Genetic Drivers of Dysregulation of Complement in C3G
A number of case series have identified the prevalence of rare genetic variants in the genes, CFH, CFI and CD46 encoding complement regulatory proteins and also the genes C3 and CFB encoding complement components of the C3 convertase. Evidence of the functional significance of these genetic variants is limited. Genetic variants in CFH may lead to loss of secretion and FH deficiency.
In familial studies of DDD and C3GN, Variants in C3 have been shown to be hyperfunctional and resistant to complement regulation resulting in complement overactivation. In one study of familial MPGN, a variant in CFH resulted in the secretion of a defective FH protein.
Studies of several pedigrees have identified genetic abnormalities of CFH-related genes. Genetic material is duplicated resulting in abnormal FH-related proteins that have an increased ability to compete with FH on cell surfaces resulting in loss of complement regulation. The most well-known example of a genetic abnormality of CFH-related gene is CFHR5 nephropathy, first identified in two large Cypriot pedigrees. CFHR5 nephropathy, and other abnormalities of CFHRs are not limited to Cypriot pedigrees.