Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events

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. Methods and 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 non-missense mutations. There were 27 aborted cardiac arrest [ACA] and 78 sudden cardiac death [SCD] events from birth through age 40 years. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for ACA or SCD (hazard ratio [95% confidence interval] vs. non-missense mutations = 2.75 [1.29-5.86, P=0.009]). β-blocker therapy was associated with a significantly greater reduction in the risk of ACA or SCD among patients with C-loop mutations than among all other patients (hazard ratios = 0.12 [0.02-0.73, P=0.02] and 0.82 [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 following sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.

Meandering Pathway Leading From Genotyping to Personalized Management of Long-QT Syndrome

“…The percentage of KCNQ1 mutations located in the small C-loop region is hard to define; it likely corresponds to a small proportion of probands. According to the Gene Connection for the Heart database (www.fsm.it/cardmoc), of 357 KCNQ1 mutations, only 54 (15%) are in the C loop ( Figure 1); this number confirms the estimate reported in the study by Barsheshet et al 15 A most interesting part of the study relates to the in vitro characterization of KCNQ1 mutations. Functional investigations performed by the authors show that, analogous to what observed in all LQTS-related mutations in the KCNQ1 gene, the I Ks current is decreased in all the C-loop mutations.…”

2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death

“…W innych chorobach, takich jak zespół Brugadów lub zespół krótkiego odstępu QT (SQTS), stratyfikacja ryzyka nie jest tak pewna, co pozostawia wątpliwości, u kogo profilaktycznie wszczepiać ICD. Informacje genetyczne można obecnie wykorzystywać do stratyfikacji ryzyka tylko w kilku chorobach, takich jak LQTS oraz kardiomiopatia rozstrzeniowa (DCM) związana z mutacjami genu laminy A/C (LMNA) [69][70][71].…”

Genetic and Clinical Advances in Congenital Long QT Syndrome

“…In patients with LQT1, missense cytoplasmic-loop mutations have been reported to cause a longer QT interval at enrolment and an increased risk of ACA/SCD. 71 As a specific mutation in KCNQ1, A341V, more than other KCNQ1 mutations (transmembrane tomatic patients who are refractory to β-blocker therapy. LCSD has been shown to reduce cardiac events significantly in LQTS with a rather high long-term cardiac-event-free survival (46%/5 years, 91 59%/2 years 92 ).…”