Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease

@article{Khajavi2006NonsensemediatedMD,
  title={Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease},
  author={Mehrdad Khajavi and Ken Inoue and James R. Lupski},
  journal={European Journal of Human Genetics},
  year={2006},
  volume={14},
  pages={1074-1081},
  url={https://api.semanticscholar.org/CorpusID:3450423}
}
The physiological role of this surveillance pathway, its implications for human diseases, and why knowledge of NMD is important to an understanding of genotype–phenotype correlations in various genetic disorders are reviewed.
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389 Citations

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The factors involved in NMD are discussed, the different models proposed for the recognition of PTCs (premature termination codons), the diverse physiological roles of NMD, the involvement of this surveillance pathway in disease and the current strategies for medical treatment of P TC-related diseases are discussed.

To NMD or Not To NMD: Nonsense-Mediated mRNA Decay in Cancer and Other Genetic Diseases.

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Understanding the complexities of NMD regulation and its interaction with other cellular processes can lead to the development of new interventions for various diseases.

Analysis of nonsense-mediated mRNA decay in mammalian cells.

This unit details some of the fundamental RNA based approaches taken to examine aspects of NMD, such as creating PTC+ reporter genes, knocking down key NMD factors via RNAi, elucidating the important functions of N MD factors by complementation assays or Tethered Function Assays, and measuring RNA levels by reverse-transcription quantitative PCR.

Nonsense-mediated decay in genetic disease: friend or foe?

Antisense suppression of the nonsense mediated decay factor Upf3b as a potential treatment for diseases caused by nonsense mutations

While minimally impacting the normal transcriptome, Upf3b-ASO treatment significantly stabilizes the PTC-containing dystrophin mRNA in mdx mice and coagulation factor IX mRNA in a hemophilia mouse model.

Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes

How NMD targets m RNAs, the types of mRNAs that are targeted, and the roles of NMD in cellular stress, differentiation and maturation processes are discussed.

Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression

It is demonstrated that NMD attenuation significantly enhances suppression therapy in vivo, and co-administration of NMDI-1 with the PTC suppression drug gentamicin enhanced alpha-L-iduronidase activity compared to gentamic in, leading to a greater reduction of GAG storage in mouse tissues, including the brain.
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61 References

Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species.

Nonsense-mediated decay approaches the clinic

This work considers how the protective function of NMD sometimes benefits heterozygous carriers and, in contrast, sometimes contributes to a clinical picture of protein deficiency by inhibiting expression of partially functional proteins.

Nonsense-mediated mRNA decay in health and disease.

The current models of NMD that have been generated during the study of model organisms and mammalian cells are presented and the physiological burden of nonsense transcripts and the emerging view that NMD plays a broad and critical role in the regulation of gene expression are discussed.

Nonsense-Mediated Decay of HumanHEXA mRNA

Transfection of Chinese hamster ovary cells showed that expression of an intronless HEXA minigene harboring the frameshift mutation or a closely located nonsense codon resulted in half the normal mRNA level, while inclusion of multiple downstream introns decreased the abundance further, to about 20% of normal.

Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells.

mRNA surveillance: the perfect persist.

In eukaryotes, the mRNA surveillance pathway works in this context by assessing the quality of mRNAs to ensure that they are suitable for translation, and prevents the synthesis of truncated and otherwise aberrant proteins, which can have dominant-negative and other deleterious effects.

Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise

Novel results document that nonsense surveillance is a crucial post-transcriptional regulatory event that influences the expression of broad classes of physiologic transcripts, has been functionally incorporated into essential homeostatic mechanisms and suppresses expression of evolutionary remnants.

Rent1, a trans-effector of nonsense-mediated mRNA decay, is essential for mammalian embryonic viability.

The consequences of loss of NMD function in vertebrates are explored through targeted disruption of the Rent1 gene in murine embryonic stem cells which encodes a mammalian ortholog of Upf1p, demonstrating that Rent1 is essential for embryonic viability and support a critical role for the pathway in the regulated expression of selected physiologic transcripts.

Separable Roles for rent1/hUpf1 in Altered Splicing and Decay of Nonsense Transcripts

It is demonstrated that rent1/hUpf1 enters the nucleus where it may directly influence early events in mRNA biogenesis, providing compelling evidence that NAS relies on a component of the nonsense surveillance machinery but is not an indirect consequence of NMD.

Boundary‐independent polar nonsense‐mediated decay

The results suggest that TCR‐β transcripts contain one or more sequence elements that elicit an unusual NMD response triggered by a novel second signal that ultimately causes boundary‐independent polar regulation.
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