Related Experiment Video
Updated: May 12, 2026
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Identification and characterization of a novel genetic mutation with prolonged QT syndrome in an unexplained
Yukiko Hata1, Hisashi Mori, Ayumi Tanaka
1Department of Legal Medicine, Faculty of Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Insights
A novel frameshift mutation in the human ether-à-go-go-related gene (hERG) disrupts cardiac potassium channel function. This hERG(ΔAT) mutation impairs protein processing, leading to fewer functional channels and potentially explaining sudden cardiac death in LQTS patients.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Ion Channel Physiology
Background:
- The human ether-à-go-go-related gene (hERG) encodes a critical cardiac potassium channel subunit.
- hERG mutations are linked to long QT syndrome (LQTS) and sudden cardiac death.
- A novel frameshift mutation, hERG(ΔAT), was identified in a LQTS patient.
Introduction:
The human ether-à-go-go-related gene (hERG) encodes the α-subunit of a cardiac potassium channel. Various mutations of hERG, including missense mutations, have been reported to cause long QT syndrome (LQTS) and severe arrhythmic disorders such as sudden cardiac death. We identified a novel hERG frameshift mutation (hERG(ΔAT)) in the S5-pore region from a LQTS patient who died suddenly and analyzed its genetic profile and the molecular and electrophysiological behaviors of the protein product to assess the pathogenicity of hERG(ΔAT).
Methods And Results:
We performed direct sequencing of hERG and evaluated its transcript level by using a whole blood sample from the patient. We performed immunoblotting, immunocytochemistry, and patch-clamp recordings of HEK-293 T cells transfected with hERG(ΔAT), wild-type hERG (hERG(WT)), or both. The patient demonstrated an AT deletion (c.1735_1736del) in hERG and a decrease in hERG mRNA transcripts. HEK-293 T cells showed lower production and cell surface expression of hERG(ΔAT) compared with hERG(WT) protein. In addition, the hERG(∆AT) protein failed to form functional channels, while the activation kinetics of functional channels, presumably consisting of hERG(WT) subunits, were unaffected.
Conclusion:
The ΔAT mutation may decrease the number of functional hERG channels by impairing the posttranscriptional and posttranslational processing of the mutant product. This decrease may partly explain the cardiac symptoms of the patient who was heterozygous for hERG(ΔAT).
