Referenced in: none

Automatically associated channels: Kv11.1 , Kv7.1

Title: Defective human Ether-à-go-go-related gene trafficking linked to an endoplasmic reticulum retention signal in the C terminus.

Authors: Sabina Kupershmidt, Tao Yang, Siprachanh Chanthaphaychith, Zhiqing Wang, Jeffrey A Towbin, Dan M Roden

Journal, date & volume: J. Biol. Chem., 2002 Jul 26 , 277, 27442-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12021266

Abstract
Mutations in the human Ether-à-go-go-Related gene (HERG), encoding the protein underlying the cardiac K(+) current, I(Kr), cause chromosome 7-linked long QT syndrome (LQT2). In this study, we show that deletion of the C-terminal 147 amino acids (HERG(Delta147)) abolished I(Kr), whereas a larger, 159-amino acid deletion (HERG(Delta159)) identified in an LQT2 kindred did generate I(Kr), albeit with reduced amplitude compared with the wild type. The 12 amino acids present in HERG(Delta147) and absent in HERG(Delta159) include a potential endoplasmic reticulum (ER) retention signal, RGR, which when mutated to LGL (HERG(Delta147-LGL)) restored I(Kr). Streptavidin selection of biotin-labeled surface proteins showed good expression of wild-type and HERG(Delta159) at the cell surface and low expression of HERG(Delta147-LGL) and HERG(Delta147). Additionally, a 100-amino acid peptide spanning the RGR triplet can rescue the defect in HERG(Delta147) when co-expressed as an ER-targeted minigene. Failure of HERG trafficking is known to cause LQT2, and this identified a molecular mechanism underlying this defect. Further, our data indicate that a key function of the C-terminal 104 amino acids is to mask the RGR ER retention signal, which becomes exposed when mutations truncate the HERG C terminus.