title: Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue.
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.
authors.affiliation: 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.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Anatomy and Embryology and.
authors.forename: Cristina
authors.initials: C
authors.lastname: D'Aniello
authors.affiliation: Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands; and.
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.affiliation: Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wrobel
authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frank
authors.affiliation: Anatomy and Embryology and.
authors.forename: Dorien
authors.initials: D
authors.lastname: Ward-van Oostwaard
authors.affiliation: Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Piccini
authors.affiliation: Anatomy and Embryology and.
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
authors.affiliation: 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.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Rao
authors.affiliation: Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany.
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
authors.affiliation: Cardiology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands;
authors.forename: Douwe E
authors.initials: DE
authors.lastname: Atsma
authors.affiliation: Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.affiliation: Anatomy and Embryology and.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
authors.affiliation: 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.
authors.forename: Boris
authors.initials: B
authors.lastname: Greber
authors.affiliation: Anatomy and Embryology and boris.greber@mpi-muenster.mpg.de m.bellin@lumc.nl.
authors.forename: Milena
authors.initials: M
authors.lastname: Bellin
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000704:Analysis of Variance; D001483:Base Sequence; D002460:Cell Line; D005808:Genes, Recessive / Q000235:genetics; D005818:Genetic Engineering; D006801:Humans; D066298:In Vitro Techniques; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D029593:Jervell-Lange Nielsen Syndrome / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology*; D051657:KCNQ1 Potassium Channel / Q000737:chemistry / Q000235:genetics*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D032383:Myocytes, Cardiac / Q000502:physiology; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human
keywords: Jervell and Lange-Nielsen syndrome; KCNQ1; disease modeling; human induced pluripotent stem cells; long QT syndrome