A DE-NOVO MISSENSE MUTATION OF HUMAN CARDIAC NA+ CHANNEL EXHIBITING NOVEL MOLECULAR MECHANISMS OF LONG QT SYNDROME

Mutations in a human cardiac Na+ channel gene (SCN5A) are responsible for chromosome 3-linked congenital long QT syndrome (LQT3). Here we ch aracterized a de novo missense mutation (R1623Q, S4 segment of domain 4) identified in an infant Japanese girl with a severe form of LQT3. W hen expressed in oocytes, mutant Na+ channels exhibited only minor abn ormalities in channel activation, but in contrast to three previously characterized LQT3 mutations, had significantly delayed macroscopic in activation, Single channel analysis revealed that R1623Q channels have significantly prolonged open times with bursting behavior, suggesting a novel mechanism of pathophysiology in Na+ channel-linked long QT sy ndrome. (C) 1998 Federation of European Biochemical Societies.