Identification of intervals on chromosomes 1, 3, and 13 linked to the development of lupus in BXSB mice

Abstract

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.

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

“…Previous linkage analyses using autoimmune (NZB, MRL and BXSB) and non-autoimmune strains (NZW, C57BL and B10) did not test the combination of OPN allotypes as in the present study (MRL vs. C3H) [2,3,5] except of a few studies [4,6,17]. In the study of BXSB Â B10 crosses [4,17], to detect the loci with additive mode of inheritance in disease susceptibility might be difficult since authors used BXSB Â (B10 Â BXSB)F 1 or B10 Â (BXSB Â B10)F1 backcrosses, not F 2 crosses. Furthermore, in these studies, BXSB strain was used as a lupus-prone strain, while BXSB type OPN might be disease resistant.…”

Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus

“…However, they intriguingly both involve non-autoimmune strains; in the case of Sles3, NZWxC57BL/6 heterozygosity, 1 and in the case of Bxs5, C57BL/10 homozygosity. 11 The confirmation of a B6-derived locus on chromosome 3 that modifies ANA titres (in combination with 129-derived genes) highlights the likelihood of epistatic interactions influencing the phenotype of a knockout strain, in spite of extensive backcrossing to B6.…”

“…6 This region has been consistently linked to autoimmune traits in a number of lupus-prone strains, including NZB (Nba2), 7,8 NZM2410 (Sle1) 9 and BXSB (Bxs3). 10,11 A congenic strain, comprising the 129-derived locus on distal chromosome 1 on a B6 background, a combination commonly created by backcrossing onto B6 a knockout strain in which the gene located in that region has been inactivated in 129 embryonic stem cells, also developed an autoimmune phenotype. The humoral autoimmunity in this congenic strain was indistinguishable to that observed in a mouse carrying a deletion of the Apcs gene, located within the lupus-linked genomic region on distal chromosome 1 and considered as a candidate gene for murine SLE.…”

Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives

“…Hormones do not appear to influence disease expression. The genetics of this model include a single gene on the Y chromosome, Yaa, which accelerates the onset and severity of autoimmunity in males in the context of at least 5 additional autosomal susceptibility loci (36). If families with affected male relatives truly are a unique genetic subset, in-depth analysis of individuals in these families could facilitate mapping for SLEsusceptibility genes.…”