Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases
ABCB4 (ATP-binding cassette subfamily B member 4) is a hepatocanalicular floppase involved in biliary phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene give rise to several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive...
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| Veröffentlicht in: | International journal of molecular sciences 2023-01, Vol.24 (2), p.1236 |
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| creator | Delaunay, Jean-Louis Elbahnsi, Ahmad Bruneau, Alix Madry, Claire Durand-Schneider, Anne-Marie Stary, Anne Housset, Chantal Gautheron, Jérémie Callebaut, Isabelle Aït-Slimane, Tounsia |
| description | ABCB4 (ATP-binding cassette subfamily B member 4) is a hepatocanalicular floppase involved in biliary phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene give rise to several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ten ABCB4 missense variations in NBD1:NBD2 homologous positions (Y403H/Y1043H, K435M/K1075M, E558K/E1200A, D564G/D1206G and H589Y/H1231Y) all localized at the conserved and functionally critical motifs of ABC transporters, six of which are mutated in patients. By combining structure analysis and in vitro studies, we found that all ten mutants were normally processed and localized at the canalicular membrane of HepG2 cells, but showed dramatically impaired PC transport activity that was significantly rescued by treatment with the clinically approved CFTR potentiator ivacaftor. Our results provide evidence that functional ABCB4 mutations are rescued by ivacaftor, paving the way for the repositioning of this potentiator for the treatment of selected patients with PFIC3 caused by mutations in the ATP-binding sites of ABCB4. |
| doi_str_mv | 10.3390/ijms24021236 |
| format | Article |
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Variations in the ABCB4 gene give rise to several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ten ABCB4 missense variations in NBD1:NBD2 homologous positions (Y403H/Y1043H, K435M/K1075M, E558K/E1200A, D564G/D1206G and H589Y/H1231Y) all localized at the conserved and functionally critical motifs of ABC transporters, six of which are mutated in patients. By combining structure analysis and in vitro studies, we found that all ten mutants were normally processed and localized at the canalicular membrane of HepG2 cells, but showed dramatically impaired PC transport activity that was significantly rescued by treatment with the clinically approved CFTR potentiator ivacaftor. Our results provide evidence that functional ABCB4 mutations are rescued by ivacaftor, paving the way for the repositioning of this potentiator for the treatment of selected patients with PFIC3 caused by mutations in the ATP-binding sites of ABCB4.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms24021236</identifier><identifier>PMID: 36674751</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>ABC transporters ; Adenosine Triphosphate ; Amino acids ; Bile ; Binding sites ; Cholestasis ; Cholestasis, Intrahepatic - drug therapy ; Cholestasis, Intrahepatic - genetics ; Disease ; Drug Repositioning ; Gallbladder diseases ; Health services ; Humans ; Lecithin ; Life Sciences ; Liver ; Localization ; Missense mutation ; Mutation ; Mutation, Missense ; Phosphatidylcholine ; Phosphatidylcholines ; Structural analysis ; Transplantation</subject><ispartof>International journal of molecular sciences, 2023-01, Vol.24 (2), p.1236</ispartof><rights>2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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Variations in the ABCB4 gene give rise to several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ten ABCB4 missense variations in NBD1:NBD2 homologous positions (Y403H/Y1043H, K435M/K1075M, E558K/E1200A, D564G/D1206G and H589Y/H1231Y) all localized at the conserved and functionally critical motifs of ABC transporters, six of which are mutated in patients. By combining structure analysis and in vitro studies, we found that all ten mutants were normally processed and localized at the canalicular membrane of HepG2 cells, but showed dramatically impaired PC transport activity that was significantly rescued by treatment with the clinically approved CFTR potentiator ivacaftor. Our results provide evidence that functional ABCB4 mutations are rescued by ivacaftor, paving the way for the repositioning of this potentiator for the treatment of selected patients with PFIC3 caused by mutations in the ATP-binding sites of ABCB4.