An ABCB11 variant registry and novel knockin mouse model of PFIC2 based on the clinically relevant ABCB11 E297G variant.

IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Eric L Bell, Jennifer K Truong, Youhwa Jo, Adrianne Kolpak, Lauren Chunn, Natalie Syverud, Melida Mahinic, Jessica R Durrant, Eitan Hoch, Bharat Reddy, Patrick Stoiber, John P Miller, Yong Ren, Jonathan Moore, Robert O Hughes, Alastair S Garfield
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引用次数: 0

Abstract

Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare pediatric cholestatic liver disease caused by genetic deficiency in the bile salt export pump (BSEP, ABCB11). BSEP is an ATP-binding cassette transporter and the primary regulator of hepatic bile acid efflux. Loss of BSEP function in PFIC2 leads to cholestasis and intrahepatic accumulation of bile acids, the native toxicity of which drives progressive liver injury, in a manner that correlates with ABCB11 genotype. Here, to support ongoing PFIC2 research, we present two novel translational tools, 1) a codified evidence-based catalogue of published disease relevant ABCB11 mutations and 2) a knockin mouse model of the PFIC2-associated missense variant E297G. Using a combination of AI-based indexing of the literature and manual review, we identified 476 non-benign ABCB11 variants in published patients with cholestatic disease, of which 240 were associated with PFIC2. Additionally, we present phenotypic validation of a novel knockin mouse model of the cholestasis associated ABCB11 E297G variant. BsepE297G homozygous mice recapitulate the core molecular and pathophysiological aspects of PFIC2, including perturbed Bsep processing and membrane trafficking, cholestasis, and hepatotoxicity. Moreover, and consistent with clinical data, pharmacological IBAT inhibition improved the cholestatic phenotype of BsepE297G mice through increased fecal BA excretion. Together, these tools can support clinical and translational efforts to advance understanding and treatment of PFIC2.

基于临床相关ABCB11 E297G变异的ABCB11变异登记和新型PFIC2敲入小鼠模型
进行性家族性肝内胆汁淤积2型(PFIC2)是一种罕见的儿童胆汁淤积性肝病,由胆盐输出泵基因缺陷(BSEP, ABCB11)引起。BSEP是一种atp结合盒转运蛋白,是肝胆汁酸外排的主要调节因子。PFIC2中BSEP功能的丧失导致胆汁淤积和肝内胆汁酸积聚,其天然毒性驱动进行性肝损伤,其方式与ABCB11基因型相关。在这里,为了支持正在进行的PFIC2研究,我们提出了两种新的翻译工具,1)已发表的疾病相关ABCB11突变的基于证据的编码目录和2)PFIC2相关错义变体E297G的敲入小鼠模型。结合基于人工智能的文献索引和人工综述,我们在已发表的胆汁沉积症患者中发现了476个非良性ABCB11变异,其中240个与PFIC2相关。此外,我们提出了一种新的敲入小鼠模型的表型验证与胆固醇沉积相关的ABCB11 E297G变异。BsepE297G纯合小鼠概括了PFIC2的核心分子和病理生理方面,包括Bsep加工和膜运输的紊乱、胆汁淤积和肝毒性。此外,与临床数据一致,IBAT药理学抑制通过增加粪便BA排泄改善BsepE297G小鼠的胆汁淤积表型。总之,这些工具可以支持临床和转化工作,以促进对PFIC2的理解和治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Lipid Research
Journal of Lipid Research 生物-生化与分子生物学
CiteScore
11.10
自引率
4.60%
发文量
146
审稿时长
41 days
期刊介绍: The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.
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