%0 Journal Article
%T An insertion mutation in ABCB4 is associated with gallbladder mucocele formation in dogs
%A Katrina L Mealey
%A Jonathan D Minch
%A Stephen N White
%A Kevin R Snekvik
%A John S Mattoon
%J Comparative Hepatology
%D 2010
%I BioMed Central
%R 10.1186/1476-5926-9-6
%X An insertion (G) mutation in exon 12 of canine ABCB4 (ABCB4 1583_1584G) was found to be significantly associated with hepatobiliary disease in Shetland Sheepdogs specifically (P < 0.0001) as well as other breeds (P < 0.0006). ABCB4 1583_1584G results in a frame shift generating four stop codons that prematurely terminate ABCB4 protein synthesis within exon 12, abolishing over half of the protein including critical ATP and a putative substrate binding site.The finding of a significant association of ABCB4 1583_1584G with gallbladder mucoceles in dogs suggests that this phospholipid flippase may play a role in the pathophysiology of this disorder. Affected dogs may provide a useful model for identifying novel treatment strategies for ABCB4-associated hepatobiliary disease in people.Bile is produced by the collective actions of a number of transporters located on the canalicular membrane of hepatocytes [1]. Active transport of biliary solutes creates an osmotic force that attracts water through tight junctions and aquaporins in the hepatocyte membrane [2,3]. Bile salts are the most important biliary solute. Other important solutes of bile include cholesterol and phospholipids. The presence of phospholipids, phosphatidylcholine (PC) in particular, in the biliary lumen is crucial for protecting the epithelial cell membranes lining the biliary system from the cytotoxic detergent actions of bile salts [3-5]. Bile salt cytotoxicity is substantially reduced in the presence of PC owing to the formation of mixed micelles (PC + bile salts) rather than simple micelles (bile salts only). Thus, a decrease in the amount of biliary PC leads to injury of epithelial cells lining the biliary system [6].ABCB4 functions exclusively as a phospholipid translocator [6]. ABCB4 is expressed on cannalicular membranes of hepatocytes where it translocates PC from the hepatocyte to the biliary canalicular lumen [7]. Proper function of ABCB4 is critical for maintaining hepatobiliary homeostasis as
%U http://www.comparative-hepatology.com/content/9/1/6