Abstract
SCN5A is abundant in heart and has a major role in INa. Loss-of-function mutation in SCN5A results in Brugada syndrome (BrS), which causes sudden death in adults. It remains unclear why disease phenotype does not manifest in the young even though mutated SCN5A is expressed in the young. The aim of the present study is to elucidate the timing of the disease manifestation in BrS. A gain-of-function mutation in SCN5A also results in Long QT syndrome type 3 (LQTS3), leading to sudden death in the young. Induced pluripotent stem cells (iPSCs) were generated from a patient with a mixed phenotype of LQTS3 and BrS with the E1784K SCN5A mutation. Here we show that electrophysiological analysis revealed that LQTS3/BrS iPSC-derived cardiomyocytes recapitulate the phenotype of LQTS3 but not BrS. Each β-subunit of the sodium channel is differentially expressed in embryonic and adult hearts. SCN3B is highly expressed in embryonic hearts and iPSC-derived cardiomyocytes. A heterologous expression system revealed that INa of mutated SCN5A is decreased and SCN3B augmented INa of mutated SCN5A. Knockdown of SCN3B in LQTS3/BrS iPSC-derived cardiomyocytes successfully unmasked the phenotype of BrS. Isogenic control of LQTS3/BrS (corrected-LQTS3/BrS) iPSC-derived cardiomyocytes gained the normal electrophysiological properties.
Highlights
Recent studies report that, following the generation of human induced pluripotent stem cells from patients with hereditary diseases, the differentiation of these iPSCs into various types of cells, including cardiomyocytes, can reproduce the disease phenotype[5,6,7,8,9,10,11]
It is of interest to examine whether iPSC-derived cardiomyocytes from patients with mixed phenotypes of Long QT syndrome type 3 (LQTS3) and Brugada syndrome (BrS) (LQTS3/BrS iPSC-derived cardiomyocytes) simulate the phenotype of LQTS3 frequently associated with young age in addition to that of BrS, which is frequently associated with adulthood, similar to that seen in patients
Because the clinical findings on syncope, electrocardiogram morphology, and drug testing suggested a mixed phenotype of LQTS3 and BrS, we genotyped the patient and identified the SCN5A E1784K (G5349A) mutation (Fig. 1B), which was shown previously to be associated with the mixed phenotype of LQTS3 and BrS
Summary
Recent studies report that, following the generation of human induced pluripotent stem cells (iPSCs) from patients with hereditary diseases, the differentiation of these iPSCs into various types of cells, including cardiomyocytes, can reproduce the disease phenotype[5,6,7,8,9,10,11]. In vitro functional characterization of these SCN5A mutants demonstrated that they exhibited loss-of-function phenotypes expected to cause BrS concurrently with a gain-of-function phenotype, which accounts for LQTS3 It is not known why loss-of-function mutations primarily affect adults. From this viewpoint, it is of interest to examine whether iPSC-derived cardiomyocytes from patients with mixed phenotypes of LQTS3 and BrS (LQTS3/BrS iPSC-derived cardiomyocytes) simulate the phenotype of LQTS3 frequently associated with young age in addition to that of BrS, which is frequently associated with adulthood, similar to that seen in patients. The temporal expression pattern of the fetal Na+ channel β-subunit SCN3B affects the manifestation of BrS phenotypes in LQTS3/BrS iPSC-derived cardiomyocytes
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