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Full-Text Articles in Life Sciences
Regulation Of Kv11.1 Isoform Expression By Polyadenylate Binding Protein Nuclear 1, Matthew R. Stump, Rachel T. Nguyen, Rachel H. Drgastin, Delaney Search, Quiming Gong, Zhengfeng Zhou
Regulation Of Kv11.1 Isoform Expression By Polyadenylate Binding Protein Nuclear 1, Matthew R. Stump, Rachel T. Nguyen, Rachel H. Drgastin, Delaney Search, Quiming Gong, Zhengfeng Zhou
Faculty Publications - Department of Biological & Molecular Science
The Kv11.1 voltage-gated potassium channel, encoded by the KCNH2 gene, conducts the rapidly activating delayed rectifier current in the heart. KCNH2 pre-mRNA undergoes alternative polyadenylation to generate two C-terminal Kv11.1 isoforms in the heart. Utilization of a poly(A) signal in exon 15 produces the full-length, functional Kv11.1a isoform, while intron 9 polyadenylation generates the C-terminally truncated, nonfunctional Kv11.1a-USO isoform. The relative expression of Kv11.1a and Kv11.1a-USO isoforms plays an important role in the regulation of Kv11.1 channel function. In this study, we tested the hypothesis that the RNA polyadenylate binding protein nuclear 1 (PABPN1) interacts with a unique 22 nt …
Upregulation Of Functional Kv11.1a Isoform Expression By Modified U1 Small Nuclear Rna, Qiuming Gong, Matthew R. Stump, Zhengfeng Zhou
Upregulation Of Functional Kv11.1a Isoform Expression By Modified U1 Small Nuclear Rna, Qiuming Gong, Matthew R. Stump, Zhengfeng Zhou
Faculty Publications - Department of Biological & Molecular Science
The KCNH2 or human ether-a go-go-related gene (hERG) encodes the Kv11.1 potassium channel that conducts the rapidly activating delayed rectifier potassium current in the heart. The expression of Kv11.1 C-terminal isoforms is directed by the alternative splicing and polyadenylation of intron 9. Splicing of intron 9 leads to the formation of a functional, full-length Kv11.1a isoform and polyadenylation of intron 9 results in the production of a non-functional, C-terminally truncated Kv11.1a-USO isoform. The relative expression of Kv11.1a and Kv11.1a-USO plays an important role in regulating Kv11.1 channel function. In the heart, only one-third of KCNH2 pre-mRNA is processed to Kv11.1a …
Upregulation Of Functional Kv11.1 Isoform Expression By Inhibition Of Intronic Polyadenylation With Antisense Morpholino Oligonucleotides, Qiuming Gong, Matthew R. Stump, Zhengfeng Zhou
Upregulation Of Functional Kv11.1 Isoform Expression By Inhibition Of Intronic Polyadenylation With Antisense Morpholino Oligonucleotides, Qiuming Gong, Matthew R. Stump, Zhengfeng Zhou
Faculty Publications - Department of Biological & Molecular Science
The KCNH2 gene encodes the Kv11.1 potassium channel that conducts the rapidly activating delayed rectifier current in the heart. KCNH2 pre-mRNA undergoes alternative processing; intron 9 splicing leads to the formation of a functional, full-length Kv11.1a isoform, while polyadenylationwithin intron 9 generates a non-functional, Cterminally truncated Kv11.1a-USO isoform. The relative expression of Kv11.1 isoforms plays an important role in the regulation of Kv11.1 channel function and the pathogenesis of long QT syndrome. In this study,we identified cis-acting elements that are required for KCNH2 intron 9 poly(A) signal activity. Mutation of these elements decreased Kv11.1a-USO expression and increased the expression of …
Position Of Premature Termination Codons Determines Susceptibility Of Herg Mutations To Nonsense-Mediated Mrna Decay In Long Qt Syndrome, Qiuming Gong, Matthew R. Stump, Zhengfeng Zhou
Position Of Premature Termination Codons Determines Susceptibility Of Herg Mutations To Nonsense-Mediated Mrna Decay In Long Qt Syndrome, Qiuming Gong, Matthew R. Stump, Zhengfeng Zhou
Faculty Publications - Department of Biological & Molecular Science
The degradation of human ether-a-go-go-related gene (hERG, KCNH2) transcripts containing premature termination codon (PTC)mutations by nonsense-mediatedmRNA decay (NMD) is an importantmechanismof long QT syndrome type 2 (LQT2). The mechanisms governing the recognition of PTC-containing hERG transcripts asNMD 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 thewild-type minigene in an NMD-dependent manner. The deletion of intron 14 prevented …
Early Lqt2 Nonsense Mutation Generates N-Terminally Truncated Herg Channels With Altered Gating Properties By The Reinitiation Of Translation, Matthew R. Stump, Qiuming Gong, Jonathan D. Packer, Zhengfeng Zhou
Early Lqt2 Nonsense Mutation Generates N-Terminally Truncated Herg Channels With Altered Gating Properties By The Reinitiation Of Translation, Matthew R. Stump, Qiuming Gong, Jonathan D. Packer, Zhengfeng Zhou
Faculty Publications - Department of Biological & Molecular Science
Mutations in the human ether-a-go-go-related gene (hERG) result in long QT syndrome type 2 (LQT2). The hERG gene encodes a K+ channel that contributes to the repolarization of the cardiac action potential. We have previously shown that hERG mRNA transcripts that contain premature termination codon mutations are rapidly degraded by nonsense-mediated mRNA decay (NMD). In this study, we identified a LQT2 nonsense mutation, Q81X, which escapes degradation by the reinitiation of translation and generates N-terminally truncated channels. RNA analysis of hERG minigenes revealed equivalent levels of wild-type and Q81X mRNA while the mRNA expressed from minigenes containing the LQT2 frameshift …