A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

“…For example, although mutations in ATP8B1 and ABCB11 have been reported for subjects with severe forms of PFIC with low serum levels of gamma-glutamyltranspeptide (γGTP), specific mutations within each gene have also been associated with milder clinical phenotypes. 15,17,[24][25][26][27][28][29][30] Equally notable is the phenotypic pleomorphism of mutations in ABCB4, which ranges from high γGTP-PFIC (or PFIC3), to intrahepatic cholestasis of pregnancy, and gallstone formation, 19,25,[31][32][33][34][35][36] and an array of mutations in JAG1 in subjects with liver and/or non-hepatic malformations (e.g. : cardiovascular and renal defects).…”

Single-nucleotide polymorphism analysis of the multidrug resistance protein 3 gene for the detection of clinical progression in Japanese patients with primary biliary cirrhosis

“…Mutations in MDR3 have been reported in patients with progressive familial intrahepatic cholestasis type 3 (PFIC3) with high serum ␥-glutamyltransferase activity, 41,42 intrahepatic cholestasis of pregnancy (ICP), 25,43,44 and "adolescent cholelithiasis with recurrent intrahepatic cholestasis of pregnancy followed by adulthood biliary cirrhosis". 44 Almost all mutations found in patients with PFIC3 and ICP were frame-shift mutations due to deletion or nonsense mutations, introducing stop codons downstream and leading to the production of inactive truncated proteins.…”

“…44 Almost all mutations found in patients with PFIC3 and ICP were frame-shift mutations due to deletion or nonsense mutations, introducing stop codons downstream and leading to the production of inactive truncated proteins. Interestingly, patients with PFIC3 and ICP, who had these frame-shift or nonsense mutations, showed similar clinical manifestations, such as inheritance, early onset in childhood, and clinical severity.…”

“…The relatively mild MDR3 dysfunction due to missense mutations allowed for a slower progression of biliary cirrhosis. 44 This suggests that MDR3 polymorphisms, especially possessing the Hap 2/Hap 2 diplotype, may more weakly alter the function of MDR3, compared with the MDR3 dysfunction caused by missense mutations found in the patient with "adolescent cholelithiasis with intrahepatic cholestasis of pregnancy followed by adulthood biliary cirrhosis". Therefore, the accumulation of the altered function of MDR3, which is thought to be caused by MDR3 polymorphisms identified in the present study, may lead to a diminution of biliary phosphatidylcholine excretion into bile from the apical membrane of hepatocytes, thus resulting in the increased toxicity of bile salts and the more severe progression of PBC.…”

Intrahepatic cholestasis of pregnancy — A heterogeneous group of pregnancy-related disorders?

“…Thus, misdiagnosis of ICP in patients with asymptomatic chronic liver diseases who developed pruritus during pregnancy may have contributed to the high rate of cirrhosis during follow-up in the present study as admitted by the authorsalthough genetic factors may explain subsequent occurrence of ICP and adult cirrhosis in single cases. 22 The reader is left with some uncertainty about which percentage of ICP patients in this retrospective analysis represent "true ICP" as defined today.…”