A spontaneously reverted iPSC line was identified from an A-T subject with heterozygous ATM truncation mutations. The reverted iPSC line expressed ATM protein and was capable of radiation-induced phosphorylation of CHK2 and H2A.X. Genome-wide SNP analysis confirmed a match to source T cells and also to a distinct, non-reverted iPSC line from the same subject. Rearranged T cell receptor sequences predict that the iPSC culture originated as several independently reprogrammed cells that resolved into a single major clone, suggesting that gene correction likely occurred early in the reprogramming process. Gene expression analysis comparing ATM-/- iPSC lines to unrelated ATM+/- cells identifies a large number of differences, but comparing only the isogenic pair of A-T iPSC lines reveals that the primary pathway affected by loss of ATM is a diminished expression of p53-related mRNAs. Gene reversion in culture, although likely a rare event, provided a novel, reverted cell line for studying ATM function.
Lin, L., Swerdel, M. R., Lazaropoulos, M. P., Hoffman, G. S., Toro-Ramos, A. J., Wright, J., … Hart, R. P. (2015). Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line. Stem Cell Reports, 5(6), 1097–1108. https://doi.org/10.1016/j.stemcr.2015.10.010