In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy

Abstract Background ABCB11 variations are responsible for a spectrum of rare liver diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) and intrahepatic cholestasis of pregnancy (ICP). Current medical treatment of these conditions mostly relies on ursodeoxycholic acid wit...

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Autores principales:	Elodie Mareux, Martine Lapalus, Amel Ben-Saad, Isabelle Callebaut, Thomas Falguières, Emmanuel Gonzales, Emmanuel Jacquemin
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	BSEP Cholestasis VX-770 Potentiator ABC transporters superfamily Paediatrics Medicine R
Acceso en línea:	https://doaj.org/article/2224e9e12283412f8afa4558224ab794
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spelling	oai:doaj.org-article:2224e9e12283412f8afa4558224ab7942021-11-21T12:26:09ZIn vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy10.1186/s13023-021-02125-41750-1172https://doaj.org/article/2224e9e12283412f8afa4558224ab7942021-11-01T00:00:00Zhttps://doi.org/10.1186/s13023-021-02125-4https://doaj.org/toc/1750-1172Abstract Background ABCB11 variations are responsible for a spectrum of rare liver diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) and intrahepatic cholestasis of pregnancy (ICP). Current medical treatment of these conditions mostly relies on ursodeoxycholic acid with limited efficacy. We report on the in vitro study of the p.A257V missense variant of ABCB11 identified in a PFIC2 patient and in her mother who experienced ICP. Results The Ala257 residue is located outside the ATP-binding site of ABCB11. We show that the p.A257V variant of ABCB11 is correctly expressed at the canalicular membrane of HepG2 cells but that its function significantly decreased when studied in MDCK cells. This functional defect can be fully rescued by Ivacaftor. Conclusion Ivacaftor could be considered as a new pharmacological tool able to respond to an unmet medical need for patients with ICP and PFIC2 due to ABCB11 variations affecting ABCB11 function, even when the residue involved is not located in an ATP-binding site of ABCB11.Elodie MareuxMartine LapalusAmel Ben-SaadIsabelle CallebautThomas FalguièresEmmanuel GonzalesEmmanuel JacqueminBMCarticleBSEPCholestasisVX-770PotentiatorABC transporters superfamilyPaediatricsMedicineRENOrphanet Journal of Rare Diseases, Vol 16, Iss 1, Pp 1-4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	BSEP Cholestasis VX-770 Potentiator ABC transporters superfamily Paediatrics Medicine R
spellingShingle	BSEP Cholestasis VX-770 Potentiator ABC transporters superfamily Paediatrics Medicine R Elodie Mareux Martine Lapalus Amel Ben-Saad Isabelle Callebaut Thomas Falguières Emmanuel Gonzales Emmanuel Jacquemin In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy
description	Abstract Background ABCB11 variations are responsible for a spectrum of rare liver diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) and intrahepatic cholestasis of pregnancy (ICP). Current medical treatment of these conditions mostly relies on ursodeoxycholic acid with limited efficacy. We report on the in vitro study of the p.A257V missense variant of ABCB11 identified in a PFIC2 patient and in her mother who experienced ICP. Results The Ala257 residue is located outside the ATP-binding site of ABCB11. We show that the p.A257V variant of ABCB11 is correctly expressed at the canalicular membrane of HepG2 cells but that its function significantly decreased when studied in MDCK cells. This functional defect can be fully rescued by Ivacaftor. Conclusion Ivacaftor could be considered as a new pharmacological tool able to respond to an unmet medical need for patients with ICP and PFIC2 due to ABCB11 variations affecting ABCB11 function, even when the residue involved is not located in an ATP-binding site of ABCB11.
format	article
author	Elodie Mareux Martine Lapalus Amel Ben-Saad Isabelle Callebaut Thomas Falguières Emmanuel Gonzales Emmanuel Jacquemin
author_facet	Elodie Mareux Martine Lapalus Amel Ben-Saad Isabelle Callebaut Thomas Falguières Emmanuel Gonzales Emmanuel Jacquemin
author_sort	Elodie Mareux
title	In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy
title_short	In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy
title_full	In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy
title_fullStr	In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy
title_full_unstemmed	In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy
title_sort	in vitro functional rescue by ivacaftor of an abcb11 variant involved in pfic2 and intrahepatic cholestasis of pregnancy
publisher	BMC
publishDate	2021
url	https://doaj.org/article/2224e9e12283412f8afa4558224ab794
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In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy

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