Gluchos1^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Gluchos1^C57BL/6J
• Name: glucose homeostasis QTL 1; C57BL/6J
• MGI ID: MGI:3626006
• QTL: Gluchos1 Location: unknown Genetic Position: Chr13, cM position of peak correlated region/allele: 65.32 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

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Candidate Genes

J:109356

Nnt maps to 64 cM on chromosome 13 and was previously identified as a strong candidate gene for Gluchos1. Gluchos1 mapped to 73 cM in an F2 intercross between C57BL/6J (impaired glucose homeostasis) and C3H/HeH (normal glucose homeostasis). C57BL/6J micehave a naturally occurring in-frame deletion of exons 7-11 in Nnt resulting in complete absence of gene product. Transgenic expression of a BAC vector containing a full-length Nnt gene derived from 129S6/SvEvTac in C57BL/6J animals resulted in Nnt protein production levels similar to C3H/HeH and rescue of glucose intolerance and insulin secretion.

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

J:106692

Linkage analysis was performed on 260 male animals from a (C57BL/6J x C3H/HeH)F2 intercross to identify QTLs for glucose tolerance impairment. Parental strain C57BL/6J exhibits glucose homeostasis impairment compared to parental strain C3H/HeH. A panel of 84 polymorphic markers at an average spacing of 15 cM was used for the genome scan.

Gluchos1 (glucose homeostasis QTL 1) mapped to 73 cM on mouse Chromosome 13 near D13Mit77 (LOD=5; LRS=22.8). This locus is linked to plasma glucose levels at T30 and T60 of the intraperitoneal glucose tolerance test (IPGTT). Interaction between Gluchos1 and 7 other loci accounts for 35% of the variance for plasma glucose clearance. Nnt (64 cM; 116 Mb) and Isl1 (113 Mb) are potential candidate genes located within 5 cM of Gluchos1. Sequence analysis of Isl1 did not detect polymorphisms between C57BL/6J and C3H/HeH. However, a missense mutation resulting in a threonine (C3H/HeH) to methionine (C57BL/6J) substitution at amino acid 35 of Nnt was detected. A second mutation identified in C57BL/6J islet and liver Nnt cDNA results in deletion of exons 7 - 11. In addition, Nnt expression analysis revealed that C3H/HeH produces 7-fold and 5-fold more Nnt transcript in liver and islet cells, respectively. Previously identified diabetes QTLs Tanidd2 (60 cM) and Bglu2 (59 cM) map near Gluchos1.

Gluchos2 (glucose homeostasis QTL 2) mapped to 2.4 cM on mouse Chromosome 11 near D11Mit2 (LOD=5.2; LRS=23.7). This locus is linked to fasting plasma glucose levels. Camk2b (0.5 cM) and Gck (1 cM) are potential candidate genes mapping within 5 cM of Gluchos2. No sequences differences were detected for Camk2b. One silent polymorphism was detected in Gck at nucleotide 131 of exon 7 of the C57BL/6J sequence. C57BL/6J animals exhibit significantly decreased glucokinase activity compared to C3H/HeH animals.

Gluchos3 (glucose homeostasis QTL 3) mapped to mouse Chromosome 9 near D9Mit1001 (LOD=6.7; LRS=30.9). This locus is linked to plasma insulin level at T30 of the IPGTT. C57BL/6J-derived alleles at Gluchos3 confer 50% decreased plasma insulin levels with a dominant mode of inheritance. Atp5l is a potential candidate genes mapping within 5 cM of Gluchos3. Isl2 may also be a candidate but lies on the edge of potential linkage.

References

• Original: J:106692 Toye AA, et al., A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia. 2005 Apr;48(4):675-86
• All: 15 reference(s)