Sle1^NZW
QTL Variant Detail

Summary

• QTL variant: Sle1^NZW
• Name: systemic lupus erythmatosus susceptibility 1; NZW
• MGI ID: MGI:3604960
• QTL: Sle1 Location: Chr1:169038741-169038913 bp Genetic Position: Chr1, cM position of peak correlated region/allele: 76.73 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: NZW

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

NZW-derived alleles at Sles1 suppress the anti-nuclear autoantibody producing phenotype in animals with NZW-derived alleles at Sle1.

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

J:67544

Systemic lupus erythematosus (Sle) is measured via anti-chromatin IgG production. Fine mapping of loci around Sle1 indicate that Sle1 actually corresponds to a cluster of loci related in part to Sle1. Various mating paradigms were used to dissect the Sle1 interval, including 493 (NZM2410 X C57BL/6J) F1 meioses. In addition (B6.Sle1 X C57BL/6J) x C57BL/6J recombinants were intercrossed to create more recombinants and to develop sublines on a C57BL/6J background.

Interestingly three non overlapping regions were identified within Sle1 designated as Sle1a, Sle1b and Sle1c. The following congenic intervals were identified.

Sle1a is included in an interval bounded by D1Mit15 and D1Mit353.

Sle1b is included in an interval bounded by D1Mit113 and D1Mit407 and by D1Mit113 and D1Mit206.

Sle1c is included in an interval bounded by D1Mit274 and D1Mit17.

J:52863

156 (NZM2410/Aeg x C57BL/6)F2 animals were screened for 193 polymorphic markers to identify QTLs affecting autoimmune lupus-like phenotypes. Inbred strain NZM2410 is susceptible to autoimmune disease while inbred strain C57BL/6 is resistant.

5 previously identified loci were detected on mouse chromosomes 1, 6, 7, and 11, and 2 new loci were identified on mouse chromosomes 10 and 11. Sle1 on mouse chromosome 1, previously identified by Morel in 1994 (J:25006), was detected for linkage to splenomegaly at D1Mit36 (LOD = 8) and suggestive linkage to anti-dsDNA IgG production at D1Mit15 (LOD = 4.18) in the present cross.

A previously identified locus on mouse chromosome 6, Lbw4 (Kono, J:20991), was detected for linkage to anti-MPO production at D6Mit14 (LOD=4.61)and anti-dsDNA production at D6Mit374 (LOD = 2.93).

1.22.2016 Curator Note: Because Lbw4 was originally mapped in 1995 in J:20991 using an (NZB/BlScr x NZW/LacScr)F2 intercross, which differs from the mapping population used here, we consider the current study a separate mapping experiment and have named this QTL Sle23, systematic lupus erythematosus susceptibility 23 .

Linkage to glomerulonephritis (GN) was detected on mouse chromosome 7 at D7Mit25 (LOD = 5.48) and linkages to anti-ssDNA IgG production, anti-thryoglobulin production, and antinuclear antibody production were detected at D7Mit85 (LOD = 4.99). This interval colocalizes with Sle3 (Morel, J:25006) and Lbw5 (Kono, J:20991). Sle3 appears to have a sex-influence in the present cross: female animals show greater GN penetrance than male animals.

1.22.2016 Curator Note: Both Sle3 and Lbw5 were originally mapped in different mapping populations then used here; we consider the current study a separate mapping experiment and have named the QTL identified on Chr 7 at D7Mit25 Sle24, systematic lupus erythematosus susceptibility 24.

Linkage to anti-dsDNA production was detected on mouse chromosome 7 at D7Mit178 (LOD = 5.47). The locus was labeled Sle20 and colocalized with Lrdm1.

A locus for GNA and anti-dsDNA IgG production was detected on mouse chromosome 11 at D11Mit20 (GN LOD = 3.26, anti-dsDNA IgG LOD = 3.10) andcolocalized with Lbw8 (Kono, J:20991). A possible candidate gene for this locus is Inf4.

Novel QTLs for acute GN Sle12 and Sle13 were detected on mouse chromosome 10 at D10Mit35 (LOD = 3.54) and mouse chromosome 11 at D11Mit39 (LOD = 2.79), respectively.Apossible candidate gene for Sle12 is Ifng.

J:25006

NZM/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 GNsusceptibility 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 D5Nds5. D5DNs5 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.

References

• Original: J:100678 Subramanian S, et al., Epistatic suppression of systemic lupus erythematosus: fine mapping of Sles1 to less than 1 mb. J Immunol. 2005 Jul 15;175(2):1062-72
• All: 2 reference(s)