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Updated: Feb 25, 2026
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Published on: October 9, 2014
The role of alternative splicing coupled to nonsense-mediated mRNA decay in human disease
Paulo J da Costa1, Juliane Menezes1, Luísa Romão1
1Department of Human Genetics, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal; Biosystems & Integrative Sciences Institute (BioISI), Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal.
Abstract:
Alternative pre-mRNA splicing (AS) affects gene expression as it generates proteome diversity. Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and selectively degrades mRNAs carrying premature translation-termination codons (PTCs), preventing the production of truncated proteins that could result in disease. Several studies have also implicated NMD in the regulation of steady-state levels of physiological mRNAs. In addition, it is known that several regulated AS events do not lead to generation of protein products, as they lead to transcripts that carry PTCs and thus, they are committed to NMD. Indeed, an estimated one-third of naturally occurring, alternatively spliced mRNAs is targeted for NMD, being AS coupled to NMD (AS-NMD) an efficient strategy to regulate gene expression. In this review, we will focus on how AS mechanism operates and how can be coupled to NMD to fine-tune gene expression levels. Furthermore, we will demonstrate the physiological significance of the interplay among AS and NMD in human disease, such as cancer and neurological disorders. The understanding of how AS-NMD orchestrates expression of vital genes is of utmost importance for the advance in diagnosis, prognosis and treatment of many human disorders.
Insights
Alternative splicing (AS) and nonsense-mediated mRNA decay (NMD) work together to control gene expression. This AS-NMD pathway is crucial for regulating protein diversity and preventing diseases like cancer.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Alternative pre-mRNA splicing (AS) generates proteome diversity by producing various mRNA transcripts from a single gene.
- Nonsense-mediated mRNA decay (NMD) is a crucial surveillance pathway that degrades aberrant mRNAs with premature translation-termination codons (PTCs), preventing disease-associated truncated proteins.
- NMD also plays a role in regulating the expression of normal cellular mRNAs, indicating a broader regulatory function.
Purpose of the Study:
- To review the mechanisms by which alternative splicing (AS) operates.
- To explore how AS is coupled with nonsense-mediated mRNA decay (NMD) to fine-tune gene expression levels.
- To demonstrate the physiological significance of the AS-NMD interplay in human diseases, including cancer and neurological disorders.
Main Methods:
- This review synthesizes existing research on alternative splicing and NMD.
- It analyzes the molecular mechanisms linking AS events to NMD-mediated degradation.
- The review examines evidence for the role of AS-NMD in various human pathologies.
Main Results:
- A significant portion (estimated one-third) of alternatively spliced mRNAs are targeted for NMD, highlighting the AS-NMD coupling as a key gene expression regulatory strategy.
- The interplay between AS and NMD influences the expression of numerous genes, impacting cellular function.
- Dysregulation of the AS-NMD pathway is implicated in the pathogenesis of major human diseases.
Conclusions:
- The coupling of alternative splicing and nonsense-mediated mRNA decay (AS-NMD) is an essential mechanism for precise gene expression regulation.
- Understanding the AS-NMD pathway is critical for developing novel diagnostic and therapeutic strategies for diseases like cancer and neurological disorders.
- Further research into AS-NMD orchestration of gene expression will advance our understanding of human health and disease.
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