A novel nonsense mutation in the SCN5A gene leads to Brugada syndrome and a silent gene mutation carrier state.
BACKGROUND
Brugada syndrome (BS) is an electrical cardiac disorder with a right bundle branch block and ST segment elevation in leads V1 to V3 on surface electrocardiograms (ECGs), and is a syndrome that may lead to sudden cardiac death.


OBJECTIVE
The aim of the present study was to screen for mutations in the SCN5A gene in a family with BS, and to characterize the consequences of the mutation on channel function.


RESULTS
A heterozygous nonsense SCN5A mutation (W822X) was identified in the index patient. The mutation was confirmed in the patient's asymptomatic 16-year-old brother and 48-year-old father. The mutation was absent in the index patient's sister and mother. The ECG of the index patient showed a BS type 2 ECG phenotype, which converted into a type 1 ECG phenotype in the presence of flecainide. The ECG of the patient's brother was not typical for BS, but ajmaline treatment unmasked a type 1 ECG phenotype. The ECG of the asymptomatic father was normal at baseline and in the presence of ajmaline. No Na+ currents could be measured in tsA201 cells transfected with W822X mutant channels. Heterozygote expression showed a nearly 50% reduction in Na+ current amplitude with no significant alterations of biophysical properties, indicating a loss of functional Na+ channels, obviously without any dominant-negative activity on wild type channels.


CONCLUSIONS
The haploinsufficiency of the Nav1.5 protein is the plausible explanation for the clinical BS phenotype in this family. Because the heterozygous W822X mutation theoretically leads to channel expression at one-half of the normal level, the authors suggest that a modifier gene may influence or rescue the phenotype in the asymptomatic family members.
Keller
Dagmar I
DI
Institut national de la santé et de la recherche médicale U582, Institut Fédératif de Recherche No 14, Pitié-Salpêtrière Hospital, Paris, France.
Barrane
Fatima-Zahara
FZ
Gouas
Laetitia
L
Martin
Johannie
J
Pilote
Sylvie
S
Suarez
Vivian
V
Osswald
Stefan
S
Brink
Marijke
M
Guicheney
Pascale
P
Schwick
Nicola
N
Chahine
Mohamed
M
D000293:Adolescent; D000328:Adult; D000404:Ajmaline; D000889:Anti-Arrhythmia Agents; D002037:Bundle-Branch Block / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D002460:Cell Line; D018389:Codon, Nonsense; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D004562:Electrocardiography; D005260:Female; D006331:Heart Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D008967:Molecular Biology; D009124:Muscle Proteins / Q000235:genetics*; D016296:Mutagenesis; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D013577:Syndrome; D014162:Transfection
D000889:Anti-Arrhythmia Agents; D018389:Codon, Nonsense; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D000404:Ajmaline