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SCN5A  is abundant in heart and has a major role in  I   Na  . 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  I   Na   of mutated SCN5A is decreased and  SCN3B  augmented  I   Na   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.

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