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Nonsense-mediated decay approaches the clinic

Abstract

Nonsense-mediated decay (NMD) eliminates mRNAs containing premature termination codons and thus helps limit the synthesis of abnormal proteins. New results uncover a broader role of NMD as a pathway that also affects the expression of wild-type genes and alternative-splice products. Because the mechanisms by which NMD operates have received much attention, we discuss here the emerging awareness of the impact of NMD on the manifestation of human genetic diseases. We explore how an understanding of NMD accounts for phenotypic differences in diseases caused by premature termination codons. Specifically, we consider 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. Potential 'NMD therapeutics' will therefore need to strike a balance between the general physiological benefits of NMD and its detrimental effects in cases of specific genetic mutations.

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Figure 1: Simplified model of NMD.
Figure 2: Position-dependent effects of nonsense mutations of NMD correlate with inheritance pattern and clinical severity of disease.

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Acknowledgements

We apologize for the limited citation of the primary literature outside of the main focus of this review. We thank N. Gehring for sharing his knowledge of the NMD literature and S. Danckwardt and J. Kunz for discussions. J.A.H. is supported by a fellowship from the Human Frontier Science Program. The experimental work of the authors is supported by the Fritz Thyssen Stiftung and the Deutsche Forschungsgemeinschaft.

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Correspondence to Matthias W Hentze or Andreas E Kulozik.

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Supplementary Fig. 1

Flow scheme for the experimental analysis of NMD-mediated modulation of PTC-mutated transcripts. (PDF 152 kb)

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Holbrook, J., Neu-Yilik, G., Hentze, M. et al. Nonsense-mediated decay approaches the clinic. Nat Genet 36, 801–808 (2004). https://doi.org/10.1038/ng1403

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