T2dm2^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: T2dm2^C57BL/6J
• Name: type 2 diabetes mellitus 2; C57BL/6J
• MGI ID: MGI:2429604
• QTL: T2dm2 Location: Chr19:55376050-55376167 bp Genetic Position: Chr19, cM position of peak correlated region/allele: 50.72 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers decreased fasting plasma insulin compared to BTBR. (J:109581)
• Inheritance: Recessive

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

This allele shows suggetive linkage to increased glucose levels.

Significant interaction was detected between T2dm1 and T2dm2. Animals homozygous for BTBR-derived alleles at T2dm1 and homozygous for C57BL/6J-derived alleles at T2dm2 exhibit the highest fasting glucose levels.

Candidate Genes

J:99477

Authors used novel data mining tool ExQuest to identify novel candidate genes for existing diabesity QTLs. Next, candidate gene expression in the liver, adipose, and pancreas of diabesity-prone Tally Ho mice and diabesity-resistant C57BL/6J mice was assessed by quantitative PCR analysis. Several potential candidate genes, some with no previous association to diabesity QTLs, were identified. Since QTL intervals may be large and could contain hundreds or thousands of potential candidate genes, this method allows researchers to focus on those with strong potential as well as identify novel candidate genes.

Potential candidate genes for Iba4 (20 cM) on mouse Chromosome 19 as identified by ExQuest are Aldh1a1 (12 cM), Aldh1a7, Vldlr (20 cM), and Plce1. Vldlr exhibits 15.6-fold increased expression in the liver of Tally Ho compared to C57BL/6 animals. For QTL Afw8 (26 cM), potential candidate genes Pi4k2a, Cpn1, and Elovl3 (47 cM) were identified. For QTLs Nobq2 (47 cM) and Bglq13 (51 cM), potential candidate genes Ins1 (49 cM), Gpam (52 cM), and Acsl5 were identified. For QTLs Tanidd1 (50 cM) and T2dm2 (53 cM), potential candidate genes Gfra1, Pnlip (29 cM), Pnliprp1 (29 cM), and Pnliprp2 were identified. Pnliprp2 exhibits 21.8-fold decreased expression in the pancreas of Tally Ho animals in response to a 4% fat diet.

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

J:65486

A Genome wide scan was performed on 160 (BTBR x C57BL/6J) F2-ob/ob intercross animals, using 99 informative markers at an average spacing of 16 cM, to identify loci affecting diabetes in obese animals. Neither parental strain BTBR nor C57BL/6J exhibit diabetes or obesity phenotypes, but lean male (BTBR x C57BL/6J) F1 hybrid animals develop severe hyperglycemia indicating the existence of diabetes susceptibility alleles in BTBR and C57BL/6J genetic backgrounds. Initial mapping indicate that mouse Chromosomes 2, 16 and 19 were involved in diabetic phenotypes. LOD values derived from multitrait composite interval mapping were used to further refine the map locations.

A locus associated with 8- and 10-week glucose and insulin levels, T2dm1 (type 2 diabetes mellitus 1), mapped to mouse Chromosome 16 with a LOD > 4.0 at D16Mit12. BTBR-derived alleles are dominant to C57BL/6J-derived alleles at T2dm1. T2dm2, a locus associated with 10-week insulin levels, mapped to mouse Chromosome 19 with a LOD >7.5 atD19Mit35. BTBR-derived alleles increase insulin levels by 38% in a dominant fashion at T2dm2. T2dm2 is also suggestively associated with glucose levels (LOD = 3.79, with C57BL/6J-derived alleles increasing glucose levels). T2dm3 mapped to mouse Chromosome 2 with a peak LOD score of >6.5 between D2Mit274 and D2Mit106 in association with insulin levels. T2dm3 appears to exhibit additive inheritance and maps near the agouti (a) and mahogany (Atrn, previously mg) genes. A suggestive locus for 8-week glucoselevels mapped to mouse Chromosome 4 (LOD = 3) and a suggestive locus for 8- and 10-week insulin levels mapped to distal mouse Chromosome 5 (LOD = 3.2 and 2.7, respectively).

References

• Original: J:65486 Stoehr JP, et al., Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci. Diabetes. 2000 Nov;49(11):1946-54
• All: 2 reference(s)