Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes

The BXSB mouse strain is an important model of glomerulonephritis observed in systemic lupus erythematosus (SLE). Linkage studies have successfully identified disease-susceptibility intervals; however, extracting the identity of the susceptibility gene(s) in such regions is the crucial next step. Congenic mouse strains present a defined genetic resource that is highly amenable to microarray analysis. We have performed microarray analysis using a series of chromosome 1 BXSB congenic mice with partially overlapping disease-susceptibility intervals. Simultaneous comparison of the four congenic lines allowed the identification of expression differences associated with both the initiation and progression of disease. Thus, we have identified a number of novel SLE disease gene candidates and have confirmed the identity of Ifi202 as a disease candidate in the BXSB strain. Sequencing of the promoter regions of Gas5 has revealed polymorphisms in the BXSB strain, which may account for the differential expression profile. Furthermore, the combination of the microarray results with the different phenotypes of these mice has allowed the identification of a number of expression differences that do not necessarily map to the congenic interval, but may be implicated in disease pathways.