Idd7^NOD/ShiLt
QTL Variant Detail

Summary

• QTL variant: Idd7^NOD/ShiLt
• Name: insulin dependent diabetes susceptibility 7; NOD/ShiLt
• MGI ID: MGI:3036765
• QTL: Idd7 Location: unknown Genetic Position: Chr7, Syntenic

Variant origin

• Strain of Specimen: NOD/ShiLt

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers resistance to insulin dependent diabetes compared to C57BL/10 and NON/Lt. This allele confer inhibition of intrathymic deletion of CD4+CD8+ AI4-expressing T-cells compared to C57BL/6. (J:28947, J:131557)
• Inheritance: Not Specified

Notes

Homozygosity for NOD/Lt-derived alleles confers type 1 diabetes resistance.

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

J:13557

123 polymorphic markers were screened in a backcross population of NOD/Lt x (B10.NOD-H2^g7 x NOD/Lt)F1 animals to identify QTLs associated with susceptibility to insulin dependent (type 1) diabetes. 106 diabetic backcross animals and 190 non-diabetic backcross animals were used in this study. Parental strain NOD/Lt spontaneously develops type 1 diabetes whereas parental strain B10.NOD-H2^g7 is resistant.

Three novel diabetes susceptibility QTLs were identified. Idd7 mapped to 4.5 cM on mouse Chromosome 7 near D7Nds6, Idd8 mapped to 2.5 cM on mouse Chromosome 14 near D14Nds1, and Idd10 mapped to 45 cM on mouse chromosome 3 near D3Nds7, D3Nds11, and D3Nds8. Idd7 and Idd8 are associated with insulitis and diabetes susceptibility. Homozygosity for NOD/Lt-derived alleles confers resistance to diabetes at Idd7 and Idd8 indicating a dominant susceptible effect of the C57BL/10-derived allele. Idd10 also shows linkage to insulitis and diabetes susceptibility.

Several previously identified QTLs were detected in this study:

Idd3 mapped to 28 cM on mouse Chromosome 3 near D3Nds1 in linkage to diabetes susceptibility and insulitis. Sequence analysis of candidate gene Il2 revealed several amino acid difference between NOD/Lt and C57BL/10.

Idd4 mapped to 43.8 cM onmouse Chromosome 11 near D11Nds1 in linkage to diabetes susceptibility.

Idd5 mapped to 19.5 cM on mouse Chromosome 1 near D1Nds6 in linkage to diabetes susceptibility and insulitis.

Idd6 mapped to 71.2 cM on mouse Chromosome 6 near D6Mit14 in linkage to diabetes susceptibility.

J:131557

Linkage analysis was performed to identify non-MHC genetic loci involved in the deletion of autoreactive CD8+ T-cells. NOD/ShiLtDvs mice carrying the H2^g7 allele display loss of ability to select against autoreactive CD8+ T-cells, which contributes to development of type 1 diabetes mellitus. C57BL/6J animals congenic for a NOD-derived portion of chromosome 17 (D17Mit21-D17Mit10) containing H2^g7 do not display this phenotype.

A population of 295 (NOD/ShiLtDvs x B6.NOD-H2^g7)F2 animals transgenic for T-cell receptor (TCR) genes Tg(TcraAI4)1Dvs and Tg(TcrbAI4)1Dvs were created. Animals were phenotyped at 5- to 6-weeks of age for the number of CD4+CD8+ T-cells co-expressing AI4 TCR transgenes. The highest and lowest expressing CD4+CD8+ F2 animals wereselected for initial genotyping of 132 SNP markers spaced ~20 cM apart.

Highly significant linkage to loss of deletion of AI4 TCR-expressing T-cells mapped to 15 cM (30.2 Mb) on mouse Chromosome 7 (LOD=8.06). The QTL interval spans approximately 6 cM -23 cM (21.2 Mb - 43.3 Mb). This locus explains 10.47% of the variance and co-localizes with the previously identified diabetes susceptibility locus Idd7 (4 cM). NOD/ShiLtDvs-derived alleles at Idd7 confer decreased intrathymic AI4 T-cell selection.

Theassociation of Idd7 with inhibition of AI4 TCR-expression T-cell deletion was confirmed in a AI4 transgene-expressing congenic line carrying C57BL/6J-derived chromosome 17 DNA from Gpi (11 cM; 33.9 Mb) to D7Mit346 (34 cM; 58.6 Mb) encompassing the Idd7 region on a NOD genetic background. The NOD.B6-(Gpi-D7Mit346) Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs animals congenic displays significantly higher double-positive thymocyte numbers compared to NOD/ShiLtDvs- Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs animals and B6.NOD-H2^g7 Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs animals, indicating the C57BL/6J-derived allele of Idd7 promotes normal deletion of autoreactive T-cells. The Idd7 locus also appears to regulate expression of the Tg(TcraAI4)1Dvs transgene as AI4 TCR alpha-chain expression is significantly decreased in NOD-Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs animals compared to NOD.B6-(Gpi-D7Mit346) Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs and B6.NOD-H2^g7 Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs animals.

Suggestive loci associated with inhibition of CD4+CD8+ T-cell deletion mapped to 77.5 cM (148.7 Mb) on chromosome 4 (LOD=1.55), 39 cM (85.4 Mb) on chromosome 12 (LOD=2.77), 36 cM (60 Mb) on chromosome 13 (LOD=2.14), and 38 cM (67 Mb) on chromosome 17 (LOD=1.38). The chromosome 4 locus overlaps with previously identified diabetes susceptibility QTLs Idd9 and Idd11, while the chromosome 13 locus overlaps with Idd14.

References

• Original: J:28947 Mcaleer MA, et al., Crosses of NOD mice with the related NON strain: A polygenic model for IDDM. Diabetes. 1995 OCT;44(10):1186-1195
• All: 3 reference(s)