Complement Factor H-related protein (CFHR)

Complement Factor H-related (CFHR) proteins are a group of five plasma proteins (CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5) that are structurally and genetically related to Complement Factor H (FH), the primary negative regulator of the alternative complement pathway [1, 3]. These proteins are encoded by the CFHR1-5 genes located in the Regulators of Complement Activation (RCA) gene cluster on chromosome 1 [8, 19]. Unlike FH, CFHR proteins lack the N-terminal regulatory domains required for complement inhibition and instead function as positive regulators by competing with FH for binding to C3b and host cell surfaces [7, 14]. This competitive inhibition effectively 'deregulates' FH, leading to enhanced complement activation, opsonization, and inflammation [17, 20]. Genetic variations in the CFHR gene cluster, such as the ΔCFHR3-CFHR1 deletion or CFHR5 mutations, are strongly associated with several complement-mediated diseases including age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and C3 glomerulopathy (C3G) [2, 4, 13]. In AMD, higher levels of FHR-4 are linked to disease progression, while the deletion of CFHR1 and CFHR3 is protective [1, 28]. Therapeutic strategies targeting CFHR proteins are currently in development, focusing on monoclonal antibodies (e.g., anti-FHR-4) and siRNA to reduce their levels or block their antagonistic effects, thereby restoring the protective balance of the complement system [24, 33, 52]. These proteins also serve as important biomarkers for patient stratification and monitoring disease activity in renal and ocular conditions [5, 32].

Other names

FHR proteinFactor H-related proteinCFHRsComplement control protein

Competitive inhibition of Factor H binding to C3b and cell surfaces, thereby enhancing alternative pathway activation. Therapeutic strategies involve reducing CFHR levels or blocking their interaction with C3b to restore Factor H-mediated regulation.