Idd16^NOD/ShiLt
QTL Variant Detail

Summary

• QTL variant: Idd16^NOD/ShiLt
• Name: insulin dependent diabetes susceptibility 16; NOD/ShiLt
• MGI ID: MGI:2683526
• QTL: Idd16 Location: unknown Genetic Position: Chr17, cM position of peak correlated region/allele: 17.98 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: NOD/ShiLt

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers susceptibility to type 1 diabetes mellitus compared to ALR/Lt. (J:86633)

Notes

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

J:86633

120 (NOD/Lt x ALR/Lt) x NOD/Lt backcross animals were genotyped at 88 loci with an average resolution of 20 cM to identify QTLs associated with reactive oxygen species-induced diabetes via pancreatic islet cell damage. Parental strain NOD/Lt is susceptible to free radical-induced diabetes whereas parental strain ALR/Lt is resistant to free radical-induced diabetes.

Idd16 on mouse Chromosome 17 was detected in this study with LOD=4.1 near D17Mit16. Idd16 maps at 17.4 cM near the H2 locus. The QTL interval of Idd16 spans 16 cM to 20 cM. This locus appears to interact with another locus on mouse Chromosome 8 named Idd21.

A novel locus named Idd21 mapped to 41 cM on mouse Chromosome 8 with LOD=4.4 at D8Mit80. The QTL interval of Idd21 spans 36 cM to 55 cM.ALR/Lt-derived alleles confer dominantly inherited resistance to diabetes at Idd21. Idd21 appears to interact with Idd16. Animals homozygous for NOD/Lt-derived alleles at both Idd16 and Idd21 exhibit significantly increased diabetes incidence.

A suggestive locus mapped to 33 cM on mouse Chromosome 3 with LOD=2.4 at D3Mit241. This locus spans 20 cM to 50 cM and overlaps with a previously mapped QTL named Susp (suppressor of superoxide production). ALR/Lt-derived alleles confer resistance to diabetes at this locus.

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.

J:75405

Tnf is considered a candidate gene for the diabetes susceptibility QTL Idd16 at 18 cM on mouse Chromosome 17. Sequence analysis of the Tnf coding region did not reveal difference between diabetes susceptible strain NOD and diabetes resistant strain CTS, however, analysis of the 5' upstream regulatory region revealed a SNP at nucleotide 3408. Resistant strain CTS carries an A allele at nucleotide 3408 whereas susceptible strain NOD carries a C allele. This nucleotide change results in a new GATA family binding site in the CTS transcript, which may explain the phenotypic difference between CTS and NOD.

J:94603

Three loci showing linkage to type I diabetes on mouse Chromosome 17 were mapped using several subcongenic lines. The congenic lines were constructed using C57BL/6J donor derived regions introgressed onto a NOD genetic background. The diabetes loci are separate and distinct from the H2 locus.

Idd16 maps between D17Mit100 (11.75 cM) and D17Mit101 (16.4 cM). C57BL/6J-derived alleles confer resistance to type I diabetes with dominant inheritance at this locus. The Idd16 region is estimated to be 3.1 Mb in length. Potential candidate genes mapping near Idd16 are Mapk13 and Mapk14. A region of human Chromosome 6 (D6S291) syntenic to the mouse Idd16 region shows linkage to type I diabetes in a Scandinavian population.

Idd23 maps to a region between D17Mit164 (4.1 cM) and D17Mit100 (11.75 cM). This locus may be up to 20 Mb in length. C57BL/6J-derived alleles appear to confer a recessive protective effect at Idd23.

The third locus, provisionally designated Idd24, maps to an interval between Lta (19 cM) and D17Mit105 (21.95 cM). Authors state that follow up and confirmation of Idd24 should be performed.

J:77545

Idd16 (18 cM) on mouse Chromosome 17 was determined to be separate and distinct from the H2 locus (23 cM) using recombinant congenic strains. A recombinant congenic strain carrying C57BL/6J-derived DNA from D17Mit199 (16.9 cM) to D17Mit16 (17.4 cM), which excludes the H2 locus, on an NOD diabetes susceptible background is resistant to diabetes. Therefore, the Idd16 locus maps proximal to and does not include H2.

Genome scan was used to identify QTLs for thyroiditis. A population of 183 (NOD-H2^k x CBA/J)F2 animals were typed for 81 polymorphic loci. Chronic experimental autoimmune thyroiditis was induced in 6- and 8-weeks old animals. Animals were sacrificed and thyroids were examined for the presence of mononuclear cell infiltrates in clusters or foci. A significant locus named Ceat1 (chronic experimental autoimmune thyroiditis 1) was identified at 11 cM on mouse Chromosome 17 near D17Mit114 and is linked to both cluster and foci phenotypes. This locus spans an 8 cM region between D17Mit114 and D17Mit100 and shows overlap with Idd16. NOD-derived alleles appear to confer dominant susceptibility to thyroiditis at Ceat1.

Suggestive linkage to thyroiditis mapped to 9 cM on mouse Chromosome 5 near D5Mit72 (P=0.015) and to 5.5 cM on mouse Chromosome 7 near D7Mit20 (P=0.005). The D5Mit72 locus shows linkage to the cluster phenotype with recessive inheritance, and the D7Mit20 locus shows linkage to the foci phenotype with a dominant mode of inheritance.

References

• Original: J:86633 Mathews CE, et al., Genetic analysis of resistance to Type-1 Diabetes in ALR/Lt mice, a NOD-related strain with defenses against autoimmune-mediated diabetogenic stress. Immunogenetics. 2003 Oct;55(7):491-6
• All: 1 reference(s)