title: Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line.
abstract: 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.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Mavis R
authors.initials: MR
authors.lastname: Swerdel
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lazaropoulos
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Hoffman
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Alana J
authors.initials: AJ
authors.lastname: Toro-Ramos
authors.affiliation: A-T Clinic, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wright
authors.affiliation: A-T Clinic, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Lederman
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA; Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Moore
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA. Electronic address: rhart@rutgers.edu.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Hart
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D065150:Cellular Reprogramming; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins