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Full-Text Articles in Physical Sciences and Mathematics
Inhibition Of Nonsense-Mediated Mrna Decay By Antisense Morpholino Oligonucleotides Restores Functional Expression Of Herg Nonsense And Frameshift Mutations In Long-Qt Syndrome, Qiuming Gong, Matthew R. Stump, Zhengfeng Zhou
Inhibition Of Nonsense-Mediated Mrna Decay By Antisense Morpholino Oligonucleotides Restores Functional Expression Of Herg Nonsense And Frameshift Mutations In Long-Qt Syndrome, Qiuming Gong, Matthew R. Stump, Zhengfeng Zhou
Faculty Publications - Department of Biological & Molecular Science
Mutations in the human ether-a-go-go-related gene (hERG) cause long-QT syndrome type 2 (LQT2). We previously described a homozygous LQT2 nonsense mutation Q1070X in which the mutant mRNA is degraded by nonsense-mediated mRNA decay (NMD) leading to a severe clinical phenotype. The degradation of the Q1070X transcript precludes the expression of truncated but functional mutant channels. In the present study, we tested the hypothesis that inhibition of NMD can restore functional expression of LQT2 mutations that are targeted by NMD. We showed that inhibition of NMD by RNA interference-mediated knockdown of UPF1 increased Q1070X mutant channel protein expression and hERG current …
Alternative Splicing And Polyadenylation Contribute To The Generation Of Herg1 C-Terminal Isoforms, Qiuming Gong, Matthew R. Stump, A. Russell Dunn, Vivianne Deng, Zhengfeng Zhou
Alternative Splicing And Polyadenylation Contribute To The Generation Of Herg1 C-Terminal Isoforms, Qiuming Gong, Matthew R. Stump, A. Russell Dunn, Vivianne Deng, Zhengfeng Zhou
Faculty Publications - Department of Biological & Molecular Science
The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel. Several hERG1 isoforms with different N- and C-terminal ends have been identified. The hERG1a, hERG1b, and hERG1-3.1 isoforms contain the full-length C terminus, whereas the hERG1USOisoforms, hERG1aUSO and hERG1bUSO, lack most of the C-terminal domain and contain a unique C-terminal end. The mechanisms underlying the generation of hERG1USOisoforms are not understood. We show that hERG1 isoforms with different C-terminal ends are generated by alternative splicing and polyadenylation of hERG1 pre-mRNA. We identified an …
Mutational Studies Uncover Non-Native Structure In The Dimeric Kinetic Intermediate Of The H2a–H2b Heterodimer, Matthew R. Stump, Lisa M. Gloss
Mutational Studies Uncover Non-Native Structure In The Dimeric Kinetic Intermediate Of The H2a–H2b Heterodimer, Matthew R. Stump, Lisa M. Gloss
Faculty Publications - Department of Biological & Molecular Science
The folding pathway of the histone H2A–H2B heterodimer minimally includes an on-pathway, dimeric, burst-phase intermediate, I2. The partially folded H2A and H2B monomers populated at equilibrium were characterized as potential monomeric kinetic intermediates. Folding kinetics were compared for initiation from isolated, folded monomers and the heterodimer unfolded in 4 M urea. The observed rates were virtually identical above 0.4Murea, exhibiting a log-linear relationship on the final denaturant concentration. Below ∼0.4 M urea (concentrations inaccessible from the 4-M urea unfolded state), a rollover in the rates was observed; this suggests that a component of the I2 ensemble contains non-native structure that …