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QTL Variant Detail
QTL variant: Lith1C57L/J
Name: lithogenic gene 1; C57L/J
MGI ID: MGI:2446828
Synonyms: Lith1s
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
Strain of Specimen:  C57L/J
Allele Type:    QTL
Mutation:    Undefined
    This allele confers susceptibility to gallstone formation compared to AKR/J. (J:66646)
Inheritance:    Dominant
View phenotypes and curated references for all genotypes (concatenated display).

Candidate Genes


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.


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.


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


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-Lith1S and AK.L-Lith1S, 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.

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)

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