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Functional characterization of ABCB4 mutations found in progressive familial intrahepatic cholestasis type 3.

 Hyo Jin Park  ;  Tae Hee Kim  ;  So Won Kim  ;  Shin Hye Noh  ;  Kyeong Jee Cho  ;  Choe Choi  ;  Eun Young Kwon  ;  Yang Ji Choi  ;  Heon Yung Gee  ;  Ji Ha Choi 
 SCIENTIFIC REPORTS, Vol.6 : 26872, 2016 
Journal Title
Issue Date
ATP Binding Cassette Transporter, Sub-Family B/deficiency* ; ATP Binding Cassette Transporter, Sub-Family B/genetics ; ATP Binding Cassette Transporter, Sub-Family B/metabolism ; Cholestasis, Intrahepatic/genetics* ; Cyclosporine/pharmacology ; Gene Expression ; Genetic Association Studies ; Genetic Predisposition to Disease ; HEK293 Cells ; Humans ; Kinetics ; Leupeptins/pharmacology ; Macrolides/pharmacology ; Mutation, Missense ; Paclitaxel/metabolism ; Protein Transport
Multidrug resistance 3 (MDR3), encoded by the ATP-binding cassette, subfamily B, member 4 gene (ABCB4), localizes to the canalicular membrane of hepatocytes and translocates phosphatidylcholine from the inner leaflet to the outer leaflet of the canalicular membrane. Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare hepatic disease caused by genetic mutations of ABCB4. In this study, we characterized 8 ABCB4 mutations found in PFIC3 patients, using in vitro molecular assays. First, we examined the transport activity of each mutant by measuring its ATPase activity using paclitaxel or phosphatidylcholine. Then, the pathogenic mechanisms by which these mutations affect MDR3 were examined through immunoblotting, cell surface biotinylation, and immunofluorescence. As a result, three ABCB4 mutants showed significantly reduced transport activity. Among these mutants, one mutation A364V, located in intracellular domains, markedly decreased MDR3 expression on the plasma membrane, while the others did not affect the expression. The expression of MDR3 on the plasma membrane and transport activity of A364V was rescued by a pharmacological chaperone, cyclosporin A. Our study provides the molecular mechanisms of ABCB4 mutations and may contribute to the understanding of PFIC3 pathogenesis and the development of a mutation-specific targeted treatment for PFIC3.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Noh, Shin Hye(노신혜)
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
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