title: Molecular mechanism for an inherited cardiac arrhythmia.
abstract: In the congenital long-QT syndrome, prolongation of the cardiac action potential occurs by an unknown mechanism and predisposes individuals to syncope and sudden death as a result of ventricular arrhythmias. Genetic heterogeneity has been demonstrated for autosomal dominant long-QT syndrome by the identification of multiple distinct loci, and associated mutations in two candidate genes have recently been reported. One form of hereditary long QT (LQT3) has been linked to a mutation in the gene encoding the human heart voltage-gated sodium-channel alpha-subunit (SCN5A on chromosome 3p21). Here we characterize this mutation using heterologous expression of recombinant human heart sodium channels. Mutant channels show a sustained inward current during membrane depolarization. Single-channel recordings indicate that mutant channels fluctuate between normal and non-inactivating gating modes. Persistent inward sodium current explains prolongation of cardiac action potentials, and provides a molecular mechanism for this form of congenital long-QT syndrome.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Bennett
authors.forename: K
authors.initials: K
authors.lastname: Yazawa
authors.forename: N
authors.initials: N
authors.lastname: Makita
authors.forename: A L
authors.initials: AL
authors.lastname: George
mesh_terms: D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D011994:Recombinant Proteins; D015222:Sodium Channels