Genetische Ursachen des Langen-QT-Syndroms

Long QT syndrome is characterized by prolongation of the QT interval on electrocardiogram. Early after depolarisations may develop to torsade de pointes degenerating into ventricular fibrillation and cause sudden cardiac death. In the present study Marburg patients were screened for mutations in 14 ion channel genes by PCR-based SSCP-analysis. One heterozygote mutation in hERG potassium channel, one heterozygote mutation in KvLQT1 potassium channel as well as one polymorphism in the Nav1.5 sodium channel, that is associated with longer QTc interval, were identified. The functional characterization of the H1153Y channel in Xenopus oocytes showed a minimal loss of channel function and no dominant negative effect on wildtype channel. However, mutant hERG channel subunits indicated normal trafficking to the plasma membrane in oocytes and mammalien cells. The functional characterization of the G269S channel in Xenopus oocytes represented a 60 % current reduction when expressed alone and no dominant negative effect could be observed when co-expressed with wildtype channel. Also the mutant channel shows an assembly defect with the ß-subunit minK. The common H558R polymorphism in the sodium channel SCN5A gene is associated with the QTc length. It is not possible to disentangle the effect of the H558R polymorphism from that of the 1141-3 C>A SNP because of their tight LD. This latter SNP is located in the acceptor splice site in intron 9 and might affect the splicing. The splicing of the C>A sequence variation was analysed using a modified version of the EBD minigene construct. The results clearly indicate that the sequence change will not interfere with the splicing. The H558R polymorphism had significantly larger peak current amplitudes than wt-hH1. However, no difference in Na+ channel activation, inactivation, recovery of inactivation and levels of persistant sodium current had been observed between the wt and H558R clones. Also in the present study a novel long QT form is characterized functionally. Andersen syndrome is a rare genetic multisystem disorder characterized by periodic paralysis, a cardiac phenotype and dysmorphic features. The N318S and W322C mutation clinically manifested only with a cardiac phenotype and without the dysmorphic features and periodic paralysis typical for AS. These results were correlated with the clinical phenotype. These two mutations were the farthest C-terminal mutations reported in Kir2.1 and the aminoacid Trp322 is well conserved among Kir family members. According to the crystal structure of Kir2.1 the localization of these two mutations was very uncommon. Both mutations represented no dominant negative effect and only a 20 % to 25 % current reduction when coexpressed with wild type. The minimal loss of channel function resulted from a deficient trafficking in case of W322C and a defect in gating for N318S. W322C displayed a perinuclear staining pattern residing in relatively large vesicular structures. Furthermore the mutations exhibited no dominante negative effects on Kir2.2 and Kir2.3 channels. The findings support the notion, that a novel LQTS form is described and as such we propose, that these clinical and electrophysiological manifestations should be considered as a subtype of LQTS7.