+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Nav1.5 Function of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A



Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Nav1.5 Function of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A



Circulation. Arrhythmia and Electrophysiology 9(11)



Several compounds have been reported to induce translational readthrough of premature stop codons resulting in the production of full-length protein by interfering with ribosomal proofreading. Here we examined the effect of 2 of these compounds, gentamicin and PTC124, in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes bearing nonsense mutations in the sodium channel gene SCN5A, which are associated with conduction disease and potential lethal arrhythmias. We generated hiPSC from 2 patients carrying the mutations R1638X and W156X. hiPSC-derived cardiomyocytes from both patients recapitulated the expected electrophysiological phenotype, as evidenced by reduced Na+ currents and action potential upstroke velocities compared with hiPSC-derived cardiomyocytes from 2 unrelated control individuals. While we were able to confirm the readthrough efficacy of the 2 drugs in Human Embryonic Kidney 293 cells, we did not observe rescue of the electrophysiological phenotype in hiPSC-derived cardiomyocytes from the patients. We conclude that these drugs are unlikely to present an effective treatment for patients carrying the loss-of-function SCN5A gene mutations examined in this study.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 058701685

Download citation: RISBibTeXText

PMID: 27784737

DOI: 10.1161/circep.116.004227


Related references

Hyperthermia Influences the Effects of Sodium Channel Blocking Drugs in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Plos One 11(11): E0166143, 2017

Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient. Journal of Molecular and Cellular Cardiology 114: 10-19, 2017

Evaluation system for arrhythmogenic potential of drugs using human-induced pluripotent stem cell-derived cardiomyocytes and gene expression analysis. Journal of Toxicological Sciences 42(6): 755-761, 2018

Switch From Fetal to Adult SCN5A Isoform in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Unmasks the Cellular Phenotype of a Conduction Disease-Causing Mutation. Journal of the American Heart Association 6(7), 2018

Ion Channel Expression and Characterization in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Stem Cells International 2018: 6067096, 2018

Association of HERG and SCN5A Transcripts Regulates Ion Channel Expression and Function in Stem Cell Derived Cardiomyocytes. Biophysical Journal 114(3): 378a-379a, 2018

Identifying the Transcriptome Signatures of Calcium Channel Blockers in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Circulation Research 2019, 2019

Effects of cardioactive drugs on human induced pluripotent stem cell derived long QT syndrome cardiomyocytes. Springerplus 5: 234, 2016

Integration-free T cell-derived human induced pluripotent stem cells (iPSCs) from a patient with recessive dystrophic epidermolysis bullosa (RDEB) carrying two compound heterozygous mutations in the COL7A1 gene. Stem Cell Research 17(1): 32-35, 2016

Human-induced pluripotent stem cell-derived cardiomyocytes from cardiac progenitor cells: effects of selective ion channel blockade. Europace 18(Suppl 4): Iv67-Iv76, 2017

The effects of gentamicin and penicillin/streptomycin on the electrophysiology of human induced pluripotent stem cell-derived cardiomyocytes in manual patch clamp and multi-electrode array system. Journal of Pharmacological and Toxicological Methods 91: 1-6, 2017

Multiparametric assessment of cardiotoxicity of chemotherapeutic drugs in human induced pluripotent stem cell (hiPsc)-derived cardiomyocytes. Journal of Pharmacological and Toxicological Methods 93: 150-151, 2018

Biophysical comparison of sodium currents in native cardiac myocytes and human induced pluripotent stem cell-derived cardiomyocytes. Journal of Pharmacological and Toxicological Methods 90: 19-30, 2017

Large-Scale Simulation of the Phenotypical Variability Induced by Loss-of-Function Long QT Mutations in Human Induced Pluripotent Stem Cell Cardiomyocytes. International Journal of Molecular Sciences 19(11), 2018

Supervised Machine Learning for Classification of the Electrophysiological Effects of Chronotropic Drugs on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Plos One 10(12): E0144572, 2016