Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy - Sorbonne Université Access content directly
Journal Articles Nature Communications Year : 2015

Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy

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 arrhyth-mias. 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 þ 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.
Fichier principal
Vignette du fichier
ncomms7955.pdf (1.73 Mo) Télécharger le fichier
Origin Publication funded by an institution
Loading...

Dates and versions

hal-01292425 , version 1 (23-03-2016)

Licence

Identifiers

Cite

Ioannis Karakikes, Francesca Stillitano, Mathieu Nonnenmacher, Christos Tzimas, Despina Sanoudou, et al.. Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. Nature Communications, 2015, 6, pp.6955. ⟨10.1038/ncomms7955⟩. ⟨hal-01292425⟩
1023 View
153 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More