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Nba2NZB
QTL Variant Detail
Nomenclature
QTL variant: Nba2NZB
Name: New Zealand Black autoimmunity 2; NZB
MGI ID: MGI:3529870
QTL: Nba2  Location: unknown  Genetic Position: Chr1, Syntenic
Variant
origin
Strain of Specimen:  NZB
Variant
description
Allele Type:    QTL
Mutation:    Undefined
    This allele confers increased susceptibility to autoimmunity compared to C57BL/6. (J:95829)
Inheritance:    Not Specified
Phenotypes
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View phenotypes for all genotypes (concatenated display).
Notes
This allele shows linkage to increased anti-chromatin and anti-DNA antibodies, increased serum gp70 immune complex levels, and severe glomerulonephritis.

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

(J:40638)
Authors localized the Nba2 quantitative trait locus (QTL) associated with lupus nephritis and the production of multiple autoantibody specificities implicated in the pathogenesis of the disorder. This locus was mapped to mouse Chromosome 1, near D1Mit148 and D1Mit111 (region estimated at 92 to 97 cM) using 82 (NZB x SM/J)F1 x NZW and 133 (B6.H2 x NZB)F1 x NZB backcross mice.

(J:46190)
Authors confirmed the linkage of Nba2 quantitative trait locus (QTL) on mouse Chromosome 1 with multiple IgG autoantibody levels associated with lupus nephritis in (B6.E x NZB)F1 x NZB backcross mice.

(J:63674)
Linkage analysis was performed on 152 female (B6.H2 x NZB/BlNJ)F1 x NZB/BlNJ backcross animals and 163 female (NZB/BlNJ x C57BL/6J)F2 intercross animals to identify QTLs linked to elevated serum gp70 (which is associated with the development of gp70 immune complexes and nephritis). 90 microsatellite markers were used in the genome scan. Parental strain NZB/BlNJ is susceptible to autoimmune nephritis compared to parental strain C57BL/6J.

In both the backcross and intercross populations two significant loci, Elsgp1 (elevated serum gp70 1) and Elsgp2, mapped to 66.6 cM on mouse Chromosome 4 (LOD=11.2 at D4Mit170) and to 40 cM on mouse Chromosome 13 (LOD=11 at D13Mit98), respectively. Elsgp2 maps near a previously identified QTL on chromosome 13 named Yaa1 (35 cM) that is also associated with serum gp70 levels. A third locus, Elsgp3, mapped to 49.6 cM on mouse Chromosome 2 (LOD=4.9 at D2Mit14). NZB/BlNJ-derived alleles confer elevated serum gp70 at all 3 loci with additive inheritance. Animals homozygous for NZB/BlNJ-derived alleles at both Elsgp1 and Elsgp2 exhibit the highest levels of serum gp70. Elsgp1, Elsgp2, and Elsgp3 together account for 83% of the phenotypic variance in F2 mice. These loci, however, do not show linkage to gp70 immune complex levels.

In the backcross population a previously identified QTL on distal mouse Chromosome 1 named Nba2 was detected in linkage to autoantibody production and nephritis, but not to serum gp70 levels. Nba2 did not show linkage in the F2 population.

(J:95829)
Linkage analysis was performed on 154 male animals from a C57BL/6 x (NZB x C57BL/6-Yaa)F1 backcross to map QTLs associated with autoimmune traits, such as anti-DNA and anti-chromatin antibody production. Parental strain C57BL/6 does not develop spontaneous autoimmune traits whereas the parental hybrid (NZB x C57BL/6-Yaa)F1 develops lupus-like nephritis and increased serum IgG anti-DNA antibodies and gp70-anti-gp70 immune complex. 95 microsatellite markers were used for the genome scan.

An interval from90 cM - 98 cM on mouse Chromosome 1 named Nba2 showed linkage to anti-DNA (LOD=7.08) and anti-chromatin antibodies (LOD=13.24). Peak linkage occurred near Fcgr2b (92.3 cM). The NZB-derived allele confers susceptibility to autoimmunity at this locus. Nba2also shows linkage to gp70 immune complex levels (LOD=7.28). Markers D1Mit36 and Fcgr2b in the Nba2 region also show linkage to glomerulonephritis. Animals heterozygous at Nba2 exhibit more severe glomerulonephritis than C57BL/6 homozygous animals. Male congenic animals carrying an NZB-derived Nba2 locus (from D1Mit47 - D1Mit461) on a C57BL/6-Yaa genetic background exhibit increased anti-DNA, anti-chromatin antibodies, and gp70 immune complex levels and severe glomerulonephritis (50% mortality rate at 14months of age) compared to control male C57BL/6-Yaa animals. Potential candidate genes for Nba2 are Fcgr2b (92.3 cM) and Ifi202a (95.3 cM).

The H2 locus at 23 cM on mouse Chromosome 17 showed linkage to anti-DNA (LOD=10.55) and anti-chromatin antibodies(3.02). The C57BL/6-derived allele confers susceptibility to autoimmunity at this locus. This locus is also linked to serum gp70 immune complex levels (LOD=8.9).

