patients, and may pave the way for new treatments of HAE.
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