Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome.
BACKGROUND
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.


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.


CONCLUSIONS
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.
Kobori
Atsushi
A
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Sarai
Nobuaki
N
Shimizu
Wataru
W
Nakamura
Yoshihide
Y
Murakami
Yosuke
Y
Makiyama
Takeru
T
Ohno
Seiko
S
Takenaka
Kotoe
K
Ninomiya
Tomonori
T
Fujiwara
Yuichiro
Y
Matsuoka
Satoshi
S
Takano
Makoto
M
Noma
Akinori
A
Kita
Toru
T
Horie
Minoru
M
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D002648:Child; D004562:Electrocardiography; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D007564:Japan; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000187:drug effects / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects / Q000235:genetics; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics; D016896:Treatment Outcome
D000319:Adrenergic beta-Antagonists; D015221:Potassium Channels