Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases

Abstract

The complement factor H (FH) mutation R1210C, which was described in association with atypical hemolytic uremic syndrome (aHUS), also confers high risk of agerelated macular degeneration (AMD) and associates with C3 glomerulopathy (C3G). To reveal the molecular basis of these associations and to provide insight into what determines the disease phenotype in FH-R1210C carriers, we identified FH-R1210C carriers in our aHUS, C3G, and AMD cohorts. Disease status, determined in patients and relatives, revealed an absence of AMD phenotypes in the aHUS cohort and, vice versa, a lack of renal disease in the AMD cohort. These findings were consistent with differences in the R1210C-independent overall risk for aHUS and AMD between mutation carriers developing one pathology or the other. R1210C is an unusual mutation that generates covalent complexes between FH and HSA. Using purified FH proteins and surface plasmon resonance analyses, we demonstrated that formation of these FH-HSA complexes impairs accessibility to all FH functional domains. These data suggest that R1210C is a unique C-terminal FH mutation that behaves as a partial FH deficiency, predisposing individuals to diverse pathologies with distinct underlying pathogenic mechanisms; the final disease outcome is then determined by R1210C-independent genetic risk factors.

Complement Dysregulation and Disease: Insights from Contemporary Genetics

“…The R1210C mutant is highly penetrant and also leads to an earlier age of onset compared to the overall AMD population (mean age of onset 65 versus 71 years). This association of the R1210C mutant with AMD has now been shown by several groups (see below) and has been reported in aHUS patients (55, 56) as well as in C3G (40, 57). …”

“…Mutations in FH have been described in AMD, aHUS, and C3G. Of interest and unexplained, although the same mutation may be found in more than one disease, more commonly, they appear to be preferentially restricted to one disease (40). …”

“…The interaction of the R1210C FH-albumin heterodimer with immobilized C3b is also impaired. Thus, this mutant in FH affects its complement regulatory function, particularly on debris or a membrane, and thereby could lead to increased AP activation at sites of debris deposition (40). …”

Mutations in Complement Factor H Impair Alternative Pathway Regulation on Mouse Glomerular Endothelial Cells in Vitro

“…Because the D1119G mutant still efficiently competes with wild type FH19 -20 for C3b/C3d, the mutation might affect the self-association characteristics of the two C-terminal CCPs, preventing binding to C3b/C3d. Recently, the aHUS/AMD-associated R1210C mutation has been shown to introduce a gain of function defect, as it enables the protein to form covalent bonds with serum albumin (49,50). The R1210A mutant used in the current study lacks the surface-exposed cysteine; therefore, the observed effects can likely be attributed to a decrease in electrostatic interactions with FH19 -20 ligands.…”

The complement system in age-related macular degeneration: A review of rare genetic variants and implications for personalized treatment

“…Through the introduction of a cysteine residue, Arg1210Cys forms covalent interactions with human serum albumin (Sanchez-Corral et al, 2002). It has been postulated that it is the albumin bound to FH rather than any functional defect of the protein itself that eventually disrupts FH function (Recalde et al, 2016). …”