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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-12, Vol.111 (50), p.17707-17707
• Main Authors: Zhang, Miao, D'Aniello, Cristina, Verkerk, Arie O., Wrobel, Eva, Frank, Stefan, Ward-van Oostwaard, Dorien, Piccini, Ilaria, Freund, Christian, Rao, Jyoti, Seebohm, Guiscard, Atsma, Douwe E., Schulze-Bahr, Eric, Mummery, Christine L., Greber, Boris, Bellin, Milena
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Analysis of Variance; Base Sequence; Biological Sciences; Cardiomyocytes; Cell Line; Genes, Recessive - genetics; Genetic Engineering; Genotype & phenotype; Humans; In Vitro Techniques; Induced Pluripotent Stem Cells - physiology; Jervell-Lange Nielsen Syndrome - drug therapy; Jervell-Lange Nielsen Syndrome - genetics; Jervell-Lange Nielsen Syndrome - physiopathology; KCNQ1 Potassium Channel - chemistry; KCNQ1 Potassium Channel - genetics; Models, Biological; Models, Molecular; Molecular Sequence Data; Mutation; Mutation, Missense - genetics; Myocytes, Cardiac - physiology; Phenotype; PNAS Plus; PNAS Plus Significance Statements; Risk assessment; Sequence Analysis, DNA; Stem cells
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1419553111

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.