Nonsense mutations in hERG cause a decrease in mutant mRNA transcripts by nonsense-mediated mRNA decay in human long-QT syndrome.
Background: Long-QT syndrome type 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene (hERG). More than 30% of the LQT2 mutations result in premature termination codons. Degradation of premature termination codon-containing mRNA transcripts by nonsense-mediated mRNA decay is incr...
| Publicado en: | Circulation Vol. 116; no. 1; pp. 17 - 25 |
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| Autores principales: | , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Lippincott Williams & Wilkins
7/3/2007
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=105994986&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 105994986 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00097322 1FV jtl: Circulation issn: 00097322 maglogo: N pubinfo: dt: 7/3/2007 vid: 116 iid: 1 pid: 433 pub: Lippincott Williams & Wilkins place: Baltimore, Maryland artinfo: ui: 105994986 105994986 NLM17576861 2009624433 NLM17576861 PMC2376840 105994986 ppf: 17 ppct: 8 formats: tig: atl: Nonsense mutations in hERG cause a decrease in mutant mRNA transcripts by nonsense-mediated mRNA decay in human long-QT syndrome. aug: au: Gong Q Zhang L Vincent GM Horne BD Zhou Z Gong, Qiuming Zhang, Li Vincent, G Michael Horne, Benjamin D Zhou, Zhengfeng affil: Division of Cardiovascular Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA sug: subj: Carrier Proteins Long QT Syndrome Mutation RNA Metabolism Adult Aged Animals Cells Metabolism Enzyme Inhibitors Pharmacodynamics Female Genes Genetic Techniques Kidney Lymphocytes Metabolism Male Middle Age Pedigree Piperidines Pharmacodynamics Proteins Antagonists and Inhibitors Proteins Physiology Proteins Rats Viruses Adult: 19-44 years Aged: 65+ years Middle Aged: 45-64 years Female Male ab: Background: Long-QT syndrome type 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene (hERG). More than 30% of the LQT2 mutations result in premature termination codons. Degradation of premature termination codon-containing mRNA transcripts by nonsense-mediated mRNA decay is increasingly recognized as a mechanism for reducing mRNA levels in a variety of human diseases. However, the role of nonsense-mediated mRNA decay in LQT2 mutations has not been explored.Methods and Results: We examined the expression of hERG mRNA in lymphocytes from patients carrying the R1014X mutation using a technique of allele-specific transcript quantification. The R1014X mutation led to a reduced level of mutant mRNA compared with that of the wild-type allele. The decrease in mutant mRNA also was observed in the LQT2 nonsense mutations W1001X and R1014X using hERG minigenes expressed in HEK293 cells or neonatal rat ventricular myocytes. Treatment with the protein synthesis inhibitor cycloheximide or RNA interference-mediated knockdown of the Upf1 protein resulted in the restoration of mutant mRNA to levels comparable to that of the wild-type minigene, suggesting that hERG nonsense mutations are subject to nonsense-mediated mRNA decay.Conclusions: These results indicate that LQT2 nonsense mutations cause a decrease in mutant mRNA levels by nonsense-mediated mRNA decay rather than production of truncated proteins. Our findings suggest that the degradation of hERG mutant mRNA by nonsense-mediated mRNA decay is an important mechanism in LQT2 patients with nonsense or frameshift mutations. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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