Functional defect of variants in the adenosine triphosphate–binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX‐770) - Sorbonne Université Access content directly
Journal Articles Hepatology Year : 2016

Functional defect of variants in the adenosine triphosphate–binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX‐770)

Alix Bruneau
  • Function : Author
Brice Hoffmann
  • Function : Author
Véronique Barbu
  • Function : Author
Emmanuel Jacquemin
  • Function : Author
Michèle Maurice
  • Function : Author
Chantal Housset
  • Function : Author
Isabelle Callebaut
  • Function : Author
Tounsia Aït‐slimane
  • Function : Author

Abstract

ABCB4 (MDR3) is an adenosine triphosphate (ATP)-binding cassette (ABC) transporter expressed at the canalicular membrane of hepatocytes, where it mediates phosphatidylcholine (PC) secretion. Variations in the ABCB4 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 ABCB4 missense variations that reside in the highly conserved motifs of ABC transporters, involved in ATP binding. Five disease-causing variations in these motifs have been identified in ABCB4 (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-770; Kalydeco), a clinically approved CFTR potentiator. Three-dimensional structural modeling predicted that all five ABCB4 variants would disrupt critical interactions in the binding of ATP and thereby impair ATPinduced nucleotide-binding 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-770). Conclusion: Diseasecausing variations in the ATP-binding 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-binding sites of ABCB4. (HEPATOLOGY 2017;65:560-570) Supported by grants from the Sorbonne Universit es (ProgrammeConvergence@SorbonneUniversit es, Investissements d'avenir), the association Mucoviscidose-ABCF2, the French Association Vaincre La Mucoviscidose, and the French Association for the Study of the Liver (AFEF). A.B. received a fellowship from the " Ministe`re de l'Enseignement Sup erieur et de la Recherche" .
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Hepatology - 2016 - Delaunay - Functional defect of variants in the adenosine triphosphate binding sites of ABCB4 and their.pdf (617.67 Ko) Télécharger le fichier
Liver International - 2020 - Mareux - Functional rescue of an ABCB11 mutant by ivacaftor A new targeted pharmacotherapy.pdf (1.54 Mo) Télécharger le fichier
Scientific Reports 02019.pdf (4.17 Mo) Télécharger le fichier
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Dates and versions

hal-03976715 , version 1 (07-02-2023)

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Jean‐louis Delaunay, Alix Bruneau, Brice Hoffmann, Anne‐marie Durand‐schneider, Véronique Barbu, et al.. Functional defect of variants in the adenosine triphosphate–binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX‐770). Hepatology, 2016, 65, pp.560 - 570. ⟨10.1002/hep.28929⟩. ⟨hal-03976715⟩
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