The Role of Alternative Splicing in Disease

Alternative splicing (AS) is a key technique for increasing transcriptome and proteomic diversity from a small genome. Almost all human gene transcripts are alternatively spliced, resulting in protein isoforms with different, sometimes antagonistic, characteristics that affect cell function.


Image Credit: Yurchanka Siarhei/

Many AS events are carefully regulated by cell type or tissue, and at different periods of development. RNA-binding proteins, such as cell- or tissue-specific splicing factors, regulate AS.

Technological advancements have established genome-wide AS programs governed by an increasing number of splicing factors in recent years. These splicing regulatory networks (SRNs) are made up of transcripts that encode proteins that interact together to influence the development and phenotypes of many cell types.

As a result, it is becoming increasingly clear that disruption of normal splicing programs mediated by many splicing factors can result in human diseases. Alternative splicing has been linked to around 15% of human genetic diseases and malignancies. AS research will help us better understand mRNA complexity and regulation, as well as provide vital insights into illness etiology and aid in the development of therapeutic approaches for splicing-related diseases.

Association of alternative splicing with human diseases

Mutations of the core splicing consensus sequences are the most common way that aberrant splicing is known to cause disease. Splice site mutations are one of the most prevalent mutations discovered in genetic disorder research.

Aside from mutations in the splice site consensus sequence, there have been numerous examples of genetic diseases in which abnormal splicing occurs due to changes in the auxiliary cis-elements mentioned earlier. The most well-known cases, such as those found in the neurofibromatosis (NF1) gene, occur in known or presumed ESE elements and frequently result in exon skipping.

Alternative RNA splicing is linked to a variety of neurological and muscular disorders. AS modulates the complexity of integral membrane proteins, including changes in their structure, solubility, and signal peptides. Aberrant alternative splicing, for example, has been linked to Parkinson's disease. The level of survival motor neuron (SMN) protein was downregulated in spinal muscular atrophy (SMA) due to alternative splicing.

AS is also reported to be associated with heart development, blood coagulation, cholesterol homeostasis, and systemic sclerosis. Heart-specific deletion of ASF/SF2, a member of the serine/arginine (SR-) rich family of splicing factors, causes cardiomyopathy and alters cardiac troponin T and LIM domain-binding protein splicing.

Alternate splicing in rare disorders

Timothy syndrome is a rare congenital condition that predominantly affects the heart, but can also impact teeth, the neurological system, and the immune system. Timothy syndrome is of two types: classical (type-1) and atypical (type-2). De novo point mutations in CACNA1C, a gene that encodes the alpha-1 subunit of a voltage-dependent calcium channel, cause both of them. CACNA1C has alternative splicing in at least 19 of its 55 exons.

Familial dysautonomia (FD) is a rare autonomic nervous system condition that affects the growth and survival of sensory sympathetic and parasympathetic nerve cells. In B-cells, FD is caused by the loss of function of kinase complex-associated protein, an inhibitor of the kappa light polypeptide gene enhancer (IKAP, also known as elongator complex protein 1, ELP1).

The majority of FD patients have a point mutation in the 20th exon the 5′ splice donor site. It's a T > C transition that weakens the intronic portion of the 5′ splice site, causing exon 20 to skip. When this mRNA is translated, it results in a shortened IKAP protein that lacks all of the amino acids encoded by exon 20. As a result, many FD symptoms are caused by a reduction in functional IKAP protein expression.

Role of alternative splicing in cancer

Splicing has a key role in oncogenesis, tumor suppression, and metastasis in cancer-related genes. Various types of cancers have been linked to changes in alternative splicing. Research reports show the role of p53, breast cancer early-onset 1 (BRCA1), kallikrein-related peptidase 12 (KLK12), protein N-arginine methyltransferases 2 (PRMT2), and CDC25 phosphatases in breast cancer.

Studies have also reported the role of tissue inhibitor of metalloproteinases-1 (TIMP1) and the cell adhesion molecule CD44 in colon cancer; androgen receptor in prostate cancer; calpain 3 in melanoma; Bcl-xL, CD44, and others in lung cancer; and Krüppel-like factor 6 (KLF6) in liver cancer. As a result, alternatively spliced variants could be used as biomarkers for cancer diagnosis and prognosis, as well as cancer therapy targets using specialized splicing correction treatments.

Intron retention (IR)

Until recently, intron retention (IR) was the least studied type of alternative splicing. Recent research has confirmed that IR is not only a conserved form of alternative splicing but also plays an important function in managing and improving gene expression complexity.

IR is a common occurrence in a variety of disorders. Point mutations at important splice control points like the donor or acceptor sites might result in partial or complete intron retention. Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare and recessively inherited immune-cell malfunctioning illness characterized by numerous autoimmunity. It occurs due to the loss-of-function mutations in the autoimmune regulator gene (AIRE).

IR events are also quite common among cancer patients, according to recent studies. One cause of head and neck cancer has been identified as partial retention of GSTP1 intron 6. CCND1 produces truncated cyclin D1b with a partially maintained intron 4, causing prostate and esophageal cancer. As per a recent large-scale transcriptome profiling investigation, IR events have been observed in solid tumors originating from the bladder, colon, head, neck, and endometrial.

Looking forward

With the help of molecular research, high-throughput sequencing, and bioinformatics tools, a lot more about alternative splicing is being learned, but there's still a lot more to understand about how it works at the cellular level.

There is also a need to dig further into the combinatorial methods by which they govern AS in different cells and tissues, and how unregulated splicing might cause disease.


  • Tang, J. Y., Lee, J. C., Hou, M. F., Wang, C. L., Chen, C. C., Huang, H. W., & Chang, H. W. (2013). Alternative splicing for diseases, cancers, drugs, and databases. TheScientificWorldJournal, 2013, 703568.
  • Cieply, B., & Carstens, R. P. (2015). Functional roles of alternative splicing factors in human disease. Wiley interdisciplinary reviews. RNA, 6(3), 311–326.
  • Jiang, W., & Chen, L. (2020). Alternative splicing: Human disease and quantitative analysis from high-throughput sequencing. Computational and structural biotechnology journal, 19, 183–195.

Further Reading

Last Updated: Nov 11, 2021


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