title: Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome.
abstract: BACKGROUND
  β-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location.
  
  
  RESULTS
  The study sample comprised 860 patients with genetically confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations=2.75; 95% confidence interval, 1.29-5.86; P=0.009). β-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02-0.73; P=0.02; and hazard ratio=0.82; 95% confidence interval, 0.31-2.13; P=0.68, respectively; P for interaction=0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to β-adrenergic stimulation.
  
  
  CONCLUSIONS
  Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Alon
authors.initials: A
authors.lastname: Barsheshet
authors.forename: Ilan
authors.initials: I
authors.lastname: Goldenberg
authors.forename: Jin
authors.initials: J
authors.lastname: O-Uchi
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Christian
authors.initials: C
authors.lastname: Jons
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Wilde
authors.forename: Scott
authors.initials: S
authors.lastname: McNitt
authors.forename: Derick R
authors.initials: DR
authors.lastname: Peterson
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zareba
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Robinson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Michael
authors.initials: M
authors.lastname: Cypress
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Gray
authors.forename: Nynke
authors.initials: N
authors.lastname: Hofman
authors.forename: Jorgen K
authors.initials: JK
authors.lastname: Kanters
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Kaufman
authors.forename: Pyotr G
authors.initials: PG
authors.lastname: Platonov
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: G Michael
authors.initials: GM
authors.lastname: Vincent
authors.forename: Coeli M
authors.initials: CM
authors.lastname: Lopes
mesh_terms: D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000328:Adult; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D006323:Heart Arrest / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D009154:Mutation; D012306:Risk; D029597:Romano-Ward Syndrome / Q000188:drug therapy / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human