To elucidate the pathophysiology of these arrhythmic events.
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 (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 ¡À 23.27 vs 567.25 ¡À 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 ¡À 2.4 to 35.1 ¡À 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.
Torsades de pointes and episodes of syncope are very likely to be due to the KCNQ1 variant L203P found in this patient.