Objective. To identify intervals containing sys-temic lupus erythematosus (SLE) susceptibility alleles in the BXSB strain of mice. Methods. We analyzed 286 (B10 [B10 BXSB]F 1) backcross mice for a range of phenotypic traits associated with the development of SLE in BXSB mice. The mice were genotyped using 93 microsatellite markers, and the linkage of these markers to disease was studied by extreme-phenotype and quantitative trait locus analysis. Results. The disease phenotype in these backcross mice was less severe than that in BXSB mice. However, antinuclear antibody production was increased compared with the parental strain. We identified 4 areas of genetic linkage to disease on chromosome 1 (Bxs1-4), 1 on chromosome 3 (Bxs5), and another interval on chromosome 13 which were associated with various aspects of the phenotype. Bxs4 and Bxs5 are located in regions not previously linked to disease in other models of SLE. Conclusion. SLE in the BXSB mouse model has a complex genetic basis and involves at least 5 distinct intervals located on chromosomes 1 and 3. There is evidence that different intervals affect particular aspects of the SLE phenotype.
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.
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