Embryonic type Na+ channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome

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.

Modeling Inherited Arrhythmia Disorders Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…Consistent with this hypothesis, quiescent hiPSC-CMs exhibited both more depolarized RMP and increased up-stroke velocity compared to their spontaneously beating counterparts, consistent with relatively higher maturity of quiescent compared to spontaneously beating hiPSC-CMs 44 . Despite the reduced AP upstroke velocity in hiPSC-CMs, patient-derived hiPSC-CMs harboring SCN5A or SCN3B mutations in large part recapitulated the abnormalities observed in CMs derived from transgenic mice with similar genetic anomalies 44,46 .…”

“…They also did not detect any consistent changes in the other currents proposed to contribute to BrS (I to or I Ca,L ) 95 . A third study of hiPSC-CMs from a patient with E1784K SCN5A mutation and a mixed LQT3 and BrS phenotype found that the hiPSC-CMs manifested electrophysiological abnormalities consistent with LQT3 but not BrS 46 . SCN3B, the embryonic beta subunit of the cardiac sodium channel, was found to be expressed in hiPSC-CMs at higher levels than in mature CMs.…”

Inherited cardiac diseases, pluripotent stem cells, and genome editing combined—the past, present, and future

“…These too have been modeled using patient-derived hiPSCs with the hiPSC-CMs showing the electrophysiological properties of both syndromes. 35,36 However, hiPSC-CMs from BrS patients without SCN5A mutations did not show sodium channel dysfunction or the BrS phenotype. 37 As the disease typically occurs in adulthood, the lack of a disease phenotype in the hiPSC-CMs could be due to the immaturity of the hiPSC-CMs or the absence of other nongenetic contributors (ie, fibrosis and environmental factors).…”

The Brugada Syndrome ― From Gene to Therapy ―

“…78, 79 If optimized, a hypothetical hiPSC-based approach could be successful in cases of frequent ICD shocks attributable to VT in spite of aggressive antiarrhythmic treatment, thus realizing "patienttailored therapy".…”