{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:17:09Z","timestamp":1790752629379,"version":"4.1.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"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":[[2016,5]]},"abstract":"<jats:p>Progressive familial intrahepatic cholestasis type 3 is caused by biallelic variations of ABCB4, most often (\u226570%) missense. In this study, we examined the effects of 12 missense variations identified in progressive familial intrahepatic cholestasis type 3 patients. We classified these variations on the basis of the defects thus identified and explored potential rescue of trafficking\u2010defective mutants by pharmacological means. Variations were reproduced in the <jats:italic toggle=\"yes\">ABCB4<\/jats:italic> complementary DNA and the mutants, thus obtained, expressed in HepG2 and HEK293 cells. Three mutants were either fully (I541F and L556R) or largely (Q855L) retained in the endoplasmic reticulum, in an immature form. Rescue of the defect, i.e., increase in the mature form at the bile canaliculi, was obtained by cell treatments with cyclosporin A or C and, to a lesser extent, B, D, or H. Five mutations with little or no effect on ABCB4 expression at the bile canaliculi caused a decrease (F357L, T775M, and G954S) or almost absence (S346I and P726L) of phosphatidylcholine secretion. Two mutants (T424A and N510S) were normally processed and expressed at the bile canaliculi, but their stability was reduced. We found no defect of the T175A mutant or of R652G, previously described as a polymorphism. In patients, the most severe phenotypes appreciated by the duration of transplant\u2010free survival were caused by ABCB4 variants that were markedly retained in the endoplasmic reticulum and expressed in a homozygous status. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> ABCB4 variations can be classified as follows: nonsense variations (I) and, on the basis of current findings, missense variations that primarily affect the maturation (II), activity (III), or stability (IV) of the protein or have no detectable effect (V); this classification provides a strong basis for the development of genotype\u2010based therapies. (H<jats:sc>epatology<\/jats:sc> 2016;63:1620\u20101631)<\/jats:p>","DOI":"10.1002\/hep.28300","type":"journal-article","created":{"date-parts":[[2015,10,17]],"date-time":"2015-10-17T09:18:57Z","timestamp":1445073537000},"page":"1620-1631","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":112,"title":["A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3"],"prefix":"10.1097","volume":"63","author":[{"given":"Jean\u2010Louis","family":"Delaunay","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, INSERM, UMR_S 938,Centre de Recherche Saint\u2010Antoine,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Marie","family":"Durand\u2010Schneider","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, INSERM, UMR_S 938,Centre de Recherche Saint\u2010Antoine,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Dossier","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, INSERM, UMR_S 938,Centre de Recherche Saint\u2010Antoine,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Falgui\u00e8res","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, INSERM, UMR_S 938,Centre de Recherche Saint\u2010Antoine,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Gautherot","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, INSERM, UMR_S 938,Centre de Recherche Saint\u2010Antoine,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Davit\u2010Spraul","sequence":"additional","affiliation":[{"name":"Assistance Publique\u2010H\u00f4pitaux de Paris, H\u00f4pital de Bic\u00eatre,Laboratoire de biochimie,Le Kremlin Bic\u00eatre,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tounsia","family":"A\u00eft\u2010Slimane","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, INSERM, UMR_S 938,Centre de Recherche Saint\u2010Antoine,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Housset","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, INSERM, UMR_S 938,Centre de Recherche Saint\u2010Antoine,Paris,France"},{"name":"Assistance Publique\u2010H\u00f4pitaux de Paris, H\u00f4pital Saint\u2010Antoine,Centre de R\u00e9f\u00e9rence Maladies Rares Maladies Inflammatoires des Voies Biliaires & Service d'H\u00e9patologie,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Jacquemin","sequence":"additional","affiliation":[{"name":"Assistance Publique\u2010H\u00f4pitaux de Paris, H\u00f4pital Bic\u00eatre, H\u00e9patologie P\u00e9diatrique & Unit\u00e9 de Transplantation H\u00e9patique,Centre de R\u00e9f\u00e9rence Maladies Rares Atr\u00e9sies des Voies Biliaires de l'Enfant,Le Kremlin Bic\u00eatre,France"},{"name":"Universit\u00e9 Paris\u2010Sud 11, 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 Universit\u00e9 Paris 06, INSERM, UMR_S 938,Centre de Recherche 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