ArticleGene2014
Position of premature termination codons determines susceptibility of hERG mutations to nonsense-mediated mRNA decay in long QT syndrome.
Article in Gene, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
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- 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
- Multiple mechanisms underlie reduced potassium conductance in the p.T1019PfsX38 variant of hERG.Physiological reports · 2022Article
- The LratInternational journal of molecular sciences · 2021Article
- Identification of a genetic variant underlying familial cases of recurrent benign paroxysmal positional vertigo.PloS one · 2021Article
- Stop codons and the +4 nucleotide may influence the efficiency of G418 in rescuing nonsense mutations of the HERG gene.International journal of molecular medicine · 2019Article
- Functional Studies and In Silico Analyses to Evaluate Non-Coding Variants in Inherited Cardiomyopathies.International journal of molecular sciences · 2016Article
- The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene.EMBO molecular medicine · 2015Article
- Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects.Acta pharmacologica Sinica · 2014Review
- Upregulation of functional Kv11.1 isoform expression by inhibition of intronic polyadenylation with antisense morpholino oligonucleotides.Journal of molecular and cellular cardiology · 2014Article
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3 authors at 1 institution in 1 country.
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Abstract
The degradation of human ether-a-go-go-related gene (hERG, KCNH2) transcripts containing premature termination codon (PTC) mutations by nonsense-mediated mRNA decay (NMD) is an important mechanism of long QT syndrome type 2 (LQT2). The mechanisms governing the recognition of PTC-containing hERG transcripts as NMD substrates have not been established. We used a minigene system to study two frameshift mutations, R1032Gfs 25 and D1037Rfs 82. R1032Gfs 25 introduces a PTC in exon 14, whereas D1037Rfs 82 causes a PTC in the last exon (exon 15). We showed that R1032Gfs 25, but not D1037Rfs 82, reduced the level of mutant mRNA compared to the wild-type minigene in an NMD-dependent manner. The deletion of intron 14 prevented degradation of R1032Gfs 25 mRNA indicating that a downstream intron is required for NMD. The recognition and elimination of PTC-containing transcripts by NMD required that the mutation be positioned >54-60 nt upstream of the 3'-most exon-exon junction. Finally, we used a full-length hERG splicing-competent construct to show that inhibition of downstream intron splicing by antisense morpholino oligonucleotides inhibited NMD and rescued the functional expression of a third LQT2 mutation, Y1078. The present study defines the positional requirements for the susceptibility of LQT2 mutations to NMD and posits that the majority of reported LQT2 nonsense and frameshift mutations are potential targets of NMD.
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