Lbw2^NZW/LacScr
QTL Variant Detail

Summary

• QTL variant: Lbw2^NZW/LacScr
• Name: lupus NZB x NZW 2; NZW/LacScr
• MGI ID: MGI:2155969
• QTL: Lbw2 Location: Chr4:98545539-128009280 bp Genetic Position: Chr4, cM position of peak correlated region/allele: 57.9 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: NZW/LacScr

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers autoimmune resistance and late mortality compared to NZB/BlScr.
• Inheritance: Recessive

Expression

In Structures Affected by this Mutation:

3 anatomical structure(s)

Notes

This allele also confers decreased edema, proteinuria, and IgM and IgG deposits in the glomeruli compared to NZB/BlScr.

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

J:20991

91 microsatellite markers were screened in a (NZB/BlScr x NZW/LacScr)F2 intercross population to identify QTLs associated with lupus susceptibility and lupus phenotypes. (NZB/BlScr x NZW/LacScr)F1 animals exhibit high susceptibility to systemic lupus erythematous (SLE) with 80% mortality by 12 months of age whereas parental strains NZB/BlScr and NZW/LacScr exhibit 16% and 11% mortality, respectively. Lupus-associated loci were detected on several chromosomes.

Lbw1 maps to 19.06 cM on mouse Chromosome 17 with marker Tnf (P<0.01) in association with mortality and glomerulonephritis.

Lbw2 maps to 55.6 cM on mouse Chromosome 4 with marker D4Nds2 (P<<0.001) in association with mortality and glomerulonephritis with NZB/BlScr-derived alleles conferring dominant lupus susceptibility at this locus. Given the early mortality for mice carrying the NZB Lbw2 allele attempts were made to more precisely map it. Based on 10 informative crossover events Lbw2 was mapped to a 9 cM span between D4Mit16 and D4Mit28.

Lbw3 maps to 81 cM on mouse Chromosome 5 with marker D5Mit101 (P<0.001) in association with mortality. NZW/LacScr-derived alleles confer recessive lupus susceptibility at Lbw3.

Lbw4 maps to 65 cM on mouse Chromosome 6 with marker D6Mit25 (P<<0.001) in association with mortality. NZB/BlScr-derived alleles confer recessive lupus susceptibility at Lbw4.

Lbw5 maps to 23 cM on mouse Chromosome 7 with marker Ngfg (P<0.01) in association with mortality with NZW/LacScr-derived alleles conferring dominant lupus susceptibility at this locus.

Lbw6 maps to 47 cM on mouse Chromosome 18 with marker D18Mit8 (P<0.005) in association with mortality and glomerulonephritis. NZW/LacScr-derived alleles confer recessive lupus susceptibility at Lbw6.

Lbw7 maps to 92.3 cM on mouse Chromosome 1 with marker D1Mit36 (P<0.005) and

Lbw8 maps to 29 cM on mouse Chromosome 11 with marker Il4 (P<0.005) in association with anti-chromatin antibody production. NZB/BlScr-derived alleles confer dominant lupus susceptibility at Lbw7 and Lbw8.

Two loci associated with splenomegaly, Sbw1 and Sbw2, were detected on mouse Chromosome 1 at 66.8 cM (P<0.005 at D1Nds1) and mouse Chromosome 4 at 44.5 cM (P<<0.001 at D4Mit9), respectively. Sbw2 was furtherlocalized to a 7 cM region between markers D4Mit16 and D4Nds2. Authors state that Sbw2 and Lbw2 map to the same region on mouse Chromosome 4 and are likely to be the same susceptibility locus.

NZB/BlScr-derived alleles confer recessive splenomegaly susceptibility at Sbw1 and dominant splenomegaly susceptibility at Sbw2.

J:98150

The Lbw2 QTL interval on mouse Chromosome 4 was refined to a 2.3 cM region between D4Mit203 (60 cM) and D4Mit70 (62.3 cM). (NZB x NZB.NZW-Lbw2)F1 x NZW animals were generated for phenotype analysis. Animals that lacked the NZB-derived Lbw2 locus exhibit increased survival compared to heterozygous animals. Edema, proteinuria, and IgM and IgG deposits were also decreased in the glomeruli of animals lacking NZB-derived alleles at Lbw2. IgM anti-ssDNA autoantibodies were decreased in animals lacking NZB-derived alleles at Lbw2. One or two copies of the NZB-derived Lbw2 locus is associated with increased spleen weight and mortality, indicating a dominant mode of inheritance.

Linkage analysis was performed on a population of 145 (NZB x NZW)F2 animals. The Lbw2 locus showed association with accelerated mortality and increased IgM anti-chromatin antibody production when derived from NZB. The region of peak linkage was between D4Mit169 (58 cM) and D4Nds2 (42.6 cM).

No candidate genes for Lbw2 were cited in this study. Previously identified autoimmunity QTLs mapping near Lbw2 are Sle2 (38 cM) and Adaz1 (49.6 cM).

References

• Original: J:20991 Kono DH, et al., Lupus susceptibility loci in New Zealand mice. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10168-72
• All: 3 reference(s)