In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy
| Autor: | Isabelle Callebaut, Martine Lapalus, Emmanuel Jacquemin, Emmanuel Gonzales, Elodie Mareux, Amel Ben-Saad, Thomas Falguières |
|---|---|
| Přispěvatelé: | Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), HAL-SU, Gestionnaire |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
Cholestasis Intrahepatic Quinolones VX-770 Aminophenols Gastroenterology Ivacaftor 03 medical and health sciences 0302 clinical medicine Cholestasis ABC transporters superfamily Internal medicine medicine Missense mutation Humans Pharmacology (medical) ABCB11 Letter to the Editor Genetics (clinical) ATP Binding Cassette Transporter Subfamily B Member 11 030304 developmental biology 0303 health sciences [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology business.industry Progressive familial intrahepatic cholestasis Paediatrics General Medicine Potentiator medicine.disease Ursodeoxycholic acid 3. Good health Pregnancy Complications BSEP Mutation Medicine 030211 gastroenterology & hepatology ATP-Binding Cassette Transporters Female business Cholestasis of pregnancy [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology medicine.drug |
| Zdroj: | Orphanet Journal of Rare Diseases Orphanet Journal of Rare Diseases, Vol 16, Iss 1, Pp 1-4 (2021) Orphanet Journal of Rare Diseases, BioMed Central, 2021, 16 (1), ⟨10.1186/s13023-021-02125-4⟩ Orphanet Journal of Rare Diseases, 2021, 16 (1), ⟨10.1186/s13023-021-02125-4⟩ |
| ISSN: | 1750-1172 |
| DOI: | 10.1186/s13023-021-02125-4⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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