A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation.
OBJECTIVE
Brugada syndrome (BS) is an inherited electrical cardiac disorder characterized by right bundle branch block pattern and ST segment elevation in leads V1 to V3 on surface electrocardiogram that can potentially lead to malignant ventricular tachycardia and sudden cardiac death. About 20% of patients have mutations in the only so far identified gene, SCN5A, which encodes the alpha-subunit of the human cardiac voltage-dependent sodium channel (hNa(v)1.5). Fever has been shown to unmask or trigger the BS phenotype, but the associated molecular and the biophysical mechanisms are still poorly understood. We report on the identification and biophysical characterization of a novel heterozygous missense mutation in SCN5A, F1344S, in a 42-year-old male patient showing the BS phenotype leading to ventricular fibrillation during fever.


METHODS
The mutation was reproduced in vitro using site-directed mutagenesis and characterized using the patch clamp technique in the whole-cell configuration.


RESULTS
The biophysical characterization of the channels carrying the F1344S mutation revealed a 10 mV mid-point shift of the G/V curve toward more positive voltages during activation. Raising the temperature to 40.5 degrees C further shifted the mid-point activation by 18 mV and significantly changed the slope factor in Na(v)1.5/F1344S mutant channels from -6.49 to -10.27 mV.


CONCLUSIONS
Our findings indicate for the first time that the shift in activation and change in the slope factor at a higher temperature mimicking fever could reduce sodium currents' amplitude and trigger the manifestation of the BS phenotype.
Keller
Dagmar I
DI
Cardiology Department, University Hospital Basel, Switzerland.
Huang
Hai
H
Zhao
Juan
J
Frank
Rudolf
R
Suarez
Vivian
V
Delacrétaz
Etienne
E
Brink
Marijke
M
Osswald
Stefan
S
Schwick
Nicola
N
Chahine
Mohamed
M
D000200:Action Potentials / Q000502:physiology; D000328:Adult; D053840:Brugada Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005334:Fever / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D032342:Muscle Cells / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction / Q000379:methods; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D014162:Transfection / Q000379:methods; D014693:Ventricular Fibrillation / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels