Key result
Gentamicin and PTC124 fail to rescue electrophysiological phenotypes in hiPSC cardiomyocytes with SCN5A nonsense mutations.
Why the study?
Several compounds have been reported to induce translational readthrough of premature stop codons to produce full-length protein, but their efficacy in hiPSC-derived cardiomyocytes with SCN5A nonsense mutations was unknown.
Do gentamicin and PTC124 rescue the electrophysiological phenotype in hiPSC-derived cardiomyocytes carrying SCN5A nonsense mutations?
Do gentamicin and PTC124 rescue the electrophysiological phenotype in hiPSC-derived cardiomyocytes carrying SCN5A nonsense mutations?
Gentamicin and PTC124 failed to rescue sodium channel function in hiPSC-derived cardiomyocytes with SCN5A nonsense mutations, indicating they are unlikely to be effective treatments for these patients.
Gentamicin and PTC124 should not be considered for SCN5A nonsense mutations; leaves open whether alternative read-through strategies merit testing in channelopathies.
Background— 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. Methods and Results— 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. Conclusions— 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.
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Kosmidis et al. (2016) studied SCN5A nonsense mutations associated with conduction disease and potential lethal arrhythmias (n=4). Gentamicin and PTC124 vs. Control individuals / untreated state was evaluated on Rescue of the electrophysiological phenotype (Na+ currents and action potential upstroke velocities). Gentamicin and PTC124 failed to rescue the electrophysiological phenotype of reduced Na+ currents and action potential upstroke velocities in hiPSC-derived cardiomyocytes with SCN5A nonsense mutations.
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