</description><subject>ABC transporters</subject><subject>Adenosine Triphosphate</subject><subject>Amino acids</subject><subject>Bile</subject><subject>Binding sites</subject><subject>Cholestasis</subject><subject>Cholestasis, Intrahepatic - drug therapy</subject><subject>Cholestasis, Intrahepatic - genetics</subject><subject>Disease</subject><subject>Drug Repositioning</subject><subject>Gallbladder diseases</subject><subject>Health services</subject><subject>Humans</subject><subject>Lecithin</subject><subject>Life Sciences</subject><subject>Liver</subject><subject>Localization</subject><subject>Missense mutation</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Phosphatidylcholine</subject><subject>Phosphatidylcholines</subject><subject>Structural analysis</subject><subject>Transplantation</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkk-P0zAQxSMEYpeFG2dkiQtIFPwvdsIBqe0CXamFFYKz5STjras0Dh6nEt-Ej0tCl1XZk0ee3xu_sV6WPWf0rRAlfed3e-SScsaFepCdM8n5jFKlH57UZ9kTxB2lXPC8fJydCaW01Dk7z35fHWxtXQpxtoHG2wQNuQ4JujTWPnQkODJfLBeSbDwidAhkM6S_LSRz56BOvrshy-iTr21LNiF5h5MqbYF8WVzie_IN-oB-kkzoNUTsJ9kBkLgQyQp6m0LlW2_jL3LpESwCPs0eOdsiPLs9L7Ifnz5-X65m66-fr5bz9ayWUqVZXfCyynPBK14VJegGirwqmS0kLaTUWjmeK9do61hZ2orWjeO6FpzSwpVCO3GRfTjO7YdqD009bh5ta_ro96MdE6w3_3c6vzU34WDKQmmhi3HA6-OA7T3Zar420x2VfDKSH9jIvrp9LIafA2Aye481tK3tIAxouFYFF4wxPaIv76G7MMRu_IqJ0pwXWsmRenOk6hgQI7g7B4yaKR7mNB4j_uJ02Tv4Xx7EHzX0t6k</recordid><startdate>20230108</startdate><enddate>20230108</enddate><creator>Delaunay, Jean-Louis</creator><creator>Elbahnsi, Ahmad</creator><creator>Bruneau, Alix</creator><creator>Madry, Claire</creator><creator>Durand-Schneider, Anne-Marie</creator><creator>Stary, Anne</creator><creator>Housset, Chantal</creator><creator>Gautheron, Jérémie</creator><creator>Callebaut, Isabelle</creator><creator>Aït-Slimane, Tounsia</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6512-5483</orcidid><orcidid>https://orcid.org/0000-0002-7727-9893</orcidid><orcidid>https://orcid.org/0000-0002-5740-2372</orcidid><orcidid>https://orcid.org/0000-0002-5356-2440</orcidid><orcidid>https://orcid.org/0000-0002-7459-859X</orcidid></search><sort><creationdate>20230108</creationdate><title>Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases</title><author>Delaunay, Jean-Louis ; 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Variations in the ABCB4 gene give rise to several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ten ABCB4 missense variations in NBD1:NBD2 homologous positions (Y403H/Y1043H, K435M/K1075M, E558K/E1200A, D564G/D1206G and H589Y/H1231Y) all localized at the conserved and functionally critical motifs of ABC transporters, six of which are mutated in patients. By combining structure analysis and in vitro studies, we found that all ten mutants were normally processed and localized at the canalicular membrane of HepG2 cells, but showed dramatically impaired PC transport activity that was significantly rescued by treatment with the clinically approved CFTR potentiator ivacaftor. 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| subjects | ABC transporters Adenosine Triphosphate Amino acids Bile Binding sites Cholestasis Cholestasis, Intrahepatic - drug therapy Cholestasis, Intrahepatic - genetics Disease Drug Repositioning Gallbladder diseases Health services Humans Lecithin Life Sciences Liver Localization Missense mutation Mutation Mutation, Missense Phosphatidylcholine Phosphatidylcholines Structural analysis Transplantation |
| title | Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases |
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