Lith3^AKR/J
QTL Variant Detail

Summary

• QTL variant: Lith3^AKR/J
• Name: lithogenic gene 3; AKR/J
• MGI ID: MGI:3052788
• QTL: Lith3 Location: Chr17:9194337-9194456 bp Genetic Position: Chr17, Syntenic

Variant origin

• Strain of Specimen: AKR/J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers susceptibility to gallstone formation compared to A/J. (J:80014)

Notes

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

J:80014

Linkage analysis was performed on 225 animals from a (A/J x AKR/J)F1 x AKR/J backcross to identify loci associated with gallstone susceptibility traits. 99 microsatellite loci at an average spacing of 16 cM were genotyped. At 8 weeks of age animals were placed on a lithogenic diet for up to 20 weeks of age. Both parental strains display accumulation of mucin gel and cholesterol supersaturation in the bile, but only parental strain AKR/J is susceptible to cholesterol gallstones with a 20% incidence. At 12weeks male A/J gallbladder volume is significantly increased compared to male AKR/J animals.

Previously identified Lith genes (Lith1 and Lith2) were not detected in this cross. A new locus named Lith3 was identified on mouse Chromosome 17 with a peak LOD=3.5 at D17Mit247. The 95% confidence interval spanned 0 to 7 cM. AKR/J supplies the susceptible allele. Homozygosity for AKR/J alleles at Lith3 confer significantly higher lithogenic score compared to heterozygosity. The confidence interval of Lith3 spans 0 cM - 7 cM. Lith3 also shows suggestive linkage to cholesterol monohydrate crystal formation (LOD=1.4). Potential candidate gene Slc22a1 maps within the Lith3 interval. Northern blot analysis of Slc22a1 mRNA did not reveal differences in transcript size or expression between A/J and AKR/J. Sequence analysis of the Slc22a1 cDNA detected 3 polymorphisms that do not lead to amino acid changes. The Lith3 interval is syntenic to human Chromosome 6q25-27.

Suggestive linkage to gallstone susceptibility mapped to 2.2 cM on mouse Chromosome 4 near D4Mit315 (LOD=1.2) and to 60.4 cM on mouse Chromosome 6 near D6Mit201 (LOD=1.5). AKR/J-derived alleles confer gallstone susceptibility at D4Mit315 and A/J-derived alleles confer gallstone susceptibility at D6Mit201. The D4Mit315 locus is also suggestively linkedto cholesterolmonohydrate crystal formation (LOD=1.5).

A locus at 73.5 cM on mouse Chromosome 15 shows linkage to bile mucin accumulation at D15Mit16 (LOD=4.2) and is named Bmca (bile mucin accumulation). The confidence interval for Bmca spans 69 cM - 77 cM. Animalshomozygous for AKR/J-derived alleles at Bmca exhibit significantly increased mucin scores compared to heterozygous animals. This locus also shows suggestive linkage to cholesterol monohydrate crystal formation (LOD=2.3). The mucin gene, Glycam1 (63 cM), maps to the Bmca interval and is considered a candidate gene. Immunohistochemistry confirmed Glycam1 expression in the gallbladder epithelium and gallbladder bile but did not reveal expression differences between A/J and AKR/J or expressiondifferences as a consequence of diet.

Suggestive linkage to bile mucin accumulation mapped to 89.2 cM on mouse Chromosome 2 near D2Mit345 (LOD=1.9), 36.4 cM and 46.4 cM on mouse Chromosome 4 near D4Mit23 (LOD=2.3) and D4Mit27 (LOD=2.3), respectively, 5.5cM and 25.5 cM on mouse Chromosome 15 (LOD=1.7 at both markers), and 38.7 cM on mouse Chromosome 16 near D16Mit19 (LOD=1.6). The D15Mit11 locus also shows suggestive linkage to cholesterol monohydrate crystal formation (LOD=1.4).

References

• Original: J:80014 Lammert F, et al., Lith genes control mucin accumulation, cholesterol crystallization, and gallstone formation in A/J and AKR/J inbred mice. Hepatology. 2002 Nov;36(5):1145-54
• All: 1 reference(s)