Atypical hemolytic uremic syndrome (aHUS) is a severe renal disease that is associated with defective complement regulation caused by multiple factors. We previously described the deficiency of factor H-related proteins CFHR1 and CFHR3 as predisposing factor for aHUS.
Homozygous deletion of a 84-kb genomic fragment in human chromosome 1 that encompasses the CFHR1 and CFHR3 genes represents a risk factor for hemolytic uremic syndrome (HUS) but has a protective effect in age-related macular degeneration (AMD). Here we identify CFHR1 as a novel inhibitor of the complement pathway that blocks C5 convertase activity and interferes with C5b surface deposition and MAC formation. This activity is distinct from complement factor H, and apparently factor H and CFHR1 control complement activation in a sequential manner. As both proteins bind to the same or similar sites at the cellular surfaces, the gain of CFHR1 activity presumably is at the expense of CFH-mediated function (inhibition of the C3 convertase). In HUS, the absence of CFHR1 may result in reduced inhibition of terminal complex formation and in reduced protection of endothelial cells upon complement attack. These findings provide new insights into complement regulation on the cell surface and biosurfaces and likely define the role of CFHR1 in human diseases. IntroductionThe complement system is important for host innate and adaptive immunity and mounts a protective immune response to invading microbes. 1 The alternative complement pathway is spontaneously activated, and generates C3 convertases (C3bBb) that cleave the central component C3 to the anaphylactic peptide C3a and C3b. 2,3 C3b attached to a foreign surface binds factor B and generates the C3 convertase (C3bBb), which enhances further complement activation resulting in opsonization and phagocytosis of particles. Binding of an additional C3b molecule to the C3 convertase forms the C5 convertase (C3bBbC3b) of the alternative pathway. This convertase cleaves C5 and generates the potent chemoattractant C5a as well as C5b, which initiates the terminal complement pathway assembly. 4 C5b immediately undergoes conformational changes and binds C6 and C7 in a nonenzymatic manner. The assembled C5b67 complex is released from the convertase and attaches to lipid bilayers. Upon binding of C8 and C9, the lytic membrane attack complex (MAC) is formed. 3,5 Once activated, this powerful defense system is tightly controlled on host cell surfaces by both membrane-anchored and surface-attached soluble regulators. Proper and coordinated function of these regulators is essential for tissue integrity. Single gene mutations predispose to severe renal and retinal diseases, that is, hemolytic uremic syndrome (HUS; OMIM no. 235400), membranoproliferative glomerulonephritis type II (MPGN II; OMIM no. 609814), or age-related macular degeneration (AMD; OMIM no. 603075). 6,7 HUS is caused by occlusion of arterioles and capillaries in the kidney, due to endothelial cell and platelet damage. 8 MPGN II is a rare renal disease, with formation of dense deposits at the glomerular basement membrane and thickening of the peripheral capillary walls. 9 Similarly, the retinal disease AMD, which causes visual impairment of elderly people, is caused by deposits (drusen) that form on the Bruch membrane and le...
Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Disease-associated mutations have been described in the genes encoding the complement regulators complement factor H, membrane cofactor protein, factor B, and factor I. In this study, we show in two independent cohorts of aHUS patients that deletion of two closely related genes, complement factor H–related 1 (CFHR1) and complement factor H–related 3 (CFHR3), increases the risk of aHUS. Amplification analysis and sequencing of genomic DNA of three affected individuals revealed a chromosomal deletion of ∼84 kb in the RCA gene cluster, resulting in loss of the genes coding for CFHR1 and CFHR3, but leaving the genomic structure of factor H intact. The CFHR1 and CFHR3 genes are flanked by long homologous repeats with long interspersed nuclear elements (retrotransposons) and we suggest that nonallelic homologous recombination between these repeats results in the loss of the two genes. Impaired protection of erythrocytes from complement activation is observed in the serum of aHUS patients deficient in CFHR1 and CFHR3, thus suggesting a regulatory role for CFHR1 and CFHR3 in complement activation. The identification of CFHR1/CFHR3 deficiency in aHUS patients may lead to the design of new diagnostic approaches, such as enhanced testing for these genes.
Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent studies have identified a factor H–associated form of HUS, caused by gene mutations that cluster in the C-terminal region of the complement regulator factor H. Here we report how three mutations (E1172Stop, R1210C, and R1215G; each of the latter two identified in three independent cases from different, unrelated families) affect protein function. All three mutations cause reduced binding to the central complement component C3b/C3d to heparin, as well as to endothelial cells. These defective features of the mutant factor H proteins explain progression of endothelial cell and microvascular damage in factor H–associated genetic HUS and indicate a protective role of factor H for tissue integrity during thrombus formation
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