d2daf70e-0951-4e0e-906f-e0e0e99e8224
title
Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome.
67330521-598e-4aa4-871b-0af0d60ad558
abstract
INTRODUCTION: Beta-blockers are widely used to prevent the lethal cardiac events associated with the long QT syndrome (LQTS), especially in  KCNQ1 -related LQTS (LQT1) patients. Some LQT1 patients, however, are refractory to this therapy. METHODS AND RESULTS: Eighteen symptomatic LQTS patients (12 families) were genetically diagnosed as having heterozygous  KCNQ1  variants and received beta-blocker therapy. Cardiac events recurred in 4 members (3 families) despite continued therapy during mean follow-up of 70 months. Three of these patients (2 families) had the same mutation [ A341V (KCNQ1) ]; and the other had  R243H (KCNQ1) . The latter patient took aprindine, which seemed to be responsible for the event. By functional assay using a heterologous mammalian expression system, we found that  A341V (KCNQ1)  is a loss-of-function type mutation (not dominant negative). Further genetic screening revealed that one  A341V (KCNQ1)  family cosegregated with  S706C (KCNH2)  and another with  G144S (KCNJ2) . Functional assay of the  S706C (KCNH2)  mutation was found to reduce the current density of expressed heterozygous KCNH2 channels with a positive shift (+8 mV) of the activation curve. Action potential simulation study was conducted based on the KYOTO model to estimate the influence of additional gene modifiers. In both models mimicking LQT1 plus 2 and LQT1 plus 7, the incidence of early afterdepolarization was increased compared with the LQT1 model under the setting of beta-adrenergic stimulation. CONCLUSION: Multiple mutations in different LQTS-related genes may modify clinical characteristics. Expanded gene survey may be required in LQT1 patients who are resistant to beta-blocker therapy.