This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 103/12/1483    most recent CIRCRESAHA.108.177055v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Teng, G. Q. Articles by Duff, H. J. Search for Related Content PubMed PubMed Citation Articles by Teng, G. Q. Articles by Duff, H. J. Related Collections Apoptosis Arrythmias-basic studies Genetically altered mice Arrhythmias, clinical electrophysiology, drugs Cardiac development

(Circulation Research. 2008;103:1483.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Homozygous Missense N629D hERG (KCNH2) Potassium Channel Mutation Causes Developmental Defects in the Right Ventricle and Its Outflow Tract and Embryonic Lethality

Guo Qi Teng^*, Xian Zhao^*, James P. Lees-Miller, F. Russell Quinn, Pin Li, Derrick E. Rancourt, Barry London, James C. Cross, Henry J. Duff

From the Libin Cardiovascular Institute (G.Q.T., J.P.L.-M., F.R.Q., P.L.), the Faculty of Veterinarian Medicine (X.Z., J.C.C.), and Biochemistry and Molecular Biology (D.E.R.), University of Calgary, Canada; and the Cardiovascular Institute (B.L.), University of Pittsburgh, Pa.

Correspondence to Henry J. Duff, MD, Libin Cardiovascular Institute, University of Calgary, 3330 Hospital Dr, NW, Calgary, Canada, T2N 4N1. E-mail hduff{at}ucalgary.ca

Loss-of-function mutations in the human ERG1 potassium channel (hERG1) frequently underlie the long QT2 (LQT2) syndrome. The role of the ERG potassium channel in cardiac development was elaborated in an in vivo model of a homozygous, loss-of-function LQT2 syndrome mutation. The hERG N629D mutation was introduced into the orthologous mouse gene, mERG, by homologous recombination in mouse embryonic stem cells. Intact homozygous embryos showed abrupt cessation of the heart beat. N629D/N629D embryos die in utero by embryonic day 11.5. Their developmental defects include altered looping architecture, poorly developed bulbus cordis, and distorted aortic sac and branchial arches. N629D/N629D myocytes from embryonic day 9.5 embryos manifested complete loss of I_Kr function, depolarized resting potential, prolonged action potential duration (LQT), failure to repolarize, and propensity to oscillatory arrhythmias. N629D/N629D myocytes manifest calcium oscillations and increased sarcoplasmic reticulum Ca⁺² content. Although the N629D/N629D protein is synthesized, it is mainly located intracellularly, whereas +/+ mERG protein is mainly in plasmalemma. N629D/N629D embryos show robust apoptosis in craniofacial regions, particularly in the first branchial arch and, to a lesser extent, in the cardiac outflow tract. Because deletion of Hand2 produces apoptosis, in similar regions and with a similar final developmental phenotype, Hand2 expression was evaluated. Robust decrease in Hand2 expression was observed in the secondary heart field in N629D/N629D embryos. In conclusion, loss of I_Kr function in N629D/N629D cardiovascular system leads to defects in cardiac ontogeny in the first branchial arch, outflow tract, and the right ventricle.

Key Words: KCNH2 (hERG) • knock-in mouse • embryo developmental defect