Referenced in: none

Automatically associated channels: Kv11.1 , Kv7.1 , Nav1.5 , Slo1

Title: A novel KCNQ1 variant (L203P) associated with torsades de pointes-related syncope in a Steinert syndrome patient.

Authors: Dany Patoine, Ibrahim Hasibu, Sylvie Pilote, Jean Champagne, Benoît Drolet, Chantale Simard

Journal, date & volume: Can J Cardiol, 2011 Mar-Apr , 27, 263.e5-12

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21459285

Abstract
A 43-year-old woman suffering from Steinert syndrome was admitted after experiencing multiple episodes of torsades de pointes-related syncope.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 (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 I(Ks) 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.