THE LONG QT SYNDROME - A NOVEL MISSENSE MUTATION IN THE S6 REGION OF THE KVLQT1 GENE

The Romano Ward long QT syndrome (LQTS) has an autosomal dominant mode of inheritance. Patients suffer from syncopal attacks often resulting in sudden cardiac death. The main diagnostic parameter is a prolonged QT((c)) interval as judged by electro-cardiographic investigation. LQ TS is a genetically heterogeneous disease with four loci having been i dentified to date: chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-2-1 (LQT3) and 4q35-26 (LQT4). The corresponding genes code for potassium channels KVLQT1 (LQT1) and HERG (LQT2) and the sodium channel SCN5A ( LQT3). The KVLQT1 gene is characterized by six transmembrane domains ( S1-S6), a pore region situated between the S5 and S6 domains and a C-t erminal domain accounting for approximately 60% of the channel. This d omain is thought to be co-associated with another protein. viz. minK ( minimal potassium channel). We have studied a Romano Ward family with several affected individuals showing a severe LQTS phenotype (syncopes and occurrence of sudden death). Most affected individuals had consid erable prolongations of QT((c)). By using haplotyping with a set of ma rkers coveting the four LQT loci, strong linkage was established to th e LQT1 locus, whereas the other loci (LQT2, LQT3 and LQT4) could be ex cluded. Single-strand conformation polymorphism analysis and direct se quencing were used to screen the KVLQT1 gene for mutations in the S1-S 6 region, including the pore domain. We identified a Gly-216-Arg subst itution in the S6 transmembrane domain of KVLQT1. The mutation was pre sent in all affected family members but absent in normal control indiv iduals, providing evidence that the mutated KVLQT1-gene product indeed caused LQTS in this family. The mutated KVLQT1-gene product thus prob ably results in a dominant negative suppression of channel activity.