title: HERG mutation predicts short QT based on channel kinetics but causes long QT by heterotetrameric trafficking deficiency.
abstract: OBJECTIVE
  Mutations in the KCNH2 (hERG, human ether-à-go-go related gene) gene may cause a reduction of the delayed rectifier current I(Kr), thereby leading to the long QT syndrome (LQTS). The reduced I(Kr) delays the repolarisation of cardiac cells and renders patients vulnerable to ventricular arrhythmias and sudden death. We identified a novel mutation in a LQTS family and investigated its functional consequences using molecular and microscopic techniques.
  
  
  RESULTS
  Genetic screening in the LQTS family revealed a heterozygous frameshift mutation p.Pro872fs located in the C-terminus of the KCNH2 gene. The mutation leads to a premature truncation of the C-terminus of the hERG protein. p.Pro872fs channels lack 282 amino acids at the C-terminus and possess an extra 4-amino acid tail. Both the kinetic and biochemical properties of the p.Pro872fs and p.Pro872fs/WT channels were studied in HEK293 cells and resulted in a novel proof of concept for heterozygous LQTS mutations: homotetrameric p.Pro872fs channels displayed near-normal expression, trafficking, and channel kinetics. Unexpectedly, upon co-expression of p.Pro872fs and WT channels, the repolarising power (the proportion of hERG current contributing to the action potential as the percentage of the total current available) was substantially higher during action potential clamp experiments as compared to WT channels alone. This would lead to a shorter rather than a prolonged QT interval. However, at the same time, heterotetramerisation of p.Pro872fs and WT channels also caused a dominant negative effect on trafficking by an increase in ER retention of these heterotetrameric channels, which surpassed the former gain in repolarising power.
  
  
  CONCLUSIONS
  The LQTS phenotype in the studied family is caused by a mutation with novel properties. We demonstrate that a KCNH2 mutation that clinically leads to long QT syndrome causes at the cellular level both a "gain" and a "loss" of HERG channel function due to a kinetic increase in repolarising power and a decrease in trafficking efficiency of heteromultimeric channels.
authors.affiliation: Department of Genetics and Cell Biology (CARIM/NUTRIM), University of Maastricht, P.O. Box 616 (#16), 6200 MD Maastricht, The Netherlands. aimee.paulussen@gen.unimaas.nl
authors.forename: Aimée D C
authors.initials: AD
authors.lastname: Paulussen
authors.forename: Adam
authors.initials: A
authors.lastname: Raes
authors.forename: Roselie J
authors.initials: RJ
authors.lastname: Jongbloed
authors.forename: Ron A H J
authors.initials: RA
authors.lastname: Gilissen
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Snyders
authors.forename: Hubert J M
authors.initials: HJ
authors.lastname: Smeets
authors.forename: Jeroen
authors.initials: J
authors.lastname: Aerssens
mesh_terms: D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D002460:Cell Line; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D021381:Protein Transport; D014162:Transfection
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D015221:Potassium Channels