ArticleProceedings of the National Academy of Sciences of the United States of America2014
Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 108 papers.
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108 citing papers in PubMed, 177 citations in OpenAlex.
- Machine learning-guided risk stratification for long QT syndrome genetic variants with hiPSC-derived cardiomyocytes.Cardiovascular research · 2026Article
- Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models.Pediatric discovery · 2026Review
- A simplified co-culture reveals altered cardiotoxic responses to doxorubicin in hPSC-derived cardiomyocytes in the presence of endothelial cells.Stem cell reports · 2026Article
- Article
- Cardiac Tissue Engineering for Translational Cardiology: From In Vitro Models to Regenerative Therapies.Bioengineering (Basel, Switzerland) · 2025Review
- Cardiac Channelopathies: Clinical Diagnosis and Promising Therapeutics.Journal of the American Heart Association · 2025Review
- Induced Pluripotent Stem Cells in Congenital Long QT Syndrome: Research Progress and Clinical Applications.Reviews in cardiovascular medicine · 2025Review
- Enhancing the Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes with an n-Type Organic Semiconductor Coating.ACS applied materials & interfaces · 2024Article
- Investigating Inherited Heart Diseases Using Human Induced Pluripotent Stem Cell-Based Models.Life (Basel, Switzerland) · 2024Review
- Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function.Nature metabolism · 2024Article
- The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block.Cardiovascular research · 2024Article
- High-throughput methods for cardiac cellular electrophysiology studies: the road to personalized medicine.American journal of physiology. Heart and circulatory physiology · 2024Review
- [Cardiogenetics in Germany- a view and review].Herzschrittmachertherapie & Elektrophysiologie · 2024Review
- Human Genetics of Cardiac Arrhythmias.Advances in experimental medicine and biology · 2024Review
- iPSC-cardiomyocytes in the preclinical prediction of candidate pharmaceutical toxicity.Frontiers in pharmacology · 2024Review
- Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain.Cell death & disease · 2023Article
- Mpox virus infection and drug treatment modelled in human skin organoids.Nature microbiology · 2023Article
- Generation of a Syngeneic HeterozygousCells · 2023Article
- RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome.Nature communications · 2023Article
- Precise homology-directed installation of large genomic edits in human cells with cleaving and nicking high-specificity Cas9 variants.Nucleic acids research · 2023Article
48 more citing papers are in PubMed but not listed here.
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15 authors at 5 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.