Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P36980 (CFHR2)
 30 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Factor H related proteins comprise a group of five plasma proteins: CFHR1, CFHR2, CFHR3, CFHR4 and CFHR5, and each member of this group binds to the central complement component C3b. Mutations, genetic deletions, duplications or rearrangements in the individual CFHR genes are associated with a number of diseases including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathies (C3 glomerulonephritis (C3GN), dense deposit disease (DDD) and CFHR5 nephropathy), IgA nephropathy, age related macular degeneration (AMD) and systemic lupus erythematosus (SLE). Although complement regulatory functions were attributed to most of the members of the CFHR protein family, the precise role of each CFHR protein in complement activation and the exact contribution to disease pathology is still unclear. Recent publications show that CFHR proteins form homo- as well as heterodimers. Genetic abnormalities within the CFHR gene locus can result in hybrid proteins with affected dimerization or recognition domains which cause defective functions. Here we summarize the recent data about CFHR genes and proteins in order to better understand the role of CFHR proteins in complement activation and in complement associated diseases.
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PMID:Complement factor H related proteins (CFHRs). 2383 46

The intrinsic similarity shared between the members of the complement factor H family, which comprises complement factor H and five complement factor H-related (CFHR) genes, leads to various recombination events. In turn these events lead to deletions of some genes or abnormal proteins, which are found in patients with atypical hemolytic uremic syndrome or C3 glomerulopathies. Here we describe a novel genetic rearrangement generated from a heterozygous deletion spanning 146 Kbp involving multiple CFHR genes leading to a CFHR1-R5 hybrid protein. This deletion was found in four family members presenting with a familial dominant glomerulopathy histologically classified as an overlap of dense deposit disease and C3 glomerulonephritis. Affected patients exhibited permanently low C3 and factor B levels and high amounts of activation fragments sC5b9 and Bb, indicating a systemic alternative pathway dysregulation. The abnormal protein, characterized by Western blot and immunoprecipitation, was shown to circulate in association with CFHR1 and CFHR2, attributable to its two N-terminal dimerization motifs. The presence of this protein is associated with a perturbation of Factor H activity on the C3 convertase decay. Thus, our study highlights the role of CFHRs in the physiopathology of C3 glomerulopathies and stresses the importance of screening CFHRs in all familial C3 glomerulopathies. Such hybrids described till now were always associated with familial forms.
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PMID:A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy. 2872 35

Factor H related-protein 5 (CFHR5) is a surface-acting complement activator and variations in the CFHR5 gene are linked to CFHR glomerulonephritis. In this study, we show that FHR5 binds to laminin-521, the major constituent of the glomerular basement membrane, and to mesangial laminin-211. Furthermore, we identify malondialdehyde-acetaldehyde (MAA) epitopes, which are exposed on the surface of human necrotic cells (Homo sapiens), as new FHR5 ligands. Using a set of novel deletion fragments, we show that FHR5 binds to laminin-521, MAA epitopes, heparin, and human necrotic cells (HUVECs) via the middle region [short consensus repeats (SCRs) 5-7]. In contrast, surface-bound FHR5 contacts C3b via the C-terminal region (SCRs8-9). Thus, FHR5 uses separate domains for C3b binding and cell surface interaction. MAA epitopes serve as a complement-activating surface by recruiting FHR5. The complement activator FHR5 and the complement inhibitor factor H both bind to oxidation-specific MAA epitopes and FHR5 competes with factor H for binding. The C3 glomerulopathy-associated FHR21-2-FHR5 hybrid protein is more potent in MAA epitope binding and activation compared with wild-type FHR5. The implications of these results for pathology of CFHR glomerulonephritis are discussed. In conclusion, we identify laminins and oxidation-specific MAA epitopes as novel FHR5 ligands and show that the surface-binding site of FHR5 (SCRs5-7) is separated from the C3b binding site (SCRs8-9). Furthermore, FHR5 competes with factor H for binding to MAA epitopes and activates complement on these modified structures.
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PMID:FHR5 Binds to Laminins, Uses Separate C3b and Surface-Binding Sites, and Activates Complement on Malondialdehyde-Acetaldehyde Surfaces. 2948 59