title: A novel KCNQ1 variant (L203P) associated with torsades de pointes-related syncope in a Steinert syndrome patient.
abstract: BACKGROUND
  A 43-year-old woman suffering from Steinert syndrome was admitted after experiencing multiple episodes of torsades de pointes-related syncope.
  
  
  OBJECTIVE
  To elucidate the pathophysiology of these arrhythmic events.
  
  
  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 I(Ks) associated with the variant L203P.
  
  
  CONCLUSIONS
  Torsades de pointes and episodes of syncope are very likely to be due to the KCNQ1 variant L203P found in this patient.
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada.
authors: Dany
authors: D
authors: Patoine
authors: Ibrahim
authors: I
authors: Hasibu
authors: Sylvie
authors: S
authors: Pilote
authors: Jean
authors: J
authors: Champagne
authors: Benoit
authors: B
authors: Drolet
authors: Chantale
authors: C
authors: Simard
mesh_terms: D000328:Adult; D004247:DNA / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000096:biosynthesis / Q000235:genetics*; D009223:Myotonic Dystrophy / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D016171:Torsades de Pointes / Q000150:complications / Q000235:genetics* / Q000378:metabolism
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D004247:DNA