Idd4^NOR/LtJ
QTL Variant Detail

Summary

• QTL variant: Idd4^NOR/LtJ
• Name: insulin dependent diabetes susceptibility 4; NOR/LtJ
• MGI ID: MGI:3582442
• QTL: Idd4 Location: unknown Genetic Position: Chr11, cM position of peak correlated region/allele: 45.76 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: NOR/LtJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers resistance to cyclophosphamide-induced insulitis in female animals compared to NOD/Jsd. This allele also confers resistance to spontaneous development of insulin dependent diabetes compared to NOD/Jsd. (J:99002)
• Inheritance: Not Specified

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

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

J:73763

Using novel congenic lines NOD.B6-Idd4/ADel, NOD.B6-Idd4/BDel, and NOD.B6-Idd4/CDel, the Idd4 locus was localized to a 5.2 cM interval on mouse Chromosome 11 and may possibly be comprised of 2 separate subloci, which the authors designate Idd4.1 and Idd4.2. Congenic line NOD.B6-Idd4/ADel carries a segment of C57BL/6J-derived DNA from D11Nds1 to D11Mit325 introgressed onto the genetic background of the diabetes type 1 susceptible NOD strain. (The C57BL/6J donor strain is diabetes type 1-resistant.) Congenic lines NOD.B6-Idd4/BDel and NOD.B6-Idd4/CDel carry C57BL6/J-derived DNA segments at D11Mit38-D11Mit325 and D11Mit38, respectively, on an NOD background. All congenic lines exhibit protection from diabetes type 1 as seen by the dramatic delay in disease onset compared to the NOD background strain (22 weeks vs 12-15 weeks). Upon examination of the congenic lines, the interval centered around D11Nds1 (Idd4.1) appears to be associated with reduced numbers of islet infiltrating cells, whereas the interval centered around D11Mit38 and D11Mit325 (Idd4.2) appears to be associated with T-cell proliferative response and delayed onset of disease. Potential candidate genes mapping to these intervals are Pafah1b1, Nos2, Ccl2, Scya3, and Scya4.

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 on mouse 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 todiabetes susceptibility.

J:25969

Linkage analysis was performed on a BXD recombinant inbred (RI) panel, a (NOD x C57BL/6)F2 intercross, and on a (NOD x C57BL/6)F1 x NOD backcross population to map QTLs associated with T-cell proliferative repsonsiveness in relation to insulin dependent diabetes mellitus. Parental strain C57BL/6 exhibits high T-cell proliferation in response to stimulation of the T cell receptor/CD3 complex whereas parental strains DBA/2 and NOD exhibits low T-cell proliferative response.

In the BXD population a statistically significant locus mapped to 49 cM on mouse Chromosome 11 near Mpo (P=0.001-0.002). This region includes Ccl2, Ccl3, Ccl4, Xmv42, and Mpmv4. In the (NOD x C57BL/6)F1 x NOD backcross and the (NOD x C57BL/6)F2 intercross, statistical significance is associated with a locus near D11Mit38 at 49 cM on mouse Chromosome 11. This locus is thought to represent Idd4. Homozygosity for C57BL/6-derived alleles confers increased T-cell proliferation at this locus.

J:99002

Development of type 1 diabetes in NOD/Jsd mice can be accelerated with cyclophosphamide treatment, but not in NOR/LtJ diabetes resistant mice. This phenotype was mapped using linkage analysis of 66 (NOD/Jsd x NOR/LtJ)F1 x NOD/Jsd backcross animals. NOR/LtJ is a recombinant inbred strain derived from a NOD genetic background (88%) with C57BLKS/J donor regions over 10 different chromosomes. Some of these regions contain Idd susceptibility loci. NOD/Jsd is susceptible to spontaneous and cyclophosphamide-accelerated type 1 diabetes whereas NOR/LtJ is resistant.

