Sle3^NZM2410/Aeg
QTL Variant Detail

Summary

• QTL variant: Sle3^NZM2410/Aeg
• Name: systemic lupus erythmatosus susceptibility 3; NZM2410/Aeg
• MGI ID: MGI:2156753
• Synonyms: Sle3^NZM2410
• QTL: Sle3 Location: Chr7:3511728-87142720 bp Genetic Position: Chr7, Syntenic

Variant origin

• Strain of Specimen: NZM2410/Aeg

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers increased serum IgM and IgG Ab levels and severe glomerulonephritis compared to C57BL/6J. (J:52863)
• Inheritance: Not Specified

Expression

In Mice Carrying this Mutation:	1 RNA-Seq or microarray experiment(s)
In Structures Affected by this Mutation:	1 anatomical structure(s)

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:25006

NZN/Aeg2410 mice are one of 27 strains derived by inbreeding progeny produced in a cross of NZB and NZW. These strains, which are termed the New Zeland mixed (NZM/Aeg) collection, exhibit a spectrum of susceptibilities to the spontaneous development of SLE and SLE-related autoimmune phenotypes. NZM/Aeg2410 mice develope highly penetrant early-onset SLE in both sexes.

Analysis focused on identifying genomic intervals containing genes that govern two phenotypes that are the hallmarks of both human and murine SLE: GN, which results from the deposition of immune complexes on glomeruluss basement membane and leads to kidney failure; and immunoglobulin G (IgG) antibody production against dsDNA.

158 (C57BL/6 x NZM/Aeg2410) F1 x NZM/Aeg2410 backcross (BC1) progeny were genotyped for informative loci contributing to SLE susceptibility by interval mapping with 77 SSR loci.

Four genomic intervals containing the GN susceptibility locus were identified.

The strongest locus, designated Sle1, was most closley linked with D1Mit15 on Chr 1, LOD=10.12, within a 95% confidence support interval of 19cM.

The second GN susceptibility locus, Sle2, mapped to Chr 4, most closely linked with D4Mit9, LOD=6.52, within a 95% confidence support interval of 25cM.

The third GN susceptibility locus, Sle3, mapped to Chr 7 most closely linked to the p locus, now Oca2; LOD=4.0. A second peak, LOD=4.48 was also identified; 4cM centromeric of D7Nds5. The two peaks and the large 95% confidence interval, 38cM, indicate the possible existence of two GN susceptibility locus in this region. However, it was not possible to confirm owing to the small number of recombinants between p and D7Nds5. D7Nds5 and p both account for the same component of variance in GN susceptibility among the BC1 progeny.

The fourth locus associated with SLE susceptibility in this cross was H-2 on Chr 17, p=0.003, LOD= < 2. GN susceptibility was associated with heterozygosity at H-2 rather than homozygosity for NZM/Aeg2410- derived alleles in contrast to the other loci. Logistic regression analysis identified H-2 as a significant GN susceptibility locus that accounted for a distinct component of the variance in GN susceptibility among BC1 progeny, p=0.0025.

Linkage anaylsis for anit-dsDNA IgG production did not identify any major recessive susceptibility loci for anti-dsDNA antibodies.

J:57246

To determine the number and locations of epistatic modifiers interacting with Sle1 homozygosity to mediate severe autoimmunity in B6 X NZW hybirds this study presents a genetic analysis of the espistatic suppression in NZW mice and presents the locations of 4 SLE supperssor loci that account for the absence of the fatal disease in NZW.

272 (B6.NZMc1[Sle1] x NZW) x NZW backrcoss progeny were assessed for autoimmune phenotypes at 12 months. B6.NZMc1 congenic mice do not exhibit fatal lupus and are Sle1 homozygous. Positions of loci contributing to the phenotypes were determined via genome scan using 122 informatives microsatellite markers distributed throughout the autosomal genome. Six intervals were identified with either significant or suggestive linkage to fatal lupus or high titered anti-dsDNA autoanitbody. The intervals could be organized into 2 groups based on whether homozygosity or herteozygosity for NZW-derived alleles were associated with disease.

Disease susceptibility was enhanced by homozygosity in 2 NZW-derived genomic intervals.

One was centered on D7Mit158, which coincided with the location of Sle3, systemic lupus erythmatosus susceptibility 3 orginally identified in 1994 in J:25006. The interval spanned markers D7Mit178 and tyr. Homozygosity for NZW at this interval was significantly associated with both lupus nephritis (LOD=8.16) and humoral autoimmunity (LOD =6.85) at peak marker D7Mit158. [Table 1].

A second locus was identified in the centromeric region of Chromosome 5, peaking with marker D5Mit4. The locus, designated Sle6, systemic lupus erythematosus susceptibility 6, was significantly associated with lupus nephritis (LOD=3.63) and only weakly associated with humoral autoimmunity (LOD=1.47). The genomic interval for Sle6 spans markers D5Mit146 and D5Mit12. [Table 1].

Four intervals were identified in which heterozygosity was associated with disease susceptibility in the (B6.NZMc1 x NZW) x NZW backcross. These loci were designated with Sles, for SLE suppressor, based on the diminuation of autoimmunity by homozygosity for NZW-derived alleles at these loci.

Sles1, systemic lupus erythmatosus suppressor 1, was identified on Chromosome 17 mapping with markers D17Mit34 and D17Mit10. Sles1 maps in the S (complement) region of the murine MHC. Heterozygosity for this interval was stongly associated with with both lupus nephritis (LOD=10.90) and humoral autoimmunity (LOD=8.54). [Table 1].

Sles2, systemic lupus erythmatosus suppressor 2, was identified on Chromosome 4 mapping with markers D4Mit9, D4Mit12, D4Mit54 and D4Mit33. Sles2 was more strongly associated with humoral autoimmunity (LOD=3.07) than lupus nephritis (LOD=2.15), centered with marker D4Mit12. [Table 1].

Sles3, systemic lupus erythmatosus suppressor 3, was indentified on Chromosome 3 peaking at marker D3Mit137, and spanning markers IL2, D3Mit137, D3Mit100, and D3Mit17. Heterozygosity at this locus acheived suggestive linkage for humoral autoimmunity (LOD=2.9) and weaker linkage with lupus nephritis (LOD=1.76).[Table 1]. Sle3 is near IL2 in a region of Chromosome 3 that has been associated with susceptibility to both diabetes and EAE in other murine models.

Sles4, systemic lupus erythmatosus suppressor 4, was identified in the centromeric region of Chromosome 9 peaking near D9Mit249. The interval spanned markers D9Mit59, D9Mit249, D9Mit42, D9Mit90 amd D9Mit2. Heterozygosity for this interval reached suggestive linkage for lupus nephritis (LOD=2.27) and showed no linkage with humoral autoimmunity (LOD=0.59). [Table 1].Sle4 was stongly gender biased in that the entire effect was male specific (LOD=2.14 for 35 males vs LOD=0.72 for 50 affected females.)

Multivariate analysis of disease penetrance as a function of suppressive Sles alleles carried supports the hypothesis that the cumulative effect of these four loci is sufficient to account for the suppression of severe autoimmunity in NZW. The number of active Sles loci were negatively correlated with the penetrance of GN and anti-dsDNA (p=0.0067 and p=0.0076, respecively.)

References

• Original: J:55031 Mohan C, et al., Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death. J Immunol. 1999 Jun 1;162(11):6492-502
• All: 27 reference(s)