Swrl3^SWR
QTL Variant Detail

Summary

• QTL variant: Swrl3^SWR
• Name: SWR lupus locus 3; SWR
• MGI ID: MGI:3576913
• QTL: Swrl3 Location: unknown Genetic Position: Chr18, Syntenic

Variant origin

• Strain of Specimen: SWR

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers increased IgG anti-dsDNA and anti-histone antibody production compared to NZB. This allele also confers increased anti-nuclear antibody production compared to NZB. (J:73097, J:96060)
• Inheritance: Other (see notes)

Notes

Swrl3 exhibits additive inheritance. This allele exhibits dominant inheritance in the experiment from J:73097.

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

J:73097

Linkage analysis was performed on 86 female animals from a NZB x (SWR x NZB)F1 backcross population to identify dominant SWR-derived QTLs associated with lupus phenotypes. (SWR x NZB)F1 hybrid animals are susceptible to lupus nephritis. 122 autosomal microsatellite markers at an average spacing of 10 cM were used for the genome scan.

Suggestive linkage to IgG anti-nuclear antibody (ANA) production mapped to 86 cM on mouse Chromosome 1 near D1Mit15 (LOD=2.89-2.91). This locus is designated Swrl1 (SWR lupus locus 1). NZB-derived alleles at Swrl1 confer increased ANA production with a dominant mode of inheritance. This locus overlaps with previously identified lupus QTLs Nba2 (95 cM) and Sle1 (88 cM). Potential candidate genes for Swrl1 are Cr2 (106.6 cM), Cfh (74 cM), and Fasl (85 cM).

Suggestive linkage to early mortality mapped to 55 cM on mouse Chromosome 4 near D4Mit147 (LOD=1.48). The NZB-derived allele confers early mortality with a recessive mode of inheritance. This locus overlaps with previously identified lupus QTLs Lbw2, Sbw2, and Sle2.

Suggestive linkage to glomerulonephritis susceptibility mapped to 75 cM on mouse Chromosome 4 near D4Mit190 (LOD=2.23). This locus is thought to be the previously identified autoimmunity QTL Nba1. NZB-derived alleles at this locus confer susceptibility to glomerulonephritis with a recessive mode of inheritance. Potential candidate genes for Nba1 are Tnfrsf4 (79 cM), Tnfrsf9 (75 cM), and Tnfrsf1b (75 cM). Nba1 appears to interact with Swrl2. Animals homozygous for NZB-derived alleles at Nba1 and heterozygous at Swrl2 exhibit significantly increased glomerulonephritis susceptibility.

07.15.2015 Curator Note: Nba1 was originally mapped in J:18261 in 1994 using an NZB/BlNJ x NZW/LacJ)F1 x NZW/BlNJ backcross which differs from the cross used here. We consider this a separate mapping experiment and have assigned this QTL as Nba8 to preserve the significance of the interaction.

Suggestive linkage to glomerulonephritis susceptibility mapped to 36 cM mouse Chromosome 14 near D14Mit37 (LOD=2.48). This locus is named Swrl2 (SWR lupus locus 2). SWR-derived alleles at Swrl2 confer glomerulonephritis susceptibility with a dominant mode of inheritance. Potential candidate genes for Swrl2 are Cdc25c (15 cM), Apc (15 cM), Mcc (21 cM), Bin1(14 cM), Camk4 (12 cM), and Egr1 (16 cM).

The H2 locus on mouse Chromosome 17 showed the strongest linkage to several phenotypes. H2 is linked to early mortality (LOD=4.59-5.38), glomerulonephritis susceptibility (LOD=2.37), and IgG anti-nuclear antibody(ANA) formation (LOD=5.48). SWR-derived alleles confer increased susceptibility/severity of the above lupus traits with a dominant mode of inheritance. Potential candidate genes for the H2 locus are H2 (23 cM),Tnf (19 cM), Lta (19 cM),C2(18.8 cM), C4(18.8 cM), Tnfsf7 (20 cM),Notch4 (18.7 cM), and Daxx (17 cM). The H2 locus shows strong interaction with Swrl3. Animals heterozygous at both H2 and Swrl3 exhibit significantly increased penetrance of the IgG ANA phenotype.

Suggestive linkage to IgG anti-nuclear antibody (ANA) production mapped to 14 cM on mouse Chromosome 18 near D18Mit17 (LOD=2.07-2.13). This locus is designated Swrl3 (SWR lupus locus 3). SWR-derived alleles confer increased ANA production with a dominant mode of inheritance.Potential candidate genes for Swrl3are Fgf17 (38 cM), Dok2 (39 cM), and Nkx3-1 (30 cM).

J:96060

Linkage analysis was performed on a population of 62 (SWR x NZB)F2 animals to identify QTLs associated with lupus nephritis. (SWR x NZB)F1 hybrid animals exhibit susceptibility to lupus nephritis. 95 polymorphic markers at a 12.2 cM resolution were used for the genome scan.

A novel QTL tentatively named Swrl5 was identified at 106 cM on mouse Chromosome 1. Swrl5 shows suggestive linkage to hypergammaglobulinemia with LOD=3.22 at Tgfbm2 (formerly D1Mit17; 106 cM). Animals homozygous for SWR-derived alleles at Swrl5 tend to have significantly increased levels of total serum IgG. Previously identified lupus QTL Sle1c at 106.3 cM overlaps with Swrl5. A potential candidate gene for both Swrl5 and Sle1c is Cr2 (106.6 cM). The Swrl5 region is syntenic to a human SLE locus on 1q.

Previously identified QTL Nba4 was detected and confirmed in this study. Nba4 maps to 15 cM on mouse Chromosome 5. This locus shows suggestive linkage to IgG anti-ssDNA antibodies, anti-dsDNA antibodies and glomerulonephritis with LOD=2.98 at D5Mit127. Animals homozygous for NZB-derived alleles at Nba4 exhibit increased autoantibody production and susceptibility to glomerulonephritis. Other autoimmunity QTLs mapping near Nba4 are Sle6 (28 cM) and Pgia18 (5 cM). Nba4 is syntenic to a human SLE locus on 4p named SLEB3.

A novel locus tentatively named Nba6 mapped to 28 cM on mouse Chromosome 13. Nba6 shows suggestive linkage to serum IgG anti-ssDNA antibodies with LOD=3.63 near D13Mit202. Animals homozygous for NZB-derived alleles at Nba6 exhibit increased autoantibody production. A previously identified arthritis QTL named Pgia15 maps near Nba6.

Previously identified QTL Swrl2 was detected and confirmed in this study. Swrl2 maps to mouse 30 cM on Chromosome 14 and shows suggestive linkage to serum IgG anti-ssDNA antibodies with LOD=2.91.

A previously identified QTL named Swrl3 on mouse Chromosome 18 was also confirmed in this study. Swrl3 maps to 13 cM and has an additive effect with SWR-derived alleles conferring increased IgG anti-dsDNA antibodies and anti-histone antibodies.

References

• Original: J:96060 Xie S, et al., Genetic origin of lupus in NZB/SWR hybrids: lessons from an intercross study. Arthritis Rheum. 2005 Feb;52(2):659-67
• All: 2 reference(s)