Characterization and mechanisms of action of novel NaV1.5 channel mutations associated with Brugada syndrome

Abstract

Background - Brugada syndrome is a heterogeneous heart rhythm disorder characterized by an atypical right bundle block pattern with ST-segment elevation and T-wave inversion in the right precordial leads. Loss-of-function mutations in SCN5A encoding the cardiac sodium channel NaV1.5 are associated with Brugada syndrome. We found novel mutations in SCN5A in 2 different families diagnosed with Brugada syndrome and investigated how those affected NaV1.5 channel function. Methods and Results - We performed genetic testing of the probands' genomic DNA. After site-directed mutagenesis and transfection, whole-cell currents were recorded for NaV1.5 wild type and mutants heterologously expressed in Chinese hamster ovary-K1 cells. Proband 1 had 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 and alteration of biophysical kinetic parameters (inactivation and recovery from inactivation), whereas NaV1.5-R620H had no significant effect on the current. Proband 2 had a novel NaV1.5-S1218I mutation. Na V1.5-S1218I had complete loss of function, and 1:1 expression of NaV1.5-wild type and NaV1.5-S1218I mimicking the heterozygous state revealed a 50% reduction in current compared with wild type, suggesting a functional haploinsufficiency in the patient. Conclusions - Na V1.5-S1218I and R811H are novel loss-of-function mutations in the SCN5A gene causing Brugada syndrome. © 2013 American Heart Association, Inc.