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Related Concept Videos

Mutations01:39

Mutations

Overview
Nuclear Export of mRNA02:31

Nuclear Export of mRNA

Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Alternative RNA Splicing02:18

Alternative RNA Splicing

Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
Mutations01:35

Mutations

Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...

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Related Experiment Video

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Nonsense mutations in hERG cause a decrease in mutant mRNA transcripts by nonsense-mediated mRNA decay in human

Qiuming Gong1, Li Zhang, G Michael Vincent

  • 1Division of Cardiovascular Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.

Circulation
|June 20, 2007
PubMed
Summary

Nonsense-mediated mRNA decay reduces hERG mRNA levels in Long-QT syndrome type 2 (LQT2) patients with premature termination codons. This degradation mechanism, not truncated proteins, explains reduced hERG mRNA in LQT2.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cardiology

Background:

  • Long-QT syndrome type 2 (LQT2) is linked to mutations in the human ether-a-go-go-related gene (hERG).
  • Over 30% of LQT2 mutations create premature termination codons (PTCs).
  • Nonsense-mediated mRNA decay (NMD) is a known pathway for degrading PTC-containing mRNA, but its role in LQT2 was unexplored.

Purpose of the Study:

  • To investigate the role of nonsense-mediated mRNA decay (NMD) in LQT2.
  • To determine if NMD affects hERG mRNA levels in LQT2 patients with PTCs.

Main Methods:

  • Allele-specific transcript quantification of hERG mRNA in patient lymphocytes.
  • Analysis of hERG minigenes in HEK293 cells and neonatal rat ventricular myocytes.
  • Assessment of NMD inhibition using cycloheximide and Upf1 knockdown.

Main Results:

  • LQT2 mutations R1014X and W1001X showed reduced mutant hERG mRNA levels compared to wild-type.
  • hERG minigenes carrying PTCs exhibited decreased mRNA levels.
  • Inhibition of protein synthesis or Upf1 restored mutant hERG mRNA levels, confirming NMD involvement.

Conclusions:

  • LQT2 nonsense mutations decrease mutant hERG mRNA levels via NMD, not by producing truncated proteins.
  • NMD-mediated degradation of hERG mutant mRNA is a significant mechanism in LQT2 patients with PTCs or frameshift mutations.