Idd10^NOD/ShiLt
QTL Variant Detail

Summary

• QTL variant: Idd10^NOD/ShiLt
• Name: insulin dependent diabetes susceptibility 10; NOD/ShiLt
• MGI ID: MGI:3036798
• QTL: Idd10 Location: unknown Genetic Position: Chr3, Syntenic

Variant origin

• Strain of Specimen: NOD/ShiLt

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele, in conjunction with NOD-derived alleles at Idd3 on a C57BL/6 background, confers defective cytokine response (IL-2, IL-4, IFN-gamma, CSF-2) when stimulated with antigens.
• Inheritance: Not Specified

Notes

Candidate Genes

J:83540

The authors narrow the critical region containing Idd10 to a genomic area bounded proximally by 70A7SSR18 and distally by D3Mit342. Within that region a likely candidate for the Idd10 phenotype is Igsf2(Cd101).

J:86885

Congenic animals were created to observe the effect of diabetes QTL Idd1 on mouse Chromosome 17. The congenic NOD.CTS-H2 carries CTS-derived DNA at the H2 locus, which is part of Idd1, on an NOD diabetes-susceptible genetic background. Parental strain CTS is diabetes resistant but shares the same H2 alleles as NOD. Interestingly the NOD.CTS-H2 congenic is susceptible to diabetes but with lower incidence compared to NOD. Authors state that the H2 locus is responsible for the diabetes susceptible effect ofIdd1 but does not explain it entirely. A closely linked but distinct QTL, Idd16 at 18 cM, may also contribute to the NOD susceptible phenotype. A candidate gene for Idd16 is Tnf (19.06 cM). Haplotype analysis was performed to assess the candidacy of Tnf.The non-diabetic inbred strain NON shares the same Tnf alleles as the diabetic strain NOD. The congenic NON.NOD-H2 carryies NON-derived DNA around the H2 locus (including Tnf) on a NOD genetic background and is diabetes susceptible. This data supports the candidacy of Tnf for Idd16.

To study the Idd3 candidate gene, Il2 (19.2 cM on mouse Chromosome 3), a congenic line was constructed. NOD.IIS-Il2 carries ISS-derived DNA at Il2 on an NOD diabetes susceptible background. Parental strain ISS is resistant to diabetes but shares alleles with NOD at Il2. The congenic is phenotypically indistinguishable from the NOD parental indicating that the NOD alleles at Il2 exert an effect on diabetes susceptibility. Another candidate gene for Idd3 is Il21. Il21 is closelylinked to and forms a haplotype with Il2, making Il21 a strong candidate for Idd3.

Idd10 maps to 48.5 cM on mouse Chromosome 3. Fcgr1 (45.2 cM) has been identified as a possible candidate gene for Idd10. Sequence analysis revealed 17 amino acid differences between NOD and C57BL/10 in addition to deletion of 75% of the cytoplasmic tail. A congenic line carrying diabetes resistant ISS-derived DNA at Idd10 on an NOD diabetes susceptible background was constructed. However, the NOD.IIS-Idd10 congenic is notsusceptible to diabetes, therefore excluding Fcgr1 from the candidate gene list. Further analysis of the Idd10 locus revealed 3 multiply linked loci: Idd10, Idd17, and Idd18.

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 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:97940

Examination of the NOD-related strains revealed a naturally occurring recombination of the Idd10 (48.5 cM) locus on mouse Chromosome 3 in IIS/Shi. The Fcgr1 sequence at 45.2 cM in inbred strain IIS/Shi is derived from NOD/Shi while the flanking regions are derived from IIS/Shi. Fcgr1 has been proposed as a candidate gene for Idd10 as the NOD allele of Fcgr1 is missing 75% of the cytoplasmic domain and results in a defective gene product. Igsf3 (formerly Cd101) at 48.5 cM is another Idd10 candidate gene located outside the NOD/Shi-derived region.

A congenic line named NOD.IIS-Idd10 was constructed by introgressing a 35 cM IIS/Shi-derived donor region between D3Mit231 (38.3 cM) and D3Mit292 (73.9 cM) onto the NOD/Shi genetic background. (Note that the Fcgr1 sequence in the congenic is derived from NOD/Shi while the Igsf3 sequence is derived from IIS/Shi.) The NOD.IIS-Idd10 congenic exhibits resistance to type 1 diabetes compared to susceptible background strain NOD/Shi. The IIS/Shi-derived Idd10 congenicregion confers dominantly-inherited diabetes resistance. Since the congenic Fcgr1 sequence is derived from NOD/Shi this gene does not appear to have an effect on diabetes and was excluded as a candidate. The Idd10 locus on mouse Chromosome 3 is possibly divided into 3 different components: Idd10 (48.5 cM), Idd17 (39 cM), and Idd18 (53.3 cM). The NOD.IIS-Idd10 congenic contains all 3 loci.

Sequence analysis revealed that the IIS/Shi sequence of Igsf3 is identical to that of C57BL/6J, another diabetes-resistant strain. The Igsf3 sequence differed between IIS/Shi and NOD/Shi at 17 SNPs, 10 of which result in amino acid substitutions. Igsf3 remains an attractive candidate gene for Idd10.

References

• Original: J:13557 Ghosh S, et al., Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nat Genet. 1993 Aug;4(4):404-9
• All: 5 reference(s)