TY - JOUR
T1 - Lith genes control mucin accumulation, cholesterol crystallization, and gallstone formation in A/J and AKR/J inbred mice
AU - Lammert, Frank
AU - Wang, David Q.H.
AU - Wittenburg, Henning
AU - Bouchard, Guylaine
AU - Hillebrandt, Sonja
AU - Taenzler, Bärbel
AU - Carey, Martin C.
AU - Paigen, Beverly
N1 - Funding Information:
SupportedinpartbyresearchandcentergrantsDK54012(toD.Q.-H.W.),DK51568(to B.P.), and DK36588, DK52911, and DK34854 (to M.C.C.) from the National Institutes ofHealth(U.S.PublicHealthService);grantsLA997/2-1and3-1(toF.L.)andWI905/1-1 (to H.W.) from the Deutsche Forschungsgemeinschaft; a grant from Ministerium für Schule, Wissenschaft und Forschung des Landes Nordrhein-Westfalen (to F.L.); and a grant from the Ellison Medical Foundation (to D.Q.-H.W.). D.Q.-H.W. is a recipient of a New Scholar Award from the Ellison Medical Foundation (1999-2003).
PY - 2002/11/1
Y1 - 2002/11/1
N2 - We recently identified 2 Lith genes that determine cholesterol gallstone formation in C57L/J inbred mice, which show a gallstone prevalence of ∼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 F1 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 billiary mucin gene Glycam1 might provide insights into primary defects of human cholelithiasis and lead to new therapeutic strategies for prestone intervention.
AB - We recently identified 2 Lith genes that determine cholesterol gallstone formation in C57L/J inbred mice, which show a gallstone prevalence of ∼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 F1 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 billiary mucin gene Glycam1 might provide insights into primary defects of human cholelithiasis and lead to new therapeutic strategies for prestone intervention.
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U2 - 10.1053/jhep.2002.36821
DO - 10.1053/jhep.2002.36821
M3 - Article
C2 - 12395324
AN - SCOPUS:0036829951
SN - 0270-9139
VL - 36
SP - 1145
EP - 1154
JO - Hepatology
JF - Hepatology
IS - 5 5 II
ER -