Characterization and mechanisms of action of novel Na_V1.5 channel mutations associated with Brugada syndrome

TY - JOUR

T1 - Characterization and mechanisms of action of novel NaV1.5 channel mutations associated with Brugada syndrome

AU - Callø, Kirstine

AU - Refaat, Marwan M.

AU - Grubb, Søren

AU - Wojciak, Julianne

AU - Campagna, Joan

AU - Thomsen, Nancy Mutsaers

AU - Nussbaum, Robert L.

AU - Scheinman, Melvin M

AU - Schmitt, Nicole

PY - 2013/2

Y1 - 2013/2

N2 - 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.

AB - 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.

U2 - 10.1161/CIRCEP.112.974220

DO - 10.1161/CIRCEP.112.974220

M3 - Journal article

C2 - 23424222

SN - 1941-3084

VL - 6

SP - 177

EP - 184

JO - Circulation. Arrhythmia and Electrophysiology (Online)

JF - Circulation. Arrhythmia and Electrophysiology (Online)

IS - 1

ER -