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An ABCB11 variant registry and novel knockin mouse model of PFIC2 based on the clinically relevant ABCB11 E297G
Eric L Bell1, Jennifer K Truong1, Youhwa Jo1
1Rectify Pharmaceuticals, Cambridge, MA, USA.
Insights
Researchers developed tools for Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2) research, including a mutation catalog and a mouse model. These resources aid in understanding and treating this rare pediatric liver disease.
Area of Science:
- Hepatology
- Genetics
- Biochemistry
Background:
- Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2) is a rare pediatric liver disease driven by genetic defects in the bile salt export pump (BSEP, ABCB11).
- BSEP deficiency impairs hepatic bile acid efflux, leading to cholestasis and toxic bile acid accumulation, causing progressive liver injury.
- Understanding ABCB11 mutations and their functional consequences is crucial for PFIC2 research and therapeutic development.
Purpose of the Study:
- To create novel translational tools to support research into PFIC2.
- To develop a comprehensive catalog of disease-relevant ABCB11 mutations.
- To validate a new knockin mouse model for studying the PFIC2-associated E297G variant.
Main Methods:
- AI-based indexing and manual review of published literature to identify ABCB11 variants in cholestatic patients.
- Creation and phenotypic validation of a knockin mouse model harboring the ABCB11 E297G missense variant.
- Assessment of BSEP processing, membrane trafficking, cholestasis, and hepatotoxicity in the mouse model.
Main Results:
- A catalog of 476 non-benign ABCB11 variants was compiled, with 240 specifically linked to PFIC2.
- The BsepE297G homozygous knockin mice exhibited core PFIC2 pathologies, including impaired BSEP function and cholestasis.
- Pharmacological inhibition of ileal bile acid transporter (IBAT) ameliorated the cholestatic phenotype in the mouse model.
Conclusions:
- The developed mutation catalog and E297G mouse model are valuable translational tools for PFIC2 research.
- These tools facilitate a deeper understanding of PFIC2 pathophysiology and genotype-phenotype correlations.
- The findings support further clinical and translational efforts to advance PFIC2 diagnosis and treatment strategies.
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 catalog 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 nonbenign 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 ileal bile acid transporter inhibition improved the cholestatic phenotype of BsepE297G mice through increased fecal bile acid excretion. Together, these tools can support clinical and translational efforts to advance understanding and treatment of PFIC2.
