{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:17:12Z","timestamp":1790752632460,"version":"4.1.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T00:00:00Z","timestamp":1618272000000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"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":[[2021,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic mutations in\n                      <jats:italic toggle=\"yes\">ABCB11<\/jats:italic>\n                      encoding the canalicular bile salt export pump (BSEP). Nonsense mutations are responsible for the most severe phenotypes. The aim was to assess the ability of drugs to induce readthrough of six nonsense mutations (p.Y354X, p.R415X, p.R470X, p.R1057X, p.R1090X, and p.E1302X) identified in patients with PFIC2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      The ability of G418, gentamicin, and PTC124 to induce readthrough was studied using a dual gene reporter system in NIH3T3 cells. The ability of gentamicin to induce readthrough and to lead to the expression of a full\u2010length protein was studied in human embryonic kidney 293 (HEK293), HepG2, and Can 10 cells using immunodetection assays. The function of the gentamicin\u2010induced full\u2010length protein was studied by measuring the [\n                      <jats:sup>3<\/jats:sup>\n                      H]\u2010taurocholate transcellular transport in stable Madin\u2010Darby canine kidney clones co\u2010expressing Na+\u2010taurocholate co\u2010transporting polypeptide (Ntcp). Combinations of gentamicin and chaperone drugs (ursodeoxycholic acid, 4\u2010phenylbutyrate [4\u2010PB]) were investigated. In NIH3T3, aminoglycosides significantly increased the readthrough level of all mutations studied, while PTC124 only slightly increased the readthrough of p.E1302X. Gentamicin induced a readthrough of p.R415X, p.R470X, p.R1057X, and p.R1090X in HEK293 cells. The resulting full\u2010length proteins localized within the cytoplasm, except for Bsep\n                      <jats:sup>R1090X<\/jats:sup>\n                      , which was also detected at the plasma membrane of human embryonic kidney HEK293 and at the canalicular membrane of Can 10 and HepG2 cells. Additional treatment with 4\u2010PB and ursodeoxycholic acid significantly increased the canalicular proportion of full\u2010length Bsep\n                      <jats:sup>R1090X<\/jats:sup>\n                      protein in Can 10 cells. In Madin\u2010Darby canine kidney clones, gentamicin induced a 40% increase of the Bsep\n                      <jats:sup>R1090X<\/jats:sup>\n                      [\n                      <jats:sup>3<\/jats:sup>\n                      H]\u2010taurocholate transport, which was further increased with additional 4\u2010PB treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study constitutes a proof of concept for readthrough therapy in selected patients with PFIC2 with nonsense mutations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.31476","type":"journal-article","created":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T16:31:45Z","timestamp":1595521905000},"page":"1449-1463","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":17,"title":["Pharmacological Premature Termination Codon Readthrough of ABCB11 in Bile Salt Export Pump Deficiency: An In Vitro Study"],"prefix":"10.1097","volume":"73","author":[{"given":"Rachida","family":"Amzal","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay,Inserm,Physiopathog\u00e9n\u00e8se et traitement des maladies du Foie,UMR_S 1193,Hepatinov, Orsay,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Th\u00e9baut","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay,Inserm,Physiopathog\u00e9n\u00e8se et traitement des maladies du Foie,UMR_S 1193,Hepatinov, Orsay,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine","family":"Lapalus","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay,Inserm,Physiopathog\u00e9n\u00e8se et traitement des maladies du Foie,UMR_S 1193,Hepatinov, Orsay,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Almes","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay,Inserm,Physiopathog\u00e9n\u00e8se et traitement des maladies du Foie,UMR_S 1193,Hepatinov, Orsay,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Grosse","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay,Inserm,Physiopathog\u00e9n\u00e8se et traitement des maladies du Foie,UMR_S 1193,Hepatinov, Orsay,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Mareux","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay,Inserm,Physiopathog\u00e9n\u00e8se et traitement des maladies du Foie,UMR_S 1193,Hepatinov, Orsay,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricette","family":"Collado\u2010Hilly","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay,Inserm,Physiopathog\u00e9n\u00e8se et traitement des maladies du Foie,UMR_S 1193,Hepatinov, Orsay,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Davit\u2010Spraul","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay,Inserm,Physiopathog\u00e9n\u00e8se et traitement des maladies du Foie,UMR_S 1193,Hepatinov, Orsay,France"},{"name":"Biochemistry Unit,Assistance Publique\u2010H\u00f4pitaux de Paris,CHU Bic\u00eatre,Le Kremlin\u2010Bic\u00eatre,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Bidou","sequence":"additional","affiliation":[{"name":"Institute for Integrative Biology of the Cell (I2BC),CEA,CNRS,Universit\u00e9 Paris\u2010Saclay,Gif sur Yvette cedex,France"},{"name":"Sorbonne Universit\u00e9s,Universit\u00e9 Pierre et Marie Curie,UPMC,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Namy","sequence":"additional","affiliation":[{"name":"Institute for Integrative Biology of the Cell (I2BC),CEA,CNRS,Universit\u00e9 Paris\u2010Saclay,Gif sur Yvette cedex,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Jacquemin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay,Inserm,Physiopathog\u00e9n\u00e8se et traitement des maladies du Foie,UMR_S 1193,Hepatinov, Orsay,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1546-3193","authenticated-orcid":false,"given":"Emmanuel","family":"Gonzales","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay,Inserm,Physiopathog\u00e9n\u00e8se et traitement des maladies du Foie,UMR_S 1193,Hepatinov, 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