@article {26577,
	title = {Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy},
	journal = {Nat CommunNat CommunNat Commun},
	volume = {6},
	year = {2015},
	note = {Karakikes, IoannisStillitano, FrancescaNonnenmacher, MathieuTzimas, ChristosSanoudou, DespinaTermglinchan, VittavatKong, Chi-WingRushing, StephanieHansen, JensCeholski, DelaineKolokathis, FotisKremastinos, DimitriosKatoulis, AlexandrosRen, LihuanCohen, NinetteGho, Johannes M I HTsiapras, DimitriosVink, AryanWu, Joseph CAsselbergs, Folkert WLi, Ronald AHulot, Jean-SebastienKranias, Evangelia GHajjar, Roger JengP50 HL112324/HL/NHLBI NIH HHS/R01 HL119046/HL/NHLBI NIH HHS/R01 HL123968/HL/NHLBI NIH HHS/T32 HL007824/HL/NHLBI NIH HHS/R00 HL104002/HL/NHLBI NIH HHS/15BGIA22730027/AHA/American Heart Association-American Stroke Association/R01 HL126527/HL/NHLBI NIH HHS/R01 HL064018/HL/NHLBI NIH HHS/R01 HL093183/HL/NHLBI NIH HHS/HL26057/HL/NHLBI NIH HHS/R37 HL026057/HL/NHLBI NIH HHS/HHSN268201000045C/HL/NHLBI NIH HHS/R01 HL117505/HL/NHLBI NIH HHS/R01 HL026057/HL/NHLBI NIH HHS/K99 HL104002/HL/NHLBI NIH HHS/HL 119046/HL/NHLBI NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tEngland2015/04/30 06:00Nat Commun. 2015 Apr 29;6:6955. doi: 10.1038/ncomms7955.},
	month = {Apr 29},
	pages = {6955},
	abstract = {A number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (PLN) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhythmias. Here we generate induced pluripotent stem cells (iPSCs) from a patient harbouring the PLN R14del mutation and differentiate them into cardiomyocytes (iPSC-CMs). We find that the PLN R14del mutation induces Ca(2+) handling abnormalities, electrical instability, abnormal cytoplasmic distribution of PLN protein and increases expression of molecular markers of cardiac hypertrophy in iPSC-CMs. Gene correction using transcription activator-like effector nucleases (TALENs) ameliorates the R14del-associated disease phenotypes in iPSC-CMs. In addition, we show that knocking down the endogenous PLN and simultaneously expressing a codon-optimized PLN gene reverses the disease phenotype in vitro. Our findings offer novel strategies for targeting the pathogenic mutations associated with cardiomyopathies.},
	keywords = {*Targeted Gene Repair, Adenoviridae, Adult, Calcium-Binding Proteins/*genetics, Cardiomyopathies/*genetics/metabolism/therapy, Deoxyribonucleases, Female, Gene Transfer Techniques, Humans, Induced Pluripotent Stem Cells, Myocytes, Cardiac/*metabolism, Phenotype, Sequence Deletion},
	isbn = {2041-1723 (Electronic)2041-1723 (Linking)},
	author = {Karakikes, I. and Stillitano, F. and Nonnenmacher, M. and Tzimas, C. and Sanoudou, D. and Termglinchan, V. and Kong, C. W. and Rushing, S. and Hansen, J. and Ceholski, D. and Kolokathis,F. and Kremastinos, D. and Katoulis, A and Ren, L. and Cohen, N. and Gho, Jmih and Tsiapras, D and Vink, A. and Wu, J. C. and Asselbergs, F. W. and Li, R. A. and Hulot, J. S. and Kranias, EG and Hajjar, R. J.}
}
