Mutation of POLB Causes Lupus in Mice

A replication study of a previous genome-wide association study (GWAS) suggested that a SNP linked to the POLB gene is associated with systemic lupus erythematosus (SLE). This SNP is correlated with decreased expression of Pol beta, a key enzyme in the base excision repair (BER) pathway. To determine whether decreased Pol beta activity results in SLE, we constructed a mouse model of POLB that encodes an enzyme with slow DNA polymerase activity. We show that mice expressing this hypomorphic POLB allele develop an autoimmune pathology that strongly resembles SLE. Of note, the mutant mice have shorter immunoglobulin heavy-chain junctions and somatic hypermutation is dramatically increased. These results demonstrate that decreased Pol beta activity during the generation of immune diversity leads to lupus-like disease in mice, and suggest that decreased expression of Pol beta in humans is an underlying cause of SLE.