Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans

Glomerulonephritis is a kidney inflammation that occurs alone or as part of other conditions, including the autoimmune disorder lupus. A novel mutation has now been identified as the cause of the disease in a rat model. The mutation affects the Fcgr3 immunoglobulin receptor, but it does not produce a defective receptor. Rather, too many copies of an otherwise normal gene are produced. A similar gene-number defect was then detected in a subset of human systemic lupus erythematosus patients with a kidney inflammation. In these patients an equivalent receptor gene, FCGR3B, is present at a low copy number. Disease seems to result when copy number is altered in either direction, so receptor levels must need to be very finely tuned. Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics1,2,3. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation3,4,5. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.