Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Université Paris-Saclay, Hepatinov, 91400, Orsay, France.
Muséum National d'Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, Sorbonne Université, 75005, Paris, France.
Orphanet J Rare Dis. 2021 Nov 18;16(1):484. 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.
ABCB11 变异可导致一系列罕见肝脏疾病，包括进行性家族性肝内胆汁淤积症 2 型（PFIC2）和妊娠肝内胆汁淤积症（ICP）。目前，这些疾病的主要治疗方法是熊去氧胆酸，但疗效有限。我们报告了在 PFIC2 患者及其经历 ICP 的母亲中发现的 ABCB11 错义变异 p.A257V 的体外研究。
Ala257 残基位于 ABCB11 的 ATP 结合位点之外。我们表明，ABCB11 的 p.A257V 变体在 HepG2 细胞的胆小管膜上正确表达，但在 MDCK 细胞中其功能显著降低。这种功能缺陷可以通过 Ivacaftor 完全挽救。
Ivacaftor 可被视为一种新的药理学工具，能够满足因 ABCB11 变异影响 ABCB11 功能而导致 ICP 和 PFIC2 患者的未满足医疗需求，即使涉及的残基不位于 ABCB11 的 ATP 结合位点。
