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Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation

Martínez-Barricarte, Rubén, Heurich, Meike, Valdes-Cañedo, Francisco, Vazquez-Martul, Eduardo, Torreira, Eva, Montes, Tamara, Tortajada, Agustín, Pinto, Sheila, Lopez-Trascasa, Margarita, Morgan, Bryan Paul, Llorca, Oscar, Harris, Claire Louise and Rodríguez de Córdoba, Santiago 2010. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. Journal of Clinical Investigation 120 (10) , pp. 3702-3712. 10.1172/JCI43343

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Abstract

Dense deposit disease (DDD) is a severe renal disease characterized by accumulation of electron-dense material in the mesangium and glomerular basement membrane. Previously, DDD has been associated with deficiency of factor H (fH), a plasma regulator of the alternative pathway (AP) of complement activation, and studies in animal models have linked pathogenesis to the massive complement factor 3 (C3) activation caused by this deficiency. Here, we identified a unique DDD pedigree that associates disease with a mutation in the C3 gene. Mutant C3923ΔDG, which lacks 2 amino acids, could not be cleaved to C3b by the AP C3-convertase and was therefore the predominant circulating C3 protein in the patients. However, upon activation to C3b by proteases, or to C3(H2O) by spontaneous thioester hydrolysis, C3923ΔDG generated an active AP C3-convertase that was regulated normally by decay accelerating factor (DAF) but was resistant to decay by fH. Moreover, activated C3b923ΔDG and C3(H2O)923ΔDG were resistant to proteolysis by factor I (fI) in the presence of fH, but were efficiently inactivated in the presence of membrane cofactor protein (MCP). These characteristics cause a fluid phase–restricted AP dysregulation in the patients that continuously activated and consumed C3 produced by the normal C3 allele. These findings expose structural requirements in C3 that are critical for recognition of the substrate C3 by the AP C3-convertase and for the regulatory activities of fH, DAF, and MCP, all of which have implications for therapeutic developments.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH426 Genetics
Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
Additional Information: Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0021-9738/ (accessed 24/02/2014)
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Date of First Compliant Deposit: 30 March 2016
Last Modified: 18 Sep 2017 10:25
URI: http://orca-mwe.cf.ac.uk/id/eprint/28639

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