Characterization Of 3 Novel Nav1.5 Channel Mutations Associated With The Brugada Syndrome

INTRODUCTION: The Brugada syndrome (BrS) is characterized by an atypical right bundle block pattern with ST segment elevation and T wave inversion in the right precordial leads. The disease transmission is autosomal dominant with incomplete penetrance. We found 3 novel mutations in SCN5A in two independent families diagnosed with BrS. METHODS: We performed genetic testing of the probands’ genomic DNA. After site-directed mutagenesis and transfection, whole-cell currents were recorded by voltage clamp for NaV1.5 WT and mutants heterologously expressed in CHO-K1 cells. RESULTS: Proband 1, a 44 male with history of recurrent episodes of syncope was found to have two novel NaV1.5 mutations; NaV1.5-R811H and NaV1.5-R620H. The NaV1.5-R811H mutation showed a significant loss-of-function in peak Na+ current density. In addition, a negative shift in steady-state inactivation as well as a slowing of Ina recovery was observed for R811H. NaV1.5-R620H had no significant effect on the current. Proband 2, 33 year-old male with history of recurrent syncope which occurred both at rest and with exercise, had a novel NaV1.5-S1218I mutation. NaV1.5-S1218I had complete loss-of-function, and 1:1 expression of NaV1.5-WT and NaV1.5-S1218I mimicking the heterozygous state, revealed a 50% reduction of current compared to WT suggesting a functional haploinsufficiency in the patient. CONCLUSION: NaV1.5-S1218I and R811H are novel loss-of-function mutations in the SCN5A gene causing Brugada syndrome, whereas R620H did not appear to alter NaV1.5 function.