isogenic hiPSC lines, correcting mutations in one of the patients and introducing frameshift deletions in DISC1 into control hiPSCs. The corrected isogenic lines showed an improvement in synaptic functionality, as evidenced by the increase in synaptic markers (co-localization of SYN1 and PSD95) and increased amplitude and frequency of spontaneous synaptic currents, while the mutated isogenic lines showed a deficit in synaptic activity. The researchers then performed RNA-seq to gain understanding of the affected molecular pathways, and, for the first time, showed differential expression in DISC1-interacting proteins. Moreover, they identified differential regulation of several genes coding for presynaptic proteins (including neurexin 1, synaptophysin, and synaptoporin) and transporters (including MEF2C), implicating mutant DISC1 as a hub of transcriptional regulation (Wen et al., 2014).
