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

• Published in: Orphanet journal of rare diseases Vol. 16; no. 1; p. 484
• Main Authors: Mareux, Elodie, Lapalus, Martine, Ben-Saad, Amel, Callebaut, Isabelle, Falguières, Thomas, Gonzales, Emmanuel, Jacquemin, Emmanuel
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18.11.2021; BioMed Central; BMC
• Subjects: ABC transporters superfamily; Aminophenols - therapeutic use; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters - genetics; Bile; Binding sites; BSEP; Carrier proteins; Cholestasis; Cholestasis, Intrahepatic - drug therapy; Cholestasis, Intrahepatic - genetics; Cystic fibrosis; Drug therapy; Female; Gallbladder diseases; Genetic aspects; Genetic variation; Glycoproteins; Health aspects; Hepatology; Human health and pathology; Humans; Ivacaftor; Jaundice, Obstructive; Letter to the Editor; Life Sciences; Liver diseases; Medical research; Medical treatment; Medicine, Experimental; Mutation; Paediatrics; Patients; Potentiator; Pregnancy; Pregnancy Complications; Pregnancy, Complications of; Quinolones; Rare diseases; Salt; Ursodeoxycholic acid; VX-770; Womens health; France; ABC transporters superfamily; BSEP; VX-770; Cholestasis; Paediatrics; Potentiator
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-021-02125-4

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. 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. 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.