ArticleFrontiers in immunology2021
Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein.
Article in Frontiers in immunology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 10 citations in OpenAlex.
- Identifying the Interaction Between Tuberculosis and SARS-CoV-2 Infections via Bioinformatics Analysis and Machine Learning.Biochemical genetics · 2024Article
- A Cell-Based Assay to Measure the Activity of the Complement Convertases.Kidney international reports · 2024Article
- Dysregulation of Immune Cell Subpopulations in Atypical Hemolytic Uremic Syndrome.International journal of molecular sciences · 2023Article
- Genetic investigation of Nordic patients with complement-mediated kidney diseases.Frontiers in immunology · 2023Article
- Protein therapeutics and their lessons: Expect the unexpected when inhibiting the multi-protein cascade of the complement system.Immunological reviews · 2023Review
- The yin and the yang of early classical pathway complement disorders.Clinical and experimental immunology · 2022Review
- In Silico Designed Gain-of-Function Variants of Complement C2 Support Cytocidal Activity of Anticancer Monoclonal Antibodies.Cancers · 2022Article
- Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein.Frontiers in immunology · 2022Article
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Authors and funding
15 authors at 7 institutions in 4 countries.
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No grant is acknowledged in the PubMed record.
Abstract
The impairment of the alternative complement pathway contributes to rare kidney diseases such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). We recently described an aHUS patient carrying an exceptional gain-of-function (GoF) mutation (S250C) in the classical complement pathway component C2 leading to the formation of hyperactive classical convertases. We now report the identification of the same mutation and another C2 GoF mutation R249C in two other patients with a glomerulopathy of uncertain etiology. Both mutations stabilize the classical C3 convertases by a similar mechanism. The presence of R249C and S250C variants in serum increases complement-dependent cytotoxicity (CDC) in antibody-sensitized human cells and elevates deposition of C3 on ELISA plates coated with C-reactive protein (CRP), as well as on the surface of glomerular endothelial cells. Our data justify the inclusion of classical pathway genes in the genetic analysis of patients suspected of complement-driven renal disorders. Also, we point out CRP as a potential antibody-independent trigger capable of driving excessive complement activation in carriers of the GoF mutations in complement C2.
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