Sudden death associated with short-QT syndrome linked to mutations in HERG.
BACKGROUND
Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG.


RESULTS
Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers.


CONCLUSIONS
We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.
Brugada
Ramon
R
Molecular Genetics Program, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501, USA. brugada@mmrl.edu
Hong
Kui
K
Dumaine
Robert
R
Cordeiro
Jonathan
J
Gaita
Fiorenzo
F
Borggrefe
Martin
M
Menendez
Teresa M
TM
Brugada
Josep
J
Pollevick
Guido D
GD
Wolpert
Christian
C
Burashnikov
Elena
E
Matsuo
Kiyotaka
K
Wu
Yue Sheng
YS
Guerchicoff
Alejandra
A
Bianchi
Francesca
F
Giustetto
Carla
C
Schimpf
Rainer
R
Brugada
Pedro
P
Antzelevitch
Charles
C
D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000401:mortality; D002460:Cell Line; D016757:Death, Sudden, Cardiac; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D007473:Ion Channels / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D013577:Syndrome
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated