Summary |
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Variant origin |
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Variant description |
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Phenotypes |
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View phenotypes and curated references for all genotypes (concatenated display).
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Notes |
Idd10 and Idd17 interact to promote disease resistance. Homozygosity for C57BL/10SnJ-derived alleles at both Idd10 and Idd17 confers significantly increased resistance to type 1 diabetes.
Candidate Genes
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).
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. Mapping and Phenotype information for this QTL, its variants and associated markersJ:13557123 polymorphic markers were screened in a backcross population of NOD/Lt x (B10.NOD-H2g7 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-H2g7 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:97940Examination 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. |
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References |
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Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 08/02/2024 MGI 6.24 |
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