A Novel KCNQ1 Variant (L203P) Associated with Torsades de Pointes-Related Syncope in a Steinert Syndrome Patient

Background: A 43-year-old woman suffering from Steinert syndrome was admitted after experiencing multiple episodes of torsades de pointes-related syncope. Objectives: To elucidate the pathophysiology of these arrhythmic events. Methods and Results: We obtained DNA from the patient and sequenced the coding region of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes. A single nucleotide change was identified in the KCNQ1 gene at position 608 (T608C), resulting in a substitution from leucine to proline at position 203 (L203P). CHO cells were used to express either wild-type KCNQ1, wild-type KCNQ1 + L203P KCNQ1 (50: 50), or L203P KCNQ1, along with KCNE1 to recapitulate the slow cardiac delayed rectifier potassium current (I-Ks). Patch-clamp experiments showed that the variant L203P causes a dominant negative effect on I-Ks. Coexpression of wild-type KCNQ1 and L203P KCNQ1 (50: 50) caused a 75% reduction in current amplitude when compared to wild-type KCNQ1 alone (131.40 +/- 23.27 vs 567.25 +/- 100.65 pA/pF, P < .001). Moreover, when compared with wild-type KCNQ1 alone, the coexpression of wild-type KCNQ1 and L203P KCNQ1 (50: 50) caused a 7.5-mV positive shift of midpoints of activation (from 27.5 +/- 2.4 to 35.1 +/- 1.2 mV, P < .05). The wild-type KCNQ1 and L203P KCNQ1 (50: 50) coexpression also caused alteration of I-Ks kinetics. The activation kinetics of the L203P variant (50: 50) were slowed compared with wild-type KCNQ1, while the deactivation kinetics of L203P (50: 50) were accelerated compared with wild type, all these further contributing to the "loss-of-function" phenotype of IKs associated with the variant L203P. Conclusion: Torsades de pointes and episodes of syncope are very likely to be due to the KCNQ1 variant L203P found in this patient.