Significant linkage to severe insulitis in cyclophosphamide-treated backcross animals mapped to 43 cM on mouse chromosome 11 near D11Mit219 (LOD=4.9) and to 60 cM on mouse Chromosome 4 near D4Mit338 (LOD=7.4). The chromosome 11 locus accounts for 30% of the variance and corresponds to previously identified diabetes QTL Idd4. The Idd4 1-LOD confidence interval spans a 7.8 cM interval on chromosome 11 between 37 cM - 44.8 cM. The chromosome 4 locus accounts for 43% of the variance and corresponds to previously identified diabetes QTL Idd9. The Idd9 1-LOD confidence interval spans a 12.4 cM interval on chromosome 4 between 53.6 cM -66 cM. All animals with progression to severe insulitis following cyclophosphamide treatment are homozygous for NOD/Jsd-derived alleles at both Idd4 and Idd9.

Analysis of reciprocal congenic strains derived from NOD/Jsd and NOR/LtJ confirmed the involvement of Idd4 and Idd9 in cylcophosphamide-accelerated insulitis. Furthermore, Idd4 was localized to a 6.9 cM interval between D11Mit30 (40 cM) and D11Mit33 (46.9 cM). NOR/LtJ-derived alleles at Idd4 confer protection from cyclophospamide-induced insulitis in female animals, but not in male animals. NOR/LtJ-derived alleles at Idd9 confer protection from cyclophosphamide-induced insulitis in both male and female animals. The NOR/LtJ allele at Idd4 also protects against spontaneous development of type 1 diabetes. The NOD/Jsd allele at Idd4 confers susceptibility to type 1 diabetes with a stronger effect observed in male animals.

Potential candidate genes mapping near the Idd4 interval are Nos2 (45.6 cM), Tnfaip1 (45.1 cM), Evi2a (46.1 cM), Tcf2 (44 cM), Cryba1 (44.7 cM), and the Scya cluster (47 cM). Previously identified QTLs Eae7 (48 cM) and Orch3 (44 cM) also map to this region.

Potential candidate genes for Idd9 include Csf3r (57.5 cM), Iapls1-19 (57.2 cM), sno (58.3 cM), and Lck (59 cM). Previously identified diabetes QTL Idd11 colocalizes with Idd9 at 65 cM on mouse Chromosome 4. Idd11 confers a protective effect against cyclophosphamide-accelerated type 1 diabetes, which corroborates with the findings from this study.

Animals doubly congenic for NOD/Jsd-derived alleles both Idd4 and Idd9 exhibit significantly greater susceptibility to cyclophosphamide-accelerated type 1 diabetes compared to NOR/LtJ controls, but less so than NOD/Jsd parentals. This finding suggested the presence of other protective loci in the NOR/LtJ background, possibly contributed by Idd5 (40 cM)onmouse Chromosome 1 or Idd13 (71 cM) on mouse Chromosome 2. Reciprocal congenic lines for Idd5 and Idd13 were derived from NOD/Jsd and NOR/LtJ to evaluate this hypothesis. NOD.NOR-Idd5 congenic animals exhibited protection from cyclophosphamide-accelerated type 1 diabetes whereas NOD.NOR-Idd13 congenics did not. However, the reciprocal congenic NOR.NOD-Idd5 did not exhibit increased susceptibility to type 1 diabetes after cyclophosphamide treatment, indicating that Idd5 only confers a protective effectwith the NOR/LtJ-derived allele. Ctla4 was previously identified as a potential candidate gene for Idd5 but since the resistant Idd5 congenic in this study carried NOD/Jsd-derived Ctla4 DNA its candidacy was excluded. Potential Idd5 candidate genes include Slc11a1 (formerly Nramp1, 39.2 cM), Chrng (52.3 cM), Col6a3 (53.9 cM), Hdlbp (55.3 cM), and Ramp1 (56 cM).

NOD/Jsd and NOR/LtJ share the same Idd1 alleles at 19.5 cM on mouse Chromosome 17. After cyclophosphamide treatment both strains show signs of insulitis, although it is mild in NOR/LtJ and severe in NOD/Jsd, progressing to diabetes after 18 days of continued treatment. Controls strains C57BL/6J and BALB/cJ do not exhibit any signs of insulitis after cyclophosphamide treatment. This finding suggests that NOD-derived alleles at Idd1 confer susceptibility to cyclophosphamide-induced insulitis.

References

• Original: J:99002 Ivakine EA, et al., Sex-specific effect of insulin-dependent diabetes 4 on regulation of diabetes pathogenesis in the nonobese diabetic mouse. J Immunol. 2005 Jun 1;174(11):7129-40
• All: 3 reference(s)