An Interdomain KCNH2 Mutation Produces an Intermediate Long QT Syndrome

Marika L. Osterbur, Renjian Zheng, Robert Marion, Christine Walsh, Thomas V. McDonald

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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. A novel mutation in the KCNH2 gene was identified in a young patient from Southeastern Asia with Long QT Syndrome. This mutation changes the gating kinetics of the gene product, hERG. This mutation caused rapid deactivation of the hERG potassium channel, leading to increased cardiac repolarization time and clinical Long QT Syndrome. We hypothesize that the protein domain in which this mutation is located is flexible, and plays an important role in mediating interactions between other protein domains, allowing for correct channel kinetics.

Original languageEnglish (US)
Pages (from-to)764-773
Number of pages10
JournalHuman Mutation
Issue number8
StatePublished - Aug 1 2015


  • Deactivation
  • HERG
  • KCNH2
  • LQT2
  • Ventricular arrhythmia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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