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Title: An insertion mutation in ABCB4 is associated with gallbladder mucocele formation in dogs

item MEALEY, KATRINA - Washington State University
item MINCH, JONATHAN - Washington State University
item White, Stephen
item SNEKVIK, K - Washington State University
item MATTOON, JOHN - Washington State University

Submitted to: Comparative Hepatology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/3/2010
Publication Date: 7/3/2010
Citation: Mealey, K.L., Minch, J.D., White, S.N., Snekvik, K.R., Mattoon, J.S. 2010. An insertion mutation in ABCB4 is associated with gallbladder mucocele formation in dogs. Comparative Hepatology. 9:6.

Interpretive Summary: Several diseases of the gallbladder and biliary system in people are known to be caused by defects in the ABCB4 gene. The ABCB4 gene product is a lipid translocator that is essential for transporting phospholipids into the bile. Phospholipids help protect the biliary system by buffering both cholesterol and bile salts. Lack of phospholipids in bile can result in gallbladder stones, cirrhosis, and jaundice. Patients may be mildly or severely affected, requiring liver transplantation. An increased incidence of gallbladder disease has been described in Shetland Sheepdogs over the past decade. We investigated ABCB4 as a candidate gene for gallbladder disease (mucocele) in Shetland Sheepdogs and identified a mutation that leaves only half of the protein intact. The identical mutation was found in three other dogs with gallbladder mucoceles (Pomeranian, Cocker Spaniel, Cairn Terrier). Awareness of this mutation may benefit both human patients and dogs. New treatment strategies can be attempted in dogs with ABCB4-associated biliary disease while genetic testing of dogs can be offered enabling breeders to eradicate this genetic defect.

Technical Abstract: The only known physiologic function of the ABCB4 gene product is translocation of phosphatidylcholine (PC) across the hepatocyte plasma membrane into biliary canaliculi. In people, mutations of the ABCB4 gene produce several disease syndromes involving the biliary system including intrahepatic cholestasis of pregnancy, progressive familial intrahepatic cholestasis (type 3), primary biliary cirrhosis, and cholelithiasis. The severity of the disease can range from fatal (without a liver transplant) to milder forms depending on whether the mutation reduces or completely eliminates ABCB4 protein function. Biliary disease, specifically gallbladder mucocele formation, has been recognized with increased frequency in dogs during the past decade. Because Shetland Sheepdogs are considered to be predisposed to gallbladder mucoceles, we initially investigated ABCB4 as a candidate gene for gallbladder mucoceles in Shetland Sheepdogs. An insertion (G) mutation in exon 12 of canine ABCB4 was identified in 14 of 15 Shetland Sheepdogs with gallbladder mucoceles, and only 1 of 21 unaffected Shetland Sheepdogs. This insertion 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 binding sites and a putative substrate (PC) binding site. A significant association (P < 0.0001) was detected between affected Shetland Sheepdogs and the insertion mutation. The identical mutation was identified in three other dogs with gallbladder mucoceles (Pomeranian, Cairn Terrier, and Cocker Spaniel), but not in unaffected dogs of other breeds (P < 0.006). The one affected Shetland Sheepdog that did not possess the insertion mutation instead had a missense mutation in exon 15 of ABCB4. ABCB4 appears to play a key role in hepatobiliary health in dogs as it does in people. Affected dogs may provide a useful model for identifying novel treatment strategies for ABCB4-associated biliary disease in people.