Exon identity crisis: disease-causing mutations that disrupt the splicing code

Timothy Sterne-Weiler,Jeremy R Sanford

doi:10.1186/gb4150

Timothy Sterne-Weiler, Jeremy R Sanford

Open Access

https://doi.org/10.1186/gb4150

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Abstract

Cis-acting RNA elements control the accurate expression of human multi-exon protein coding genes. Single nucleotide variants altering the fidelity of this regulatory code and, consequently, pre-mRNA splicing are expected to contribute to the etiology of numerous human diseases.

Highlights

Genes span 33.4% of the human genome from start codon to stop codon, only 3.66% of their sequence comprises protein coding sequences [1]
Given that other review articles have already done an exceptional job at summarizing the pleiotropic effects of RNA binding protein (RBP) and toxic RNA elements on pathogenesis [9,10,11,12,13], here we focus on aberrant protein-RNA interactions implicated in monogenic human diseases
Functional characterization of both germline and somatic variants remains a considerable challenge. This is due in part to the limited understanding of the gene architectural contexts that give rise to varying degrees of susceptibility to aberrant processing

Summary

Introduction

Genes span 33.4% of the human genome from start codon to stop codon, only 3.66% of their sequence comprises protein coding sequences [1]. Most mRNA isoforms produced by alternative splicing will be exported from the nucleus and translated into functional polypeptides, different mRNA isoforms from a single gene can vary greatly in their translation efficiency [42] Those mRNA isoforms with premature termination codons at least 50 bp upstream of an exon junction complex are likely to be targeted for degradation by the nonsense-mediated mRNA decay (NMD) pathway [43]. Future studies that include mutations affecting intronic cis-acting elements may shed light on an additional class of splicing-sensitive variants We find it intriguing that the architecture of different genes renders some more sensitive to mutation-induced aberrant splicing than others. Most inherited disease-related genes do not have a backup copy similar to SMN2 to serve as a template for RNA targeted therapies, this scenario does illuminate the potential feasibility of rational nucleic acid-based therapeutics in the coming years

Conclusion

15. Berget SM

25. Blencowe BJ

38. Black DL

Findings

70. Ladomery M