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C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H-related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear. Using in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant's association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population. Duplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome. Our findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G. Copyright © 2022 by the American Society of Nephrology.


Bárbara Márquez-Tirado, Josué Gutiérrez-Tenorio, Agustín Tortajada, Laura Lucientes Continente, Fernando Caravaca-Fontán, Talat H Malik, Raquel Roldán Montero, Sandra Elías, Ana Saiz Gonzalez, Gema Fernández-Juarez, Pilar Sánchez-Corral, Matthew C Pickering, Manuel Praga, Santiago Rodríguez de Córdoba, Elena Goicoechea de Jorge. Factor H-Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy. Journal of the American Society of Nephrology : JASN. 2022 Jun;33(6):1137-1153

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PMID: 35545301

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