An Interdomain KCNH2 Mutation Produces an Intermediate Long QT Syndrome.
Hereditary long QT syndrome is caused by deleterious mutation in one of several genetic loci, including locus LQT2 that contains the KCNH2 gene (or hERG, human ether-a-go-go related gene), causing faulty cardiac repolarization. Here, we describe and characterize a novel mutation, p.Asp219Val in the hERG channel, identified in an 11-year-old male with syncope and prolonged QT interval. Genetic sequencing showed a nonsynonymous variation in KCNH2 (c.656A>T: amino acid p.Asp219Val). p.Asp219Val resides in a region of the channel predicted to be unstructured and flexible, located between the PAS (Per-Arnt-Sim) domain and its interaction sites in the transmembrane domain. The p.Asp219Val hERG channel produced K(+) current that activated with modest changes in voltage dependence. Mutant channels were also slower to inactivate, recovered from inactivation more readily and demonstrated a significantly accelerated deactivation rate compared with the slow deactivation of wild-type channels. The intermediate nature of the biophysical perturbation is consistent with the degree of severity in the clinical phenotype. The findings of this study demonstrate a previously unknown role of the proximal N-terminus in deactivation and support the hypothesis that the proximal N-terminal domain is essential in maintaining slow hERG deactivation.
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY.
Marika L
ML
Osterbur
Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY.
Renjian
R
Zheng
Department of Pediatrics, Division of Genetics, Children's Hospital at Montefiore, Bronx, NY.
Robert
R
Marion
Department of Pediatrics, Division of Cardiology, Children's Hospital at Montefiore, Bronx, NY.
Christine
C
Walsh
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY.|Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY.|Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY.
Thomas V
TV
McDonald
D002648:Child; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human
KCNH2; LQT2; deactivation; hERG; ventricular arrhythmia