Generation of isogenic gene-corrected lines originating from two individuals with JAG1-mutated Alagille Syndrome by CRISPR/Cas9

Authors

• E Evans
• G Chen
• I Pavlinov
• X Huang
• K Linask
• C Liu
• A Rodriguez Lopez
• RE Hartke
• C Chen
• J Zou
• W Zheng

Abstract

Alagille syndrome (ALGS) is a rare autosomal dominant disorder that results primarily from mutations in JAG1, a gene responsible for encoding the cell surface protein Jagged-1 (JAG1). JAG1 is active in multiple pathways including its role as a ligand to the Notch transmembrane receptor family. Notch signaling is highly active during development of multiple tissues and promotes cell fate determination and proliferation. Proper liver development involves intercellular binding of JAG1 and Notch2, and mutations in JAG1 result in lack of bile duct formation and cholestasis, as have been observed in ALGS patients. A small percentage of ALGS cases involve mutations in NOTCH2. We have generated two CRISPR/Cas9 corrected human iPSC lines originated from previously described lines TRNDi037-A and TRNDi038-A, both of which are ALGS patient-specific lines carrying heterozygous mutation in gene of JAG1. The corrected lines are useful as isogenic controls of the ALGS iPSC lines. Here, we demonstrate that the corrected iPSC lines exhibited the pluripotent potential for self-renewal and differentiation to form three germ layers. The generation of both ALGS mutant and corrected control lines, offer great potential to study the role of JAG1 in the regulation of liver development via Notch signaling pathway and identify potential therapeutic targets in patients.

Scientific Focus Area: Stem Cell Biology

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