Key result
The DSP-H1684R genetic variant in iPSC-derived cardiomyocytes altered ion channel activity and shortened action potentials compared to healthy donors.
Why the study?
Mutations in desmosomal genes cause arrhythmogenic cardiomyopathy, but the effect of the novel DSP-H1684R genetic variant on ion channel activity remained to be investigated.
Does the DSP-H1684R genetic variant affect ion channel activity and action potential properties in iPSC-derived cardiomyocytes?
Does the DSP-H1684R genetic variant affect ion channel activity and action potential properties in iPSC-derived cardiomyocytes?
The DSP-H1684R genetic variant in desmoplakin alters multiple ion channel activities and shortens action potentials in iPSC-derived cardiomyocytes, suggesting a mechanism for aggravated arrhythmia in progressive cardiac conduction disease.
DSP-H1684R effects on ion channels remain hypothesis-generating in iPSC models; clinical relevance for PCCD requires validation.
BACKGROUND/AIMS: Mutations of desmosomal genes are known to cause arrhythmogenic cardiomyopathy characterized by arrhythmias and sudden cardiac death. Previously, we described a novel genetic variant H1684R in desmoplakin gene (DSP), associated with a progressive cardiac conduction disease (PCCD). In the present study, we aimed to investigate an effect of the DSP-H1684R genetic variant on the activity of ion channels. METHODS: We used cardiomyocytes derived from induced pluripotent stem cells (iPSC cardiomyocytes) from a patient with DSP-H1684R genetic variant and from two healthy donors. Immunofluorescent staining and western blot analyses were used to characterize patient-specific cardiomyocytes. By the whole-cell voltage-clamp technique we estimated the activity of voltage-gated sodium, calcium, and potassium channels that are responsible for action potential generation and its shape. Action potentials' parameters were measured using whole-cell current-clamp technique. RESULTS: 1.5 channels and L-type calcium channels, but higher amplitude of current through transient-outward potassium channels in comparison to donor cardiomyocytes. Current-clamp measurements revealed shortening of action-potential in DSP-H1684R-carrying iPSC cardiomyocytes. Therefore, observed alterations in the channels activity might have a great impact on the properties of action potential and development of PCCD. CONCLUSION: Our results show that desmoplakin genetic variants, besides conduction slowing caused by structural heart remodeling, could affect multiple ion channel activity aggravating arrhythmia manifestation in PCCD.
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Gusev et al. (2020) studied Progressive cardiac conduction disease (PCCD) (n=3). DSP-H1684R genetic variant vs. Healthy donors was evaluated on Ion channel activity and action potential parameters. The DSP-H1684R genetic variant in iPSC-derived cardiomyocytes altered ion channel activity and shortened action potentials compared to healthy donors.
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