| First Author | Lammert F | Year | 1997 |
| Journal | Hepatology | Volume | 26 |
| Pages | 358A (Abstr.) | Mgi Jnum | J:54870 |
| Mgi Id | MGI:1339665 | Citation | Lammert F, et al. (1997) Genetic mapping of Hepatocanalicular transporters establishes sister-p-glycoprotein (spgp) as a candidate for the major gallstone gene (Lith1). Hepatology 26:358A (Abstr.) |
| abstractText | Full text of Abstract: 920. Genetic mapping of hepatocanalicular transporters establishes sister- P-Glycoprotein (spgp) as a candidate for the major gallstone gene (Lith1). Frank Lammert, David R. Beier, David O.-H. Wang, Martin C. Carey, Beverly Paigen* and David E. Cohen. Divisions of Gastroenterology and Genetics, Brigham and Women's Hospital, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA; and * The Jackson Laboratory, Bar Harbor, ME. We have demonstrated that hypersecretion of biliary cholesterol is a hallmark of genetically determined gallstone formation in inbred mice and is associated with derangements of hepatic cholesterol metabolism and trafficking. Mapping of the major gallstone gene Lith1 to chromosome 2 by quantitative trait locus (QTL) analysis has excluded pathophysiologically relevant defects in structural genes encoding key hepatic lipid regulatory enzymes, cytosolic transfer proteins, and the P-glycoprotein 2 (mdr2) required for biliary phosphatidylcholine secretion. We therefore explored whether genes encoding the other cloned hepatocanalicular transporters, spgp and mrp2/cmoat (canalicular multispecific organic anion transporter), co-localize with Lith1. Methods. Oligonucleotide primer pairs designed to correspond to 3Õ untranslated regions of murine cDNA homologs of pig spgp and rat cmoat were employed for PCR amplification of genomic DNA fragments from C57BL/6J mice as well as from SPRET/Ei mice. Single strand conformation polymorphism (SSCP) analysis, which employs gel electrophoresis to detect nucleotide sequence polymorphisms that alter secondary structures of single-stranded DNA, revealed a polymorphism for each canalicular transporter. Genetic mapping was performed using SSCP analysis of the Jackson Laboratory's BSS backcross panel [(C57BL/6J x SPRET/Ei)F1 x SPRET/Ei]. Results: Linkage analysis of the resulting SSCP strain distribution patterns localized spgp to proximal chromosome 2 [non-recombinant with D2Mit11 in 92 backcross progeny] and cmoat to a distal segment of chromosome 19 [D19Mit11 - (1.2 +/- 1.2 cM) Ð cmoat - (2.3 +/- 1.6 cM) Ð D19Mit3]. Conclusion: Because spgp maps to the major gallstone QTL locus, we conclude that spgp is a strong candidate for Lith1. We speculate that spgp may encode a hepatocanalicular transporter for cholesterol, and that the defective gene permits hypersecretion of biliary cholesterol. |
