FIGURE 2.

Schematic for modeling rare neuromuscular disorders using genetically engineered iPSCs. (A) KOLF2 iPSCs genetically engineered to carry CMT-associated GARS mutations can be differentiated into motor neurons, which are affected by CMT, and cortical neurons, which are not affected by CMT. The wild-type parental cells and revertant cells (which have had the introduced GARS mutation corrected back to WT) can be used as controls. (B) Translation assays, high content imaging and morphometrics, and gene expression analysis can be used to determine if the ISR is activated in GARS mutant motor neurons. (C) If motor neurons have the expected phenotype (ISR induction), then they can be used for further mechanistic experiments, such as ribosome stalling assays and analysis of biochemical properties of tRNA sequestration. These cells can also be used for high-throughput screens of therapeutics.