title: A nonsense SCN5A mutation associated with Brugada-type electrocardiogram and intraventricular conduction defects.
abstract: Mutations of SCN5A, gene-encoding alpha-subunit of cardiac sodium channel, can cause mixed phenotypes of Brugada syndrome (BrS) and cardiac conduction diseases (CCD). We have identified a nucleotide change of SCN5A (4178T > G), which results in a nonsense mutation, L1393X, in a 36-year-old Caucasian man who presented with intraventricular conduction delays and BrS-type electrocardiogram change. To study biophysical characteristics of L1393X-SCN5A, electrophysiological and immuno-staining studies were performed using mammalian expression systems. While WT-SCN5A showed significant currents (93.3 +/- 10.6 pA/pF; 1 microg plasmid), L1393X (5 microg) did not generate any significant currents in NIH-3T3 cells. The cells cotransfected with WT (0.5 microg) and L1393X (0.5 microg) showed approximately 50% current amplitudes compared to the WT (1 microg). Voltage dependency of a steady-state activation and inactivation was not affected by the cotransfection of L1393X. Immuno-histochemical stainings demonstrated that L1393X proteins were expressed in the plasma membranes. Our study demonstrated that L1393X-SCN5A does not form functional channel proteins, which might account for the patient's mixed phenotypes of BrS and CCD.
authors.affiliation: Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke's Episcopal Hospital, Houston, Texas.
authors.forename: Kaveh
authors.initials: K
authors.lastname: Samani
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ai
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
authors.forename: Mossaab
authors.initials: M
authors.lastname: Shuraih
authors.forename: Yutao
authors.initials: Y
authors.lastname: Xi
authors.forename: Geru
authors.initials: G
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
mesh_terms: D000328:Adult; D053840:Brugada Syndrome / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006329:Heart Conduction System / Q000002:abnormalities*; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels