Bradycardia-induced long QT syndrome caused by a de novo missense mutationin the S2-S3 inner loop of HERG

Long QT syndrome is a congenital disorder that presents with a defective ca rdiac ion channel and is either associated with prolonged action potential or, more commonly, known as an acquired form in which "torsades de pointes" type arrhythmias specifically occur after secondary causes, We report a ca se of a novel HERG mutation (A490T) that caused a bradycardia-associated fo rm of long QT syndrome. A 27-year-old woman exhibited recurrent syncope due to torsades de pointes associated with a disturbance of the cardiac conduc tion system. By using polymerase chain reaction and single strand conformat ional polymorphism analyses, we identified a heterozygous single nucleotide substitution of HERG (G to A at nt 1468), This mutational change was not p resent in 140 Japanese control individuals. Electrophysiological assays for the A490T mutant HERG channel were conducted in the heterologous expressio n system with COS7 cells. The mutant channel was found to reconstitute func tional channel currents, suggesting the homomeric mutant channel was functi onal. The mutation did not change the properties of the activation gate and inward rectification, however the current density of this mutant channel w as small compared with that of wild type HERG, Taken together, this mutant may cause subtle changes in HERG channel functions (I-Kr) in vivo. In this case, genetic background and unexpected bradycardia may have contributed to the development of long QT syndrome. (C) 2001 Wiley-Liss, Inc.