Nidd4n^NSY
QTL Variant Detail

Summary

• QTL variant: Nidd4n^NSY
• Name: non-insulin-dependent diabetes mellitus 4 in NSY; NSY
• MGI ID: MGI:3036077
• QTL: Nidd4n Location: unknown Genetic Position: Chr11, cM position of peak correlated region/allele: 9.41 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: NSY

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers impaired glucose tolerance compared to C3H/HeCrj. (J:55284)
• Inheritance: Other (see notes)

Notes

This allele is consistent with an additive or recessive mode of inheritance.

Candidate Genes

J:91835

The correlation between gene expression and dietary interaction was examined in a population of (BALB/cStCrlfC3H/Nctr x VY/WffC3Hf/Nctr-A(vy)/a)F1 animals. A/a and A/A^vy animals were placed on a 70% (calorie restricted) or 100% (non-restricted) diet andliver mRNA levels were assessed for over 18,000 genes using DNA microarrays. Twenty-eight known genes showing statistically significant differential expression between the 70% and 100% calorie diets and A/a and A/A^vy genotypes mapped near known diabesity QTLs. These genes may be considered further for candidate genes.

On mouse Chromosome 11, candidate genes for diabesity QTL Nidd4n (2 cM) are Dbn1 (34 cM- **Note: Location of Dbn1 is 34 cM on mouse Chromosome 13 according to mapping data in the MGI database**) and Dvl2 (36.5 cM). Both Dbn1 and Dvl2 show differential expression on the restricted and unrestricted diets on the A/A^vy background.

Candidate genes for diabesity QTLs Nidd1n (31 cM), Bwtq5 (27.8 cM), Wt10q3 (32 cM), Wt6q3 (36 cM) are Nola2 (28.5 cM, formerly Nhp2), Sept8 (28.75 cM), Skp1a (31 cM), and Mpdu1 (39 cM). Skp1a and Nola2 both show differential expression between restricted and unrestricted diets on the A/A^vy background. Sept8 shows differential expression between A/a and A/A^vy animals on the restricted diet.

Candidate genes for diabesity QTLs Wg4 (46 cM) and Bw4 (55 cM) are Dusp14 (48 cM), Spag7 (42 cM), Derl2 (42 cM, formerly Flana), Sfrs1 (49 cM), and Rara (57.8 cM). Dusp14, Derl2, and Spag7 all show differential expression between A/a and A/A^vy animals on the restricted diet. Sfrs1 shows differential expression between the restricted and unrestricted diets on the A/a background. Rara shows differential expression between the restricted and unrestricted diet on the A/a background as well as between A/a and A/A^vy animals on the restricted diet.

Fasn (72 cM) and Grb2 (75 cM) are candidate genes for diabesity QTL Nidd4 (68 cM). Fasn shows differential expression between restricted and unrestricted diets on the A/A^vy background while Grb2 shows differential expression between A/a and A/A^vy animals on the unrestricted diet.

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

J:55284

Genome scan was performed on 42 animals from a (C3H/HeNCrlCrlj x NSY/NcuOs)F2 intercross to identify QTLs associated with type 2 diabetes phenotypes. Parental strain NSY is non-obese and develops insulin resistance and impaired insulin response in an age-dependent manner leading to development of type 2 diabetes.

Significant linkage to diabetes phenotypes was detected on mouse Chromosomes 6 (Nidd3n), 11 (Nidd1n and Nidd4n), and 14 (Nidd2n). Nidd1n maps to 20 cM - 47 cM on mouse Chromosome 11 between D11Mit236 and D11Mit95 and is associated with glucose tolerance (LOD=9.5), blood glucose levels at all ages (LOD=8.49), and fasting blood glucose levels (LOD=4.33) at 36 weeks of age. NSY-derived alleles confer impaired glucose tolerance in a dominant or additive fashion. A possible candidate gene for Nidd1n is Tcf2. Sequence analysis revealed a threonine to alanine (T222A) allelic variation between strains NSY/NcuOs and C3H/HeNCrlCrlj in the DNA binding domain of Tcf2.

Nidd2n maps to 15 cM - 40 cM on mouse Chromosome 14 between D14Mit160 and D14Mit59 and is associated with glucose tolerance after 24 weeks of age (LOD=4.88) and basal insulin levels (LOD=4.52). Nidd2n does not affect glucose tolerance in early life (12 weeks). NSY-derived alleles confer impaired glucose tolerance in a recessive or additive fashion at Nidd2n. Nidd3n maps to 32.5 cM - 38.5 cM on mouse Chromosome 6 between D6Mit209 and D6Mit178 and is associated with epididymal fat weight (Efw) (LOD=6.75), basal insulin levels (LOD=4.69), blood glucose levels at 36 weeks (LOD=3.51), and insulin/glucose ratio (LOD=3.2). Linkage to glucose levels at 36 weeks of age peaked near D6Mit52 (appx. 69.4 cM).

Nidd3n affects glucose tolerance after 24 weeks of age but not in early life (12 weeks). NSY-derived alleles confer impaired glucose tolerance in a dominant fashion at Nidd3n. Nidd4n maps to 2 cM on mouse Chromosome 11 near D11Mit76 and is associated with glucose tolerance (LOD=5.79) in early life (12 weeks) and insulin/glucose ratio (LOD=5.35).NSY-derived alleles confer impaired glucose tolerance in a recessive or additive fashion at Nidd4n.

Nidd1n, Nidd2n, and Nidd3n show overlap with previously mapped type 1 diabetes susceptibility QTLs Idd4, Idd12, and Idd6, respectively.

Efw mapped to mouse Chromosome 6 within a region including D6Mit209 and D6Mit178.

References

• Original: J:55284 Ueda H, et al., Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex trait. Diabetes. 1999 May;48(5):1168-74
• All: 1 reference(s)