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Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5383-92. doi: 10.1073/pnas.1419553111. Epub 2014 Dec 1.

Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue.

Author information

1
Human Stem Cell Pluripotency Group, Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany; Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany; Departments of.
2
Anatomy and Embryology and.
3
Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands; and.
4
Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany.
5
Cardiology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands;
6
Human Stem Cell Pluripotency Group, Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany; Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany; Departments of boris.greber@mpi-muenster.mpg.de m.bellin@lumc.nl.
7
Anatomy and Embryology and boris.greber@mpi-muenster.mpg.de m.bellin@lumc.nl.

Abstract

Jervell and Lange-Nielsen syndrome (JLNS) is one of the most severe life-threatening cardiac arrhythmias. Patients display delayed cardiac repolarization, associated high risk of sudden death due to ventricular tachycardia, and congenital bilateral deafness. In contrast to the autosomal dominant forms of long QT syndrome, JLNS is a recessive trait, resulting from homozygous (or compound heterozygous) mutations in KCNQ1 or KCNE1. These genes encode the α and β subunits, respectively, of the ion channel conducting the slow component of the delayed rectifier K(+) current, IKs. We used complementary approaches, reprogramming patient cells and genetic engineering, to generate human induced pluripotent stem cell (hiPSC) models of JLNS, covering splice site (c.478-2A>T) and missense (c.1781G>A) mutations, the two major classes of JLNS-causing defects in KCNQ1. Electrophysiological comparison of hiPSC-derived cardiomyocytes (CMs) from homozygous JLNS, heterozygous, and wild-type lines recapitulated the typical and severe features of JLNS, including pronounced action and field potential prolongation and severe reduction or absence of IKs. We show that this phenotype had distinct underlying molecular mechanisms in the two sets of cell lines: the previously unidentified c.478-2A>T mutation was amorphic and gave rise to a strictly recessive phenotype in JLNS-CMs, whereas the missense c.1781G>A lesion caused a gene dosage-dependent channel reduction at the cell membrane. Moreover, adrenergic stimulation caused action potential prolongation specifically in JLNS-CMs. Furthermore, sensitivity to proarrhythmic drugs was strongly enhanced in JLNS-CMs but could be pharmacologically corrected. Our data provide mechanistic insight into distinct classes of JLNS-causing mutations and demonstrate the potential of hiPSC-CMs in drug evaluation.

KEYWORDS:

Jervell and Lange-Nielsen syndrome; KCNQ1; disease modeling; human induced pluripotent stem cells; long QT syndrome

PMID:
25453094
PMCID:
PMC4273331
DOI:
10.1073/pnas.1419553111
[Indexed for MEDLINE]
Free PMC Article

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