Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases.
Jean-Louis DelaunayAhmad ElbahnsiAlix BruneauClaire MadryAnne-Marie Durand-SchneiderAnne StaryChantal HoussetJérémie GautheronIsabelle CallebautTounsia Aït-SlimanePublished in: International journal of molecular sciences (2023)
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.
Keyphrases
- cystic fibrosis
- intellectual disability
- end stage renal disease
- ejection fraction
- newly diagnosed
- dna damage
- peritoneal dialysis
- oxidative stress
- transcription factor
- autism spectrum disorder
- gene expression
- dna repair
- patient reported outcomes
- dna methylation
- risk assessment
- genome wide
- high resolution
- mass spectrometry
- replacement therapy
- atomic force microscopy
- single molecule
- patient reported
- drug administration