Referenced in: none

Automatically associated channels: Nav1.5

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

Authors: Kirstine Calloe, Marwan M Refaat, Soren Grubb, Julianne Wojciak, Joan Campagna, Nancy Mutsaers Thomsen, Robert L Nussbaum, Melvin M Scheinman, Nicole Schmitt

Journal, date & volume: Circ Arrhythm Electrophysiol, 2013 Feb , 6, 177-84

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23424222

Abstract
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 Na(V)1.5 are associated with Brugada syndrome. We found novel mutations in SCN5A in 2 different families diagnosed with Brugada syndrome and investigated how those affected Na(V)1.5 channel function.We performed genetic testing of the probands' genomic DNA. After site-directed mutagenesis and transfection, whole-cell currents were recorded for Na(V)1.5 wild type and mutants heterologously expressed in Chinese hamster ovary-K1 cells. Proband 1 had two novel Na(V)1.5 mutations: Na(V)1.5-R811H and Na(V)1.5-R620H. The Na(V)1.5-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 Na(V)1.5-R620H had no significant effect on the current. Proband 2 had a novel Na(V)1.5-S1218I mutation. Na(V)1.5-S1218I had complete loss of function, and 1:1 expression of Na(V)1.5-wild type and Na(V)1.5-S1218I mimicking the heterozygous state revealed a 50% reduction in current compared with wild type, suggesting a functional haploinsufficiency in the patient.Na(V)1.5-S1218I and R811H are novel loss-of-function mutations in the SCN5A gene causing Brugada syndrome.