Agnm3^C3H/HeJ
QTL Variant Detail

Summary

• QTL variant: Agnm3^C3H/HeJ
• Name: autoimmune glomerulonephritis in MRL 3; C3H/HeJ
• MGI ID: MGI:3582425
• QTL: Agnm3 Location: unknown Genetic Position: Chr5, Syntenic

Variant origin

• Strain of Specimen: C3H/HeJ

Variant description

• Allele Type: QTL
• Inheritance: Other (see notes)

Notes

Agnm3 exhibits additive inheritance.

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

J:97786

Linkage analysis was performed on 527 animals from a (MRL/MpJ-Fas^lpr x C3H/HeJ-Fas^lpr)F2 intercross to identify loci associated with susceptibility to systemic lupus erythrematosus (SLE). 106 polymorphic microsatellite markers at an average spacing of 12 cM were used for the genome scan. Glomerulonephritis incidence was used to measure SLE susceptibility. Parental strain MRL/MpJ-Fas^lpr is susceptible to SLE (68.2% incidence) whereas parental strain C3H/HeJ-Fas^lpr is resistant (5.1% incidence). F1hybrids and F2 intercross animals exhibit intermediate SLE resistance with 24% and 28.8% disease incidence, respectively.

Significant linkage to SLE susceptibility mapped to 2 different loci on mouse Chromosome 4. The first QTL, named Agnm1 (autoimmuneglomerulonephritis in MRL 1), is located between D4Mit89 (19.8 cM) and D4Mit241 (24.1 cM). MRL/MpJ-derived alleles at Agnm1 confer recessive susceptibility to SLE, or increased glomerulonephritis, with LOD=8.2. The second QTL, named Agnm2 (autoimmune glomerulonephritis in MRL 2), is located between D4Mit187 (49 cM) and D4Mit147 (57.6 cM). MRL/MpJ-derived alleles at Agnm2 confer additive susceptibility to SLE, or increased glomerulonephritis, with LOD=5.5. These loci colocalize with previously identified QTLs Arvm1 (19.8 cM) and Arvm2 (58 cM) and are suspected to harbor the same underlying genes.

Significant linkage to SLE susceptibility mapped to 56 cM on mouse Chromosome 5 near D5Mit115 (LOD=4.0). This locus is named Agnm3 (autoimmune glomerulonephritis in MRL 3) and was confirmed by composite interval mapping. MRL/MpJ-derived alleles at Agnm3 confer additive susceptibility to SLE (as measured by increased glomerulonephritis). The Agnm3 interval spans approximately 54 cM - 65 cM on chromosome 5. Previously identified loci mapping near Agnm3 are Lprm4 (54 cM) and Tsz1 (56 cM). A range between D5Mit23 and D5Mit136 can be outlined for Agnm3.

The marker of peak linkage, D5Mit115, is located in the promoter of Spp1 (formerly Opn), a possible candidate gene. Analysis of the Spp1 promoter region showed a 12 bp insertion as well as a deletion SNP in C3H/HeJ. The MRL/MpJ allele of D5Mit115 is shared among inbred strains C57BL/6J-Fas^lpr, NZW, and NZW. The C3H/HeJ allele of D5Mit115 is shared with the BXSB strain. Previous analysis of the Spp1 sequence revealed 10 amino acid differences between MRL/MpJ and C3H/HeJ. Functional analysis of MRL/MpJ-derived Spp1 protein and C3H/HeJ-derived Spp1 protein was carried out using a cell-free protein synthesis system. The MRL/MpJ-derived Spp1 protein exhibits significantly increased induction of Tnfa and Il1b in bone marrow derived macrophages, significantly increased induction of Ifng in splenocytes, and significantly higher IgG3, IgG2, and IgM secretion from splenocytes compared to the C3H/HeJ-derived Spp1 protein.

References

• Original: J:97786 Miyazaki T, et al., Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice. Eur J Immunol. 2005 May;35(5):1510-20
• All: 1 reference(s)