oxadiazoles and Brugada-Syndrome

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. 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.

Topics: Action Potentials; Adult; Brugada Syndrome; Cardiac Conduction System Disease; Cells, Cultured; Codon, Nonsense; Electrophysiologic Techniques, Cardiac; Gentamicins; Humans; Induced Pluripotent Stem Cells; Male; Middle Aged; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Oxadiazoles; Phenotype