title: Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans.
abstract: Brugada syndrome is a genetic disease associated with sudden cardiac death that is characterized by ventricular fibrillation and right precordial ST segment elevation on ECG. Loss-of-function mutations in SCN5A, which encodes the predominant cardiac sodium channel alpha subunit NaV1.5, can cause Brugada syndrome and cardiac conduction disease. However, SCN5A mutations are not detected in the majority of patients with these syndromes, suggesting that other genes can cause or modify presentation of these disorders. Here, we investigated SCN1B, which encodes the function-modifying sodium channel beta1 subunit, in 282 probands with Brugada syndrome and in 44 patients with conduction disease, none of whom had SCN5A mutations. We identified 3 mutations segregating with arrhythmia in 3 kindreds. Two of these mutations were located in a newly described alternately processed transcript, beta1B. Both the canonical and alternately processed transcripts were expressed in the human heart and were expressed to a greater degree in Purkinje fibers than in heart muscle, consistent with the clinical presentation of conduction disease. Sodium current was lower when NaV1.5 was coexpressed with mutant beta1 or beta1B subunits than when it was coexpressed with WT subunits. These findings implicate SCN1B as a disease gene for human arrhythmia susceptibility.
authors.affiliation: Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Koopmann
authors.forename: Solena
authors.initials: S
authors.lastname: Le Scouarnec
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Christiana R
authors.initials: CR
authors.lastname: Ingram
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.forename: Sophie
authors.initials: S
authors.lastname: Demolombe
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Frédéric
authors.initials: F
authors.lastname: Anselme
authors.forename: Denis
authors.initials: D
authors.lastname: Escande
authors.forename: Ans C P
authors.initials: AC
authors.lastname: Wiesfeld
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Can
authors.initials: C
authors.lastname: Hasdemir
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
mesh_terms: D000293:Adolescent; D000328:Adult; D053840:Brugada Syndrome / Q000235:genetics* / Q000473:pathology; D004594:Electrophysiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D011690:Purkinje Fibers / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics*; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
chemical_list: C470379:SCN1B protein, human; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit