Review Article | Published:

RNA mis-splicing in disease

Nature Reviews Genetics volume 17, pages 1932 (2016) | Download Citation


The human transcriptome is composed of a vast RNA population that undergoes further diversification by splicing. Detecting specific splice sites in this large sequence pool is the responsibility of the major and minor spliceosomes in collaboration with numerous splicing factors. This complexity makes splicing susceptible to sequence polymorphisms and deleterious mutations. Indeed, RNA mis-splicing underlies a growing number of human diseases with substantial societal consequences. Here, we provide an overview of RNA splicing mechanisms followed by a discussion of disease-associated errors, with an emphasis on recently described mutations that have provided new insights into splicing regulation. We also discuss emerging strategies for splicing-modulating therapy.

Key points

  • The human transcriptome is the product of a coordinated series of transcriptional, co-transcriptional and post-transcriptional regulatory events.

  • RNA splicing is a key regulatory step in gene expression that allows a limited genome to express an impressive diversity of coding and non-coding RNAs.

  • RNA mis-splicing causes a large array of human diseases due to hereditary and somatic mutations.

  • Mis-splicing may result from mutations to RNA cis-regulatory elements, core spliceosomal components or trans-acting regulatory factors.

  • Mutations in some genes, such as lamin A (LMNA), cause multiple types of diseases, from muscular dystrophy to premature ageing syndromes.

  • A key small nuclear RNA (snRNA) component of the minor spliceosome functions as a stress-activated switch to control expression levels of genes containing minor introns.

  • Some splicing factors linked to diseases, such as amyotrophic lateral sclerosis, contain low-complexity regions with prion-like domains that are susceptible to abnormal aggregation.

  • Splicing modulatory therapeutic strategies have been developed that target a range of diseases, including muscular dystrophies and motor neuron diseases, and are currently being tested in clinical trials.

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The authors regret that many important studies were not cited owing to space limitations. Work in the authors' laboratories is funded by grants to M.S.S. from the US National Institutes of Health (NIH AR046799, NS058901), the Muscular Dystrophy Association (MDA276063), the W.M. Keck Foundation (F013635) and the Marigold Foundation. M.M.S. is the recipient of an NIH pre-doctoral traineeship (NIAMS T32 AR7605-15).

Author information


  1. Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida 32610–3610 USA.

    • Marina M. Scotti
    •  & Maurice S. Swanson


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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Maurice S. Swanson.


Long non-coding RNAs

(lncRNAs). RNAs of >200 nucleotides in length that generally do not encode proteins.


Non-functional versions of genes that are generated either by duplication and mutation or by retrotransposition.

Splicing factors

Proteins that participate in splicing regulation but are not stable constituents of small nuclear ribonucleoprotein particles (snRNPs).

Single-nucleotide polymorphisms

(SNPs). Variations in individual nucleotides that are common in the human genome and can influence splicing regulation.

Nonsense-mediated decay

(NMD). A process of enhanced RNA turnover induced by a premature termination codon (PTC) which is designed to block the synthesis of truncated proteins and modulate the appearance of full-length proteins during development.


The percentage of individuals carrying a disease mutation who show clinical symptoms. Incomplete, or reduced, penetrance occurs when not all individuals with a particular genetic mutation develop the associated disease.


The degree to which a mutant gene is phenotypically expressed. Variable expressivity refers to the symptomatic range that is displayed by different individuals with the same mutation.

Core consensus sequences

Conserved RNA sequence motifs, including the 5′ and 3′ splice sites and the branch point region, which are required for spliceosome recruitment.

Branch point

(BP). A partially conserved sequence, generally <50 nucleotides upstream of the 3′ splice site (see Box 1), that reacts with the 5′ splice site during the first step of the splicing reaction.


The large RNA–protein complex that catalyses splicing and is composed of multiple small nuclear RNAs (snRNAs) and many associated protein factors. Whereas the major and minor spliceosomes both contain U5, the other snRNA components differ (for the major spliceosome, U1, U2, U4, U6; for the minor spliceosome, U11, U12, U4atac, U6atac) (see Fig. 2).


A preassembled complex of U4 snRNA hybridized to U6 (U4/U6 or U4atac/U6atac) that also contains U5 (U4/U6.U5) together with associated proteins (see Fig. 2).


A condition due to inactivating mutations in one copy of a gene when expression from the remaining copy is insufficient to produce an unaffected phenotype.


(High-throughput sequencing of RNA isolated by crosslinking immunoprecipitation; also known as CLIP–seq). A technique to map the binding sites of splicing, and other, factors on target RNAs. Related techniques include photoactivatable-ribonucleoside-enhanced-CLIP (PAR-CLIP) and individual-nucleotide resolution CLIP (iCLIP).

Cryptic splice sites

Splice sites that are not normally recognized by the spliceosome but can be activated either by mutations in cis-acting elements or trans-acting factors.

Splicing regulatory elements

RNA sequence motifs in either exons or introns that modulate splicing primarily by binding trans-acting splicing regulatory factors.


An antisense oligomer with standard nucleic acid bases but instead of deoxyribose contains a six-member morpholine ring linked with phosphorodiamidate (PMO). PMOs function by steric blocking and vivo-morpholinos, composed of a morpholino oligomer covalently attached to an octa-guanidine dendrimer, are optimized for in vivo delivery.

Human transcriptome

All of the RNAs transcribed from the human genome.

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