In this article, we will answer questions such as ‘what is exon deletion’, ‘what happens as a result of exon deletion’, ‘which exons deletion causes DMD disease’ for those who are curious.
Duchenne Muscular Dystrophy (DMD) is a severe form of muscular dystrophy, a genetic disorder that leads to progressive muscle degeneration and weakness. DMD predominantly affects boys, with symptoms typically appearing in early childhood. The condition is caused by mutations in the Dystrophin gene located on the X chromosome, which is responsible for producing the dystrophin protein. [Read More: What is Duchenne?]
Dystrophin plays a crucial role in maintaining the structural integrity of muscle cells by linking the internal cytoskeleton to the muscle cell membrane. Without this protein, muscles are unable to function properly, leading to the progressive breakdown of muscle tissue. The lack of dystrophin results in the hallmark signs of DMD, including muscle weakness, loss of motor function, and, eventually, respiratory and cardiac complications.
One of the key genetic mutations in DMD is exon deletion. This article explores what exon deletion means, how it contributes to DMD, and what causes exon deletions in the dystrophin gene.
Table of Contents
What is Exon Deletion?
To understand exon deletion, it is important to first have a basic grasp of the structure of a gene. Genes are made up of sequences of DNA that encode proteins, and these sequences can be broken down into two primary components: exons and introns.
- Exons are the coding regions of a gene, which contain the information necessary to build proteins.
- Introns are non-coding regions that are spliced out during the process of gene expression.
In normal gene function, the exons are transcribed into messenger RNA (mRNA), and this mRNA is then translated into a protein. However, in some genetic disorders, including DMD, certain parts of the gene may be deleted, disrupting the protein’s function.
An exon deletion occurs when a section of exons from a gene is missing due to a genetic mutation. In the case of DMD, exon deletions in the dystrophin gene result in the production of an incomplete or non-functional version of the dystrophin protein. This leads to the hallmark symptoms of muscle weakness and degeneration that characterize the disease.
What Does Exon Deletion Mean in DMD?
In Duchenne Muscular Dystrophy, the dystrophin gene (located on the X chromosome) is responsible for encoding the dystrophin protein. This protein is crucial for maintaining muscle fiber integrity by connecting the cytoskeleton of muscle cells to the surrounding extracellular matrix. When the dystrophin protein is missing or defective, it results in muscle cell damage and weakness.
Exon deletion refers to the process by which one or more of the exons in the dystrophin gene are lost, leading to a shorter or incomplete version of the dystrophin protein. There are several ways this can happen, including large deletions where entire sections of the gene are lost or smaller deletions where only a single exon or a few exons are removed.
When exons are deleted in the dystrophin gene, the mRNA produced by the gene will be abnormal. This abnormal mRNA will lead to a truncated dystrophin protein or a complete absence of dystrophin altogether. Since dystrophin is essential for proper muscle function, its absence results in progressive muscle weakness and degeneration seen in DMD patients.
Causes of Exon Deletion in Duchenne Muscular Dystrophy
Exon deletions in the dystrophin gene are typically the result of specific types of genetic mutations. The primary causes of exon deletions in DMD include:
1. Chromosomal Deletions
The most common cause of exon deletions in DMD is chromosomal deletion, which occurs when a segment of the dystrophin gene is lost due to a mistake during DNA replication or during the process of recombination. This loss can affect one or multiple exons. Chromosomal deletions can occur spontaneously, with no apparent cause, or they can be inherited from a carrier mother who carries a mutated X chromosome.
2. Frameshift Mutations
A frameshift mutation occurs when the deletion of exons disrupts the normal reading frame of the gene. In the case of DMD, this frameshift mutation alters the way the mRNA is read and translated into protein, leading to the production of a truncated and nonfunctional dystrophin protein. As a result, muscle cells are unable to maintain their structural integrity, leading to progressive muscle damage.
3. Exon Skipping
In some cases, the deletion of exons in the dystrophin gene may not result in a complete absence of the dystrophin protein but instead leads to exon skipping. Exon skipping is a phenomenon where the mutation causes the splicing machinery to bypass the deleted exons, resulting in the exclusion of those exons from the final mRNA transcript. This can sometimes produce a partially functional version of the dystrophin protein, but in many cases, the protein is still insufficient to perform its normal functions in the muscle cells. [Learn More: What is exon skipping and how does it work?]
4. Copy Number Variations (CNVs)
Sometimes, copy number variations (CNVs) in the dystrophin gene can result in the deletion or duplication of one or more exons. CNVs occur when there are large-scale alterations in the number of copies of a specific DNA region. In the case of DMD, deletions of exons 45-55 in the dystrophin gene are among the most common CNVs identified in patients with the condition. [Learn More: The impact of genotype with DMD: A single-center study of 555 patients]
The Impact of Exon Deletion on DMD Symptoms
The consequences of exon deletions depend on the specific exons that are missing and how this affects the dystrophin protein. Some exon deletions lead to a milder form of muscular dystrophy called Becker Muscular Dystrophy (BMD), in which the dystrophin protein is partially functional. In contrast, exon deletions that disrupt critical regions of the dystrophin gene typically result in Duchenne Muscular Dystrophy, which is characterized by a more severe and progressive form of muscle weakness. [Read More: Differences Between DMD and BMD]
Interestingly, the location and extent of exon deletions can influence the progression of the disease. For example, patients with deletions in the central part of the dystrophin gene (exons 18-32) tend to have a more severe phenotype compared to those with deletions in the terminal regions of the gene.
Therapies for Exon Deletion in DMD
In recent years, several therapies have been developed to address exon deletions in DMD. These include:
1. Exon Skipping Therapy
Exon skipping is a promising approach to treating DMD caused by exon deletions. This therapy uses synthetic oligonucleotides (short pieces of DNA) to promote the skipping of specific exons during the splicing process, enabling the production of a shortened but functional dystrophin protein. Eteplirsen is one of the FDA-approved drugs that uses this technique for patients with specific exon 51 deletions. [Read More: Next Generation Exon Skipping Therapies]
2. Gene Therapy
Gene therapy aims to introduce a functional copy of the dystrophin gene into the patient’s muscle cells. This therapy is still in its experimental stages but holds great promise for treating various types of DMD mutations, including those caused by exon deletions. Learn More: Potential Upcoming New Gene Therapies]
3. CRISPR/Cas9 and Genome Editing
CRISPR/Cas9 gene-editing technology has the potential to correct exon deletions at the genetic level by directly editing the DNA in patients’ cells. While this technology is still under investigation, it could offer a permanent solution to DMD caused by exon deletions in the future. [Learn More: Cures of Duchenne (List of All Researches)]
Conclusion
Exon deletion is a significant genetic mutation that underlies the development of Duchenne Muscular Dystrophy. The deletion of specific exons from the dystrophin gene results in the absence of the dystrophin protein, leading to the progressive muscle weakness and degeneration characteristic of DMD. The causes of exon deletions include chromosomal deletions, frameshift mutations, exon skipping, and copy number variations.
Advancements in genetic therapies, including exon skipping, gene therapy, and gene editing, offer hope for patients affected by DMD, with ongoing research focused on finding effective treatments and potentially a cure for this devastating disease.
