Lith genes control mucin accumulation, cholesterol crystallization, and gallstone formation in A/J and AKR/J inbred mice.

Abstract

We recently identified 2 Lith genes that determine cholesterol gallstone formation in C57L/J inbred mice, which show a gallstone prevalence of approximately 80% on feeding 1.0% cholesterol and 0.5% cholic acid. The aim of this study was to explore if the same Lith loci contribute to the variation in gallstone susceptibility in a new experimental cross. After 12 weeks of feeding the lithogenic diet to inbred mice of strains A/J and AKR/J as well as their F(1) progeny, we used microscopy of bile to assess mucin accumulation, crystallization pathways, and stone formation. Backcross progeny (n = 225) were phenotyped and genotyped selectively for microsatellite markers spanning the genome. Quantitative trait loci (QTL) affecting gallstone phenotypes were identified by linkage analysis. Both inbred strains showed accumulation of mucin gel and cholesterol supersaturation. However, only strain AKR developed gallstones (prevalence of 20%), whereas strain A showed a stable liquid crystalline state and no stones. QTL analysis identified a gallstone locus on chromosome 17 (Lith3). A second gene locus on chromosome 15 that controls mucin accumulation harbors the mucin gene Glycam1, which was shown to be expressed in gallbladder epithelia by immunohistochemistry. Gallstone and mucin loci colocalized with potential QTLs affecting the formation of cholesterol crystals. In conclusion, QTL analysis identified specific gene loci determining mucin accumulation, cholesterol crystallization, and gallstone formation. Characterization of the pathophysiologic roles of Lith3 and the new biliary mucin gene Glycam1 might provide insights into primary defects of human cholelithiasis and lead to new therapeutic strategies for prestone intervention.

• Authors: Frank Lammert, David Q-H Wang, Henning Wittenburg, Guylaine Bouchard, Sonja Hillebrandt, Bärbel Taenzler, Martin C Carey, Beverly Paigen
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 36 Issue 5 Pg. 1145-54 (Nov 2002) ISSN: 0270-9139 [Print] United States
• PMID: 12395324 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Mucins
• sulfated glycoprotein p50
• Cholesterol

Topics

• Animals
• Cholelithiasis (chemistry, epidemiology, genetics)
• Cholesterol (chemistry)
• Chromosomes, Mammalian
• Crystallization
• Female
• Gene Expression
• Genetic Predisposition to Disease
• Hybridization, Genetic
• Lod Score
• Male
• Mice
• Mice, Inbred A
• Mice, Inbred AKR
• Microsatellite Repeats
• Mucins (genetics, metabolism)
• Phenotype
• Prevalence