Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family.
BACKGROUND
The SCN5A gene encoding the human cardiac sodium channel alpha subunit plays a key role in cardiac electrophysiology. Mutations in SCN5A lead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, and isolated progressive cardiac conduction defect (Lenègre disease).


RESULTS
In the present study, we report the identification of a novel single SCN5A missense mutation causing either Brugada syndrome or an isolated cardiac conduction defect in the same family. A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the sodium channel protein. Among 45 family members, 13 were carrying the G1406R SCN5A mutation. Four individuals from 2 family collateral branches showed typical Brugada phenotypes, including ST-segment elevation in the right precordial leads and right bundle branch block. One symptomatic patient with the Brugada phenotype required implantation of a cardioverter-defibrillator. Seven individuals from 3 other family collateral branches had isolated cardiac conduction defects but no Brugada phenotype. Three flecainide test were negative. One patient with an isolated cardiac conduction defect had an episode of syncope and required pacemaker implantation. An expression study of the G1406R-mutated SCN5A showed no detectable Na(+) current but normal protein trafficking.


CONCLUSIONS
We conclude that the same mutation in the SCN5A gene can lead either to Brugada syndrome or to an isolated cardiac conduction defect. Our findings suggest that modifier gene(s) may influence the phenotypic consequences of a SCN5A mutation.
Kyndt
F
F
Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, INSERM U533, Paris, France.
Probst
V
V
Potet
F
F
Demolombe
S
S
Chevallier
J C
JC
Baro
I
I
Moisan
J P
JP
Boisseau
P
P
Schott
J J
JJ
Escande
D
D
Le Marec
H
H
D000818:Animals; D019556:COS Cells; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005192:Family Health; D005260:Female; D005602:France; D049452:Green Fluorescent Proteins; D006327:Heart Block / Q000235:genetics / Q000503:physiopathology; D006329:Heart Conduction System / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009154:Mutation; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics*; D013577:Syndrome
D008164:Luminescent Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011993:Recombinant Fusion Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels; D049452:Green Fluorescent Proteins; D004247:DNA