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

Title
Functional characterization of ABCB4 mutations found in progressive familial intrahepatic cholestasis type 3
Authors
Park, Hyo JinKim, Tae HeeKim, So WonNoh, Shin HyeCho, Kyeong JeeChoi, ChoeKwon, Eun YoungChoi, Yang JiGee, Heon YungChoi, Ji Ha
Ewha Authors
최지하
SCOPUS Author ID
최지하scopus
Issue Date
2016
Journal Title
SCIENTIFIC REPORTS
ISSN
2045-2322JCR Link
Citation
vol. 6
Publisher
NATURE PUBLISHING GROUP
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
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.
DOI
10.1038/srep26872
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의학전문대학원 > 의학과 > Journal papers
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