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Characterization of complement factor H–related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome

AuthorsAbarrategui-Garrido, Cynthia; Martínez-Barricarte, Rubén ; López-Trascasa, Margarita; Rodríguez de Córdoba, Santiago ; Sánchez-Corral, Pilar
Keywordsproteins genetically and structurally
atypical hemolytic uremic syndrome (aHUS)
patients with aHUS
patients with type II membranoproliferative glomerulonephritis
Issue Date5-Nov-2009
PublisherAmerican Society of Hematology
CitationBlood 114:4261-4271 (2009)
AbstractThe factor H–related protein family (CFHR) is a group of minor plasma proteins genetically and structurally related to complement factor H (fH). Notably, deficiency of CFHR1/CFHR3 associates with protection against age-related macular degeneration and with the presence of anti-fH autoantibodies in atypical hemolytic uremic syndrome (aHUS). We have developed a proteomics strategy to analyze the CFHR proteins in plasma samples from controls, patients with aHUS, and patients with type II membranoproliferative glomerulonephritis. Here, we report on the identification of persons carrying novel deficiencies of CFHR1, CFHR3, and CFHR1/CFHR4A, resulting from point mutations in CFHR1 and CFHR3 or from a rearrangement involving CFHR1 and CFHR4. Remarkably, patients with aHUS lacking CFHR1, but not those lacking CFHR3, present anti-fH autoantibodies, suggesting that generation of these antibodies is specifically related to CFHR1 deficiency. We also report the characterization of a novel CFHR1 polymorphism, resulting from a gene conversion event between CFH and CFHR1, which strongly associates with aHUS. The risk allotype CFHR1*B, with greater sequence similarity to fH, may compete with fH, decreasing protection of cellular surfaces against complement damage. In summary, our comprehensive analyses of the CFHR proteins have improved our understanding of these proteins and provided further insights into aHUS pathogenesis.
Description8 Tables. 7 Figures. The online version of this article contains a data supplement.
Publisher version (URL)http://bloodjournal.hematologylibrary.org/content/114/19/4261.abstract
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