ArticleHeart rhythm2011
Nonsense-mediated mRNA decay caused by a frameshift mutation in a large kindred of type 2 long QT syndrome.
Article in Heart rhythm, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 31 citations in OpenAlex.
- NS1643 enhances the activity of T1019PfsX38 and Q1070X hERG channels associated with long QT syndrome type 2.Pflugers Archiv : European journal of physiology · 2026Article
- Nonsense-Mediated mRNA Decay: Mechanisms and Recent Implications in Cardiovascular Diseases.Cells · 2025Review
- A Novel Frameshift Variant of the ELF4 Gene in a Patient with Autoinflammatory Disease: Clinical Features, Transcriptomic Profiling and Functional Studies.Journal of clinical immunology · 2024Article
- Posttranscriptional Regulation by Proteins and Noncoding RNAs.Advances in experimental medicine and biology · 2024Article
- Pairwise biosynthesis of ion channels stabilizes excitability and mitigates arrhythmias.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Non-missense variants of KCNH2 show better outcomes in type 2 long QT syndrome.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Four NovelInternational journal of molecular sciences · 2022Article
- The LratInternational journal of molecular sciences · 2021Article
- A Comprehensive Analysis and Splicing Characterization of Naturally Occurring Synonymous Variants in theFrontiers in genetics · 2020Article
- Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations.The Journal of physiology · 2016Article
- Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy.Journal of muscle research and cell motility · 2016Article
- Identification of Kv11.1 isoform switch as a novel pathogenic mechanism of long-QT syndrome.Circulation. Cardiovascular genetics · 2014Article
- Article
- Identification and characterization of a novel genetic mutation with prolonged QT syndrome in an unexplained postoperative death.International journal of legal medicine · 2014Review
- LQT2 nonsense mutations generate trafficking defective NH2-terminally truncated channels by the reinitiation of translation.American journal of physiology. Heart and circulatory physiology · 2013Article
- Identifying potential functional impact of mutations and polymorphisms: linking heart failure, increased risk of arrhythmias and sudden cardiac death.Frontiers in physiology · 2013Review
- Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Early LQT2 nonsense mutation generates N-terminally truncated hERG channels with altered gating properties by the reinitiation of translation.Journal of molecular and cellular cardiology · 2012Article
- Suppression of premature termination codons as a therapeutic approach.Critical reviews in biochemistry and molecular biology · 2012Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundNonsense and frameshift mutations are common in congenital long QT syndrome type 2 (LQT2). We previously demonstrated that hERG nonsense mutations cause degradation of mutant mRNA by nonsense-mediated mRNA decay (NMD) and are associated with mild clinical phenotypes. The impact of NMD on the expression of hERG frameshift mutations and their phenotypic severity is not clear.
objectiveThe purpose of this study was to examine the role of NMD in the pathogenesis of a hERG frameshift mutation, P926AfsX14, identified in a large LQT2 kindred and characterize genotype-phenotype correlations.
methodsGenetic screening was performed among family members. Phenotyping was performed by assessment of ECGs and LQTS-related cardiac events. The functional effect of P926AfsX14 was studied using hERG cDNA and minigene constructs expressed in HEK293 cells.
resultsSignificant cardiac events occurred in carriers of the P926AfsX14 mutation. When expressed from cDNA, the P926AfsX14 mutant channel was only mildly defective. However, when expressed from a minigene, the P926AfsX14 mutation caused a significant reduction in mutant mRNA, protein, and hERG current. Inhibition of NMD by RNA interference knockdown of up-frameshift protein 1 partially restored expression of mutant mRNA and protein and led to a significant increase in hERG current in the mutant cells. These results suggest that NMD is involved in the pathogenic mechanism of the P926AfsX14 mutation.
conclusionOur findings suggest that the hERG frameshift mutation P926AfsX14 primarily results in degradation of mutant mRNA by the NMD pathway rather than production of truncated proteins. When combined with environmental triggers and genetic modifiers, LQT2 frameshift mutations associated with NMD can manifest with a severe clinical phenotype.
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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 OpenQuestion graph.