A novel KCNQ1 variant (L203P) associated with torsades de pointes-related syncope in a Steinert syndrome patient |
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Authors: | Patoine Dany Hasibu Ibrahim Pilote Sylvie Champagne Jean Drolet Benoit Simard Chantale |
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Institution: | a Centre de recherche de l''Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada b Faculté de pharmacie, Université Laval, Québec, Québec, Canada c Faculté de médecine, Université Laval, Québec, Québec, Canada |
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Abstract: | BackgroundA 43-year-old woman suffering from Steinert syndrome was admitted after experiencing multiple episodes of torsades de pointes-related syncope.ObjectivesTo elucidate the pathophysiology of these arrhythmic events.Methods and ResultsWe 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 (IKs). Patch-clamp experiments showed that the variant L203P causes a dominant negative effect on IKs. 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 IKs 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.ConclusionTorsades de pointes and episodes of syncope are very likely to be due to the KCNQ1 variant L203P found in this patient. |
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