Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 KCNH2 (hERG) Mutations and Identifying New Patients.

Makoto Ono,Bin Sun,Brian P Delisle,Claude S Elayi,Kalyan Immadisetty,Corey L Anderson,Don E Burgess,Elizabeth A Schroder,Peter M Kekenes-Huskey,Craig T January

doi:10.3390/biom10081144

Abstract

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the KCNH2 gene (also known as the human ether-à-go-go-related gene or hERG). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies suggest that about 90% of these mutations disrupt the intracellular transport, or trafficking, of the KCNH2-encoded Kv11.1 channel protein to the cell surface membrane. In this review, we discuss emerging strategies that improve the trafficking and functional expression of trafficking-deficient LQT2 Kv11.1 channel proteins to the cell surface membrane and how new insights into the structure of the Kv11.1 channel protein will lead to computational approaches that identify which KCNH2 missense variants confer a high-risk for LQT2.

Highlights

Congenital long QT syndrome (LQTS) is an arrhythmogenic disorder that can manifest as an abnormal prolongation in the heart rate-corrected QT (QTc) interval measured on an electrocardiogram (ECG) [1,2]
Western blot analysis for over 100 mutant Class 2 LQTS type 2 (LQT2) channel proteins showed that culturing cells in the high-affinity inKgCNdHel2aeynecdodreesctifier K+ current (IKr) blocker E-4031 increased the terminal glycosylation for 47% of Kv11.1a channel proteins with Class 2 mutations in BtiohmeolPecAulSesd20o2m0,a1i0n, 1, 13434% of the Kv11.1 channel proteins with Class 2 mutations in the pore domain4,oaf 1n5d 21% of the Kv11.1 channel proteins with Class 2 mutations in the CNB domain
Western blot analysis for over 100 mutant Class 2 LQT2 channel proteins showed that culturing cells in the high-affinity IKr blocker E-4031 increased the terminal glycosylation for 47% of Kv11.1a channel proteins with Class 2 mutations in the PAS domain, 33% of the Kv11.1 channel proteins with Class 2 mutations in the pore domain, and 21% of the Kv11.1 channel proteins with Class 2 mutations in the CNB domain

Summary

Introduction

Congenital long QT syndrome (LQTS) is an arrhythmogenic disorder that can manifest as an abnormal prolongation in the heart rate-corrected QT (QTc) interval measured on an electrocardiogram (ECG) [1,2]. Western blot analysis for over 100 mutant Class 2 LQT2 channel proteins showed that culturing cells in the high-affinity IKr blocker E-4031 increased the terminal glycosylation for 47% of Kv11.1a channel proteins with Class 2 mutations in BtiohmeolPecAulSesd20o2m0,a1i0n, 1, 13434% of the Kv11.1 channel proteins with Class 2 mutations in the pore domain4 ,oaf 1n5d 21% of the Kv11.1 channel proteins with Class 2 mutations in the CNB domain. These thderusgecsrhetaovreylpimatihtewdatyhienracpoeautotimc eproatesnsoticailatseindcpertohteeyinbIlIo(cCkOIKPrIaI)nvdecsaiculsees dtoruthge-iEnRduGcoedlgLi iQnTteSr.mediate compaMrtomstednrtu(gEsRtGhIaCt )blaoncdk GIKor blgini dcotmo pthaertimnneenrt a[q33u]e.oAuss vKevs1ti1b.u1alepartottheeinYs6t5r2affiancdthFr6o5u6grhestihdeuGe ionlgSi6 aopfpathraetuKsv, 1th1e.1Na -αli-nskuebdungiltyc[a5n4,s5o5n]. KFvic1k1e.1r αan-sdubcuonllietacghuaensn(e2l0p0r2o)tefionusnadrettheartmeinngalilnyegelryincogsaymlatiendo aancdid thsueibrsmtitoulteicounlsaratmFa6s5s6inrcerdeuacseeds tboo~th15t5hekDafafi[n3i4ty]. oAfttthhee dcerullgsubrlfoacckeemr oefmIbKrr aanned, Kthve11p.h1acrhmanacnoellosgairceal ccoonrtriencutaiollny ionfteCrnlaaslsize2dLaQnTd2recchyacnlenbelacpkrototetihnes c[e4l5l ]s.uCrfoancevemrseemlyb,raennegienveeerryincgoucperletaoinf maimnuintoesafocird sseuvebrsatilthuotiuornssbaetfotrheethYe6y5a2reretasirdgueteed(ef.ogr.,dYeg65ra2dCa)timonitiingaltyesdostohmeetsra[3ff5i,c3k6i]n. gT-hdeerfeicaierentsepvheeranloetyxcpeelslenfotr resevvieewrasl tdhiaftfedreetnatilCKlavs1s1.21 cLhQanTn2eml turataffiticoknisng[,5c6h].apTehreosneesla, tatenrd dthaetabiaorpehaynsiceaxlafmunpcletioonf oinf tKravg1e1n.1ic casdhnuaidspneipnaderseelenss-/tscIiiaKfoyurns[n,1ine5wwg,1h6LeC,3rQle1aTb,s3y2s7p]v2TaathrLiieiaQsnnrTttess2vbiaeemtfwouYrite6sa5ttfih2oocencuyo.ssmeTudpaffokeennernsatahltetieofnegf-eeotwhtrhreteerhras,ettertpnahriteneimggriaeeerssvyueblnemtsitn.isgdfoedmledvoiennlgostprdeaedtfeetoctthtrcaeatautcsLleeQdaTnb2lyy separating drug block and pharmacological correction might not be possible

Long QT Syndrome Type 2

Findings

Summary