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 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 BC1progeny.

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 notidentify any major recessive susceptibility loci for anti-dsDNA antibodies.