Multiple Lupus Susceptibility Loci Map to Chromosome 1 in BXSB Mice

Abstract

BXSB mice spontaneously develop a lupus-like syndrome that is accelerated by the Yaa gene (Y-linked autoimmune accelerator). We studied the phenotype of disease in (B10 × BXSB)F1 and (BXSB × (B10 × BXSB)F1) backcross mice and genotyped 224 backcross animals to allow a microsatellite-based genome-wide linkage analysis to be conducted. In the backcross population, three intervals on chromosome 1 showed significant linkage to disease, suggesting that multiple loci contribute to the production of autoimmune disease. D1Mit5 at 32.8 cM was linked to development of nephritis (χ2 = 15.68, p = 7.5 × 10−5), as was D1Mit12 at 63.1 cM (χ2 = 20.17, p = 7.1 × 10−6). D1Mit403 at 100 cM was linked to anti-dsDNA Ab production (χ2 = 17.28, p = 3.2 × 10−5). Suggestive linkages to antinuclear Abs and nephritis were identified on chromosome 3, to splenomegaly on chromosome 4, and to anti-ssDNA Ab production on chromosome 10. Chromosome 4 and the telomeric region of chromosome 1 have previously been linked to disease in other mouse models of systemic lupus erythematosus; however, the centromeric regions of chromosome 1 and chromosomes 3 and 10 are unique to BXSB. This implies that, though some loci may be common to a number of mouse models of lupus, different clusters of disease genes confer disease susceptibility in different strains of mice.