Idd6.2^C3H/HeJ
QTL Variant Detail

Summary

• QTL variant: Idd6.2^C3H/HeJ
• Name: insulin dependent diabetes susceptibility 6.2; C3H/HeJ
• MGI ID: MGI:3711830
• QTL: Idd6.2 Location: Chr6:143556651-146215056 bp Genetic Position: Chr6, cM position of peak correlated region/allele: 77.7 cM
• QTL Note: genome coordinates based on the boundaries of the QTL region

Variant origin

• Strain of Specimen: C3H/HeJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers diabetes resistance compared to NOD. (J:115021)

Notes

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

J:120148

Congenic line analysis was used to identify potential candidate genes for Idd6b at approximately 72 cM on mouse Chromosome 6. N.B-Idd6-15 is a congenic carrying C57BL/6-derived DNA from D6Mit200 (71.6 cM) to D6Mit304 (75 cM) on a NOD genetic background and excludes the Idd6b locus. A reverse congenic line, B6.NOD-Idd6, carrying NOD-derived DNA from D6Mit259 (67 cM) to D6Mit304 (75 cM) contains the Idd6b locus. Parental strain NOD is susceptible to type 1 diabetes compared to C57BL/6, with 89% of females and 42% of males affected by 40 weeks of age.

Expression analysis of twelve genes within the Idd6b QTL interval was performed using RT-PCR on thymocyte RNA. Lrmp (71 cM) expression is significantly decreased in NOD thymocytes compared to C57BL/6 thymocytes. Furthermore, Lrmp expression segregates with the Idd6b locus as congenic B6.NOD-Idd6 displays decreased Lrmp expression relative to C57BL/6 controls. Congenic N.B-Idd6-15, which does not carry the Idd6b locus, displays similar levels of Lrmp expression as NOD controls. The Idd6b locus also appears to affect Lrmp expression in bone marrow and spleen cells from NOD, C57BL/6, and B6.NOD-Idd6 animals. Authors conclude that Lrmp is a plausible candidate gene for Idd6b but does not exclude other genes in the QTL region.

J:115021

The Idd6 (insulin dependent diabetes 6) locus on mouse Chromosome 6 was resolved into 3 distinct QTLs named Idd6a, Idd6b, and Idd6c using subcongenic lines derived from NOD (diabetes susceptible background strain) and C3H/HeJ (diabetes resistant donor strain). Diabetes incidence was tested weekly over a period of 30 weeks. In all subcongenic lines, the incidence of diabetes was significantly decreased compared to NOD controls.

Idd6a maps to an interval between D6Mit373 (147.9 Mb) and the chromosome 6 telomere (149.8 Mb).

Idd6b maps to an interval between D6Mit113 (144.4 Mb) and D6Mit294 (147.2 Mb).

Idd6c was localized to a 700 kb interval between D6Mit15 (147.3 Mb) and D6Mit373 (147.9 Mb). Transfer of splenocytes derived from congenic mice carrying Idd6c into NOD/scid mice confers increased protection against diabetes. Arntl2 (146.7 Mb) is a potential candidate gene for Idd6c. Arntl2 expression in the spleen and thymus is significantly increased in NOD.C3 congenic mice compared to NOD controls. Furthermore, several SNP polymorphisms are found between NOD and C3H/HeJ Arntl2 sequences, and putative strain-specific splice isoforms were observed. The Idd6c locus is syntenic to human Chromosome 12p11-p12.2.

J:137837

C3H/HeJ alleles at Idd6 (insulin dependent diabetes susceptibility 6) on mouse Chromosome 6 confer protection against diabetes mellitus on a NOD genetic background as previously observed in the congenic line NOD.C3H-Idd6. In the current study authors observe a significant decrease in invariant natural killer (iNKT) cell frequency and numbers in spleen, liver and thymus of NOD.C3H-Idd6 congenics compared to NOD and C3H/HeJ parental strains. In NOD.C3H-Idd6 congenic animals, CD4+ iNTK cell numbers were at30%-50% of the levels seen in NOD animals, and at 20%-25% of the levels seen in C3H/HeJ animals. The pancreas of NOD.C3H-Idd6 congenic mice displayed reduced iNKT cell proportions compared to NOD mice. IL-4 and IFN-gamma secretion following induced cytokine production were also reduced in NOD.C3H-Idd6 animals compared to NOD mice.

Subcongenic lines were analyzed to localize the interval responsible for reduced iNKT cell frequency. Subcongenic lines NOD.C3H-Idd6a and NOD.C3H-Idd6c displayed similar iNKT cell frequencies compared to NOD inbred mice. However, NOD.C3H-Idd6b showed low iNKT cell number and low CD4+/double negative iNKT cell ratios similar to that observed in NOD.C3H-Idd6 congenic animals. Authors conclude the Idd6b locus [from approximately 70cM (D6Mit13) to 73.4 cM (D6Mit294)] influences diabetes resistance as well as iNKT cell population frequencies.

References

• Original: J:115021 Hung MS, et al., Identification of the transcription factor ARNTL2 as a candidate gene for the type 1 diabetes locus Idd6. Hum Mol Genet. 2006 Sep 15;15(18):2732-42
• All: 2 reference(s)