A locus on mouse Chromosome 13 named Sgp3 showed linkage to serum gp70 production with peak linkage occurring near D13Mit193 (43 cM; LOD=8.77). Sgp3 is also strongly linked to gp70 immune complex levels (LOD=8.27). Markers D13Mit250 and D13Mit122 in the Sgp3 region also show linkage to glomerulonephritis. Animals heterozygous at Sgp3 exhibit more severe glomerulonephritis than C57BL/6 homozygous animals. Male congenic animals carrying an NZB-derived Sgp3 locus (from D13Mit250 - D13Mit73) on a C57BL/6-Yaa genetic background exhibit increased serum gp70 levels compared to control male C57BL/6-Yaa animals. A potential candidate gene for Sgp3 is Gv1 at 36 cM.

A novel locus showing association to gp70 immune complex levels named Nba5 mapped to 23 cM on mouse Chromosome 7 near D7Nds5 (LOD=4.65). Male congenic animals carrying an NZB-derived Nba5 locus (from D7Mit154 - D7Mit194) on a C57BL/6-Yaa genetic background exhibit increased serum gp70 immune complex levels. Congenic males also show some increase in severe glomerulonephritis (1/3 mortality rate at 14 months of age) compared to control male C57BL/6-Yaa animals.

(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 tentatively 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.

Suggestive linkage to glomerulonephritis susceptibility mapped to 36 cM mouse Chromosome 14 near D14Mit37 (LOD=2.48). This locus is tentatively 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 tentatively designated Swrl3 (SWR lupus locus 3). SWR-derived alleles confer increased ANA production with a dominant mode of inheritance.Potential candidate genes for Swrl3 are Fgf17 (38 cM), Dok2 (39 cM), and Nkx3-1 (30 cM).

(J:134128)
The effect of Tnfsf13b over-expression on accelerating systemic lupus erythematosus phenotypes was studied in C57BL/6-derived strains carrying SLE-susceptibility loci. The Tg(Tnfsf13b)1Fma transgene (BAFF-Tg) was cross onto C57BL/6-Sle1 and C57BL/6-Nba2 genetic backgrounds. Transgenic and control animals were phenotyped for splenic B- and T-cell populations, serum immunoglobulins, proteinuria and renal pathology. Sle1 and Nba2 are previously identified SLE susceptibility loci mapping to mouse Chromosome 1 at 103 cM and 95 cM, respectively. C57BL/6-Sle1 and C57BL/6-Nba2 animals produce IgG antichromatin antibodies by 8-9 months of age and display mild glomerulonephritis.

Presence of the Tg(Tnfsf13b)1Fma transgene increases populationsof splenic CD3+, CD4+, CD8+, total B cells and marginal zone B cells in C57BL/6-Sle1 Tg(Tnfsf13b)1Fma, C57BL/6-Nba2 Tg(Tnfsf13b)1Fma, and C57BL/6-Tg(Tnfsf13b)1Fma animals compared to non-transgenic animals. The transgene also increases numbers of splenic IgG-secreting cells, serum total IgM andserum total IgG in C57BL/6-Sle1 Tg(Tnfsf13b)1Fma, C57BL/6-Nba2 Tg(Tnfsf13b)1Fma and C57BL/6-Tg(Tnfsf13b)1Fma animals compared to non-transgenic animals.

Presence of the Tg(Tnfsf13b)1Fma transgene appears to accelerate development of glomerulonephritis in SLE susceptible animals, but did not result in proteinuria. Approximately 33% of transgenic C57BL/6-Sle1 Tg(Tnfsf13b)1Fma and C57BL/6-Nba2 Tg(Tnfsf13b)1Fma animals display class III/IV glomerulonephritis by 3 months of age. In contrast, non-susceptible animals C57BL/6 and C57BL/6-Tg(Tnfsf13b)1Fma do not display renal histological changes at 3 months.

A positive correlation was observed between serum Tnfsf13b expression and glomerulonephritis severity in transgenic C57BL/6-Sle1 Tg(Tnfsf13b)1Fma mice, but not in transgenic C57BL/6-Nba2 Tg(Tnfsf13b)1Fma mice.

The level of serum IgG anti-dsDNA Abs, but not serum IgG anti-chromatin Abs, is correlated with glomerulonephritis severity in C57BL/6-Nba2 and transgenic C57BL/6-Nba2 Tg(Tnfsf13b)1Fma animals.

Authors hypothesize that over-expression of Tnfsf13b alone may not be sufficient to initiate onset of SLE disease, but may amplify latent SLE susceptibility. In addition, IgG anti-chromatin and anti-dsDNA Abs, while pathogenic in other systems, may not be involved in the pathway to glomerulonephritis in these animals.

References
Original:  J:95829 Kikuchi S, et al., Differential role of three major New Zealand black-derived loci linked with Yaa-induced murine lupus nephritis. J Immunol. 2005 Jan 15;174(2):1111-7
All:  7 reference(s)

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last database update
04/08/2014
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