Not all hERG pore domain mutations have a severe phenotype: G584s has an inactivation gating defect with mild phenotype compared to G572s, which has a dominant negative trafficking defect and a severe phenotype

Zhao, Jing Ting, Hill, Adam P., Varghese, Anthony, Cooper, Antony A., Swan, Heikki, Laitinen-Forsblom, Paivi J., Rees, Mark I., Skinner, Jonathan R., Campbell, Terence J. and Vandenberg, Jamie I. 2009. Not all hERG pore domain mutations have a severe phenotype: G584s has an inactivation gating defect with mild phenotype compared to G572s, which has a dominant negative trafficking defect and a severe phenotype. Journal of Cardiovascular Electrophysiology 20 (8) , pp. 923-930. 10.1111/j.1540-8167.2009.01468.x

Full text not available from this repository.

Abstract

Distinct Phenotypes in hERG Pore Domain Mutations. Introduction: Mutations in the pore domain of the human ether-a-go-go-related gene (hERG) potassium channel are associated with higher risk of sudden death. However, in many kindreds clinical presentation is variable, making it hard to predict risk. We hypothesized that in vitro phenotyping of the intrinsic severity of individual mutations can assist with risk stratification. Methods and Results: We analyzed 2 hERG pore domain mutations, G572S and G584S. Similar to 90% of hERG missense mutations, G572S-hERG subunits did not traffic to the plasma membrane but could coassemble with WT subunits and resulted in a dominant negative suppression of hERG current density. The G584S-hERG subunits traffic normally but have abnormal inactivation gating. Computer models of human ventricular myocyte action potentials (AP), incorporating Markov models of the hERG mutants, indicate that G572S-hERG channels would cause more severe AP prolongation than that seen with G584ShERG channels. Conclusions: hERG-G572S and -G584S are 2 pore domain mutations that involve the same change in sidechain but have very different in vitro phenotypes; G572S causes a dominant negative trafficking defect, whereas G584S is the first hERG missense mutation where the cause of disease can be exclusively attributed to enhanced inactivation. The G572S mutation is intrinsically more severe than the G584S mutation, consistent with the overall clinical presentation in the 2 small kindreds studied here. Further investigation, involving a larger number of cohorts, to test the hypothesis that in vitro phenotyping of the intrinsic severity of a given mutation will assist with risk stratification is therefore warranted.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > R Medicine (General)
Uncontrolled Keywords:	long-QT syndrome; protein trafficking; kinetic modeling; arrhythmia; human ether-a-go-go-related gene
Publisher:	Wiley
ISSN:	1045-3873
Last Modified:	05 Jul 2013 22:02
URI:	https://orca.cardiff.ac.uk/id/eprint/27465

Citation Data

Cited 47 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item