Accelerated inactivation in a mutant Na+ channel associated with idiopathic ventricular fibrillation

Idiopathic ventricular fibrillation (IVF) can cause sudden death in both ad ults and children. One form of IVF (Brugada syndrome), characterized by S-T segment elevation (STE) in the electrocardiogram, has been linked to mutat ions of SCN5A, the gene encoding the voltage-gated cardiac Na+ channel. A m issense mutation of SCN5A that substitutes glutamine for leucine at codon 5 67 (L567Q, in the cytoplasmic linker between domains I and II) is identifie d with sudden infant death and Brugada syndrome in one family. However, nei ther the functional effect of the L567Q mutation nor the molecular mechanis m underlying the pathogenicity of the mutation is known. Patch-clamp analys is of L567Q channels expressed in human embryonic kidney cells revealed a m arked acceleration and a negative shift in the voltage dependence of inacti vation. Unlike other Brugada mutations, this phenotype was expressed indepe ndently of temperature or auxiliary beta (1)-subunits. These results suppor t a proposed linkage between Brugada syndrome and some instances of sudden infant death and the hypothesis that reduced Na+ conductance is the primary cause of IVF with STE.