{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:17:05Z","timestamp":1790752625358,"version":"4.1.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2016,12,24]],"date-time":"2016-12-24T00:00:00Z","timestamp":1482537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2016,12,24]],"date-time":"2016-12-24T00:00:00Z","timestamp":1482537600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,2]]},"abstract":"<jats:p>ABCB4 (MDR3) is an adenosine triphosphate (ATP)\u2010binding cassette (ABC) transporter expressed at the canalicular membrane of hepatocytes, where it mediates phosphatidylcholine (PC) secretion. Variations in the <jats:italic toggle=\"yes\">ABCB4<\/jats:italic> gene are responsible for several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of <jats:italic toggle=\"yes\">ABCB4<\/jats:italic> missense variations that reside in the highly conserved motifs of ABC transporters, involved in ATP binding. Five disease\u2010causing variations in these motifs have been identified in <jats:italic toggle=\"yes\">ABCB4<\/jats:italic> (G535D, G536R, S1076C, S1176L, and G1178S), three of which are homologous to the gating mutations of cystic fibrosis transmembrane conductance regulator (CFTR or ABCC7; i.e., G551D, S1251N, and G1349D), that were previously shown to be function defective and corrected by ivacaftor (VX\u2010770; Kalydeco), a clinically approved CFTR potentiator. Three\u2010dimensional structural modeling predicted that all five <jats:italic toggle=\"yes\">ABCB4<\/jats:italic> variants would disrupt critical interactions in the binding of ATP and thereby impair ATP\u2010induced nucleotide\u2010binding domain dimerization and ABCB4 function. This prediction was confirmed by expression in cell models, which showed that the ABCB4 mutants were normally processed and targeted to the plasma membrane, whereas their PC secretion activity was dramatically decreased. As also hypothesized on the basis of molecular modeling, PC secretion activity of the mutants was rescued by the CFTR potentiator, ivacaftor (VX\u2010770). <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Disease\u2010causing variations in the ATP\u2010binding sites of ABCB4 cause defects in PC secretion, which can be rescued by ivacaftor. These results provide the first experimental evidence that ivacaftor is a potential therapy for selected patients who harbor mutations in the ATP\u2010binding sites of ABCB4. (H<jats:sc>epatology<\/jats:sc> 2017;65:560\u2010570)<\/jats:p>","DOI":"10.1002\/hep.28929","type":"journal-article","created":{"date-parts":[[2016,11,5]],"date-time":"2016-11-05T14:59:21Z","timestamp":1478357961000},"page":"560-570","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":62,"title":["Functional defect of variants in the adenosine triphosphate\u2013binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX\u2010770)"],"prefix":"10.1097","volume":"65","author":[{"given":"Jean\u2010Louis","family":"Delaunay","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Univ Paris 06, INSERM, UMR_S 938, Saint\u2010Antoine Research Center,F\u201075012,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alix","family":"Bruneau","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Univ 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Publique\u2010H\u00f4pitaux de Paris, Saint\u2010Antoine Hospital, Reference Center for Rare Disease, Inflammatory Biliary Diseases & Hepatology Department,F\u201075012,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Jacquemin","sequence":"additional","affiliation":[{"name":"Assistance Publique\u2010H\u00f4pitaux de Paris, Faculty of Medicine Paris Sud, CHU Bic\u00eatre, Pediatric Hepatology & Pediatric Hepatic Transplant Department, Reference Center for Rare Pediatric Liver Diseases,F\u201094275,Le Kremlin Bic\u00eatre,France"},{"name":"Universit\u00e9 Paris Sud, INSERM, UMR_S 1174, Hepatinov,Orsay,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mich\u00e8le","family":"Maurice","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Univ Paris 06, INSERM, UMR_S 938, Saint\u2010Antoine Research Center,F\u201075012,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Housset","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Univ Paris 06, INSERM, UMR_S 938, Saint\u2010Antoine Research Center,F\u201075012,Paris,France"},{"name":"Assistance Publique\u2010H\u00f4pitaux de Paris, Saint\u2010Antoine Hospital, Reference Center for Rare Disease, Inflammatory Biliary Diseases & Hepatology Department,F\u201075012,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Callebaut","sequence":"additional","affiliation":[{"name":"IMPMC, Sorbonne Universit\u00e9s, UPMC Univ Paris 06, UMR CNRS 7590,Museum National d'Histoire Naturelle, IRD UMR 206, IUC, Case 115, 4 Place Jussieu,75005,Paris Cedex 05,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tounsia","family":"A\u00eft\u2010Slimane","sequence":"additional","affiliation":[{"name":"Sorbonne 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