Lith1^AKR/J
QTL Variant Detail

Summary

• QTL variant: Lith1^AKR/J
• Name: lithogenic gene 1; AKR/J
• MGI ID: MGI:2446827
• QTL: Lith1 Location: Chr2:45347635-145312647 bp Genetic Position: Chr2, cM position of peak correlated region/allele: 47.93 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: AKR/J

Variant description

• Allele Type: QTL
• Inheritance: Recessive

Notes

Candidate Genes

J:88844

Authors indicate that Nfe212 may be the causitive gene for the Lith1 QTL. However other genes within the QTL region may also effect the Lith1 phenotype.

J:88544

Abcb11, a candidate gene for Lith1 on mouse Chromosome 2, was examined in this study. Sequencing of Abcb11 failed to detect polymorphisms in the gene coding region between gallstone susceptible strain C57L/J and gallstone resistant strain AKR/J. Northernand Western blot analysis detected 3-fold increased mRNA and protein expression in C57L/J compared to AKR/J. However, Abcb11 transport function was decreased 9-fold in C57L/J compared to AKR/J. In addition, Abcb11-null mice display lithogenic bile. These results support the candidacy of Abcb11 as a candidate gene for Lith1.

J:104062

Lith1 is a previously identified gallstone susceptibility QTL mapping to 41 cM on mouse Chromosome 2. Abcb11 at 38.4 cM colocalizes with Lith1 and is overexpressed in the gallstone-susceptible inbred strain C57/L compared to the gallstone-resistant inbred strain AKR/J. Authors evaluated animals carrying the Tg(RP23-291P1)1Flp transgene on an FVB/NJ genetic background to determine if Abcb11 overexpression accelerates gallstone formation. Male transgenic and FVB/NJ control animals were fed a lithogenic diet for up to 7 days.

On the CHOW diet, Tg(RP23-291P1)1Flp transgenic animals and FVB/NJ controls did not develop cholesterol crsytals or gallstones. However, gallbladder bile from transgenic animals was significantly more hydrophobic compared to FVB/NJwild type controls.

On day 4 of the lithogenic diet, 100% of transgenic animals exhibited bile cholesterol crystals and 25% had gallstones compared to 43% and 0%, respectively, of FVB/NJ controls. On day 7 of the lithogenic diet, 80% of transgenic animals had gallstones compared to 41% of FVB/NJ controls. These results support the hypothesis that overexpression of Abcb11 is responsible for the gallstone-susceptible effect of Lith1.

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

J:66646

Male animals from a (AKR/J x C57L/J)F1 x AKR/J backcross were typed for microsatellite markers at an average spacing of 20 cM to identify loci linked to cholesterol gallstone weight. When fed a lithogenic diet, inbred strain AKR/J is gallstone resistant while inbred strain C57L/J is gallstone susceptible. C57L/J susceptibility alleles appear to be dominant as (AKR/J x C57L/J)F1 hybrids are susceptible to gallstones when fed a lithogenic diet.

A major locus, Lith1, mapped to mouse Chromosome 2 from 30 cM - 80 cM with a LOD = 4.5 near D2Mit56 and is associated with the C57L/J-derived allele. Fig4 displays QTL interval mapping between D2Mit88 and D2Mit109 with a peak at D2Mit14a.

A second locus, Lith2, mapped to mouse Chromosome 19 from 40 cM - 85 cM with LOD = 1.8 near D19Mit58 and is associated with the C57L/J-derived allele. Fig4 displays QTL interval mapping between D19Mit19 and D19Mit71 with a peak at D19Mit58.

Both loci were confirmed by constructing congenic strains carrying C57L/J-derived Lith1or Lith2 on an AKR/J background. These congenics were named AK.L-Lith1^S and AK.L-Lith1^S, respectively. Both congenics retained the susceptibility phenotype of donor strain C57L/J.

A candidate gene for Lith1 is Abcb11 and a candidate gene for Lith2 is Abcc2.

Suggestive loci were also mapped to mouse Chromosome 6 with a maximum LOD = 2.3 at D6Mit25, mouse Chromosome 7 with a maximum LOD = 3.0 at D7Mit85, mouse Chromosome 8 with a maximum LOD = 1.3 at D8Mit40, mouse Chromosome 10 with a maximum LOD = 2.2 at D10Mit2, and mouse Chromosome X with a maximum LOD = 1.6 at DXMit46.

References

• Original: J:66646 Paigen B, et al., Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice. Physiol Genomics. 2000 Nov 9;4(1):59-65
• All: 1 reference(s)