Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration

Abstract

We sequenced the whole exome of 35 cases and 7 controls from 9 age-related macular degeneration (AMD) families in whom known common genetic risk alleles could not explain their high disease burden and/or their early-onset advanced disease. Two families harbored novel rare mutations in CFH (R53C and D90G). R53C segregates perfectly with AMD in 11 cases (heterozygous) and 1 elderly control (reference allele) (LOD = 5.07, P = 6.7 × 10(-7)). In an independent cohort, 4 out of 1676 cases but none of the 745 examined controls or 4300 NHBLI Exome Sequencing Project (ESP) samples carried the R53C mutation (P = 0.0039). In another family of six siblings, D90G similarly segregated with AMD in five cases and one control (LOD = 1.22, P = 0.009). No other sample in our large cohort or the ESP had this mutation. Functional studies demonstrated that R53C decreased the ability of FH to perform decay accelerating activity. D90G exhibited a decrease in cofactor-mediated inactivation. Both of these changes would lead to a loss of regulatory activity, resulting in excessive alternative pathway activation. This study represents an initial application of the whole-exome strategy to families with early-onset AMD. It successfully identified high impact alleles leading to clearer functional insight into AMD etiopathogenesis.

Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome

“…Indeed, the observed C3 consumption is similar to that seen in certain type II mutations expressed but functionally altered in the N-terminal part of FH (such as R53C, A161S, or R78G 23,[57][58][59] (V. Fremeaux-Bacchi and M. Noris, unpublished data, 2014). Nevertheless, 3 genetic changes in C3, which are distant from the FH CCP1-4 binding surface and influence only FH CCP19-20 binding (such as P1092L, D1093N, and G1094R), induce C3 consumption in patients as well.…”

Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes

“…This variant (Y402H) is associated with functional consequences, as it limits the binding of CFH to various complement-activating targets, reducing its inhibitory activity and thus prolonging the activity of C3 convertase (Herbert et al, 2007;Laine et al, 2007). Other rare variants in CFH have also been reported (R1210C, R53C and D90G) (Raychaudhuri et al, 2011;Yu et al, 2014). R1210C is extremely rare, with a minor allele frequency of 0.0173% (ExAC database accessed 16.11.15), but has an even stronger association with AMD than Y402H, perhaps acting as a functionally null allele (Raychaudhuri et al, 2011).…”

Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD

“…None of the family members carried the rare AMD risk alleles at CFH R53C, CFH D90G, CFH P503A, or CFH R1210C [14][15][16]18 nor did they carry risk alleles for macular diseases in the BEST1, ABCA4, or other retinal degeneration-associated genes 25 . We measured serum FH levels in each family in order to assess the effects of the four CFH variants on secretion of the FH protein.…”

“…Rare variants in CFH as well as other genes in the complement pathway have since been identified, and carry a higher risk of disease [14][15][16][17][18] . The CFH R53C variant, located in CCP1, decreases the ability of FH to perform decay accelerating activity 15 ; the CFH D90G variant, located in CCP2, was found to decrease cofactor-mediated inactivation 15 ; and the CFH R1210C variant, located in CCP20, shows defective binding of FH to C3d, C3b, heparin/glycosaminoglycans, and endothelial cells (Table 3) 14,30-33 . Another rare variant was found to segregate with AMD in an Amish family, but no functional work was done to determine the effect of the mutation on FH protein.…”