Many different mutations in the DMD gene can lead to Duchenne muscular dystrophy (DMD). In fact, more than 2,000 mutations in the gene have been identified.
As variant-specific treatments like exon-skipping therapies progress, knowing which mutation a person has can help guide treatment options or clinical trial eligibility. Understanding even the basics of DMD gene variants might feel intimidating — but it doesn’t have to.
What is the DMD gene, and why is it important?
To understand each of the different mutations that can cause DMD, we first need to understand the basic structure of the DMD gene.
The DMD gene codes for the protein dystrophin, which is primarily found in the skeletal and cardiac muscles. There, it works with other proteins to protect the muscles from injury.
Read more about DMD causes and risk factors
In humans, the DMD gene is the largest known gene, making it more prone to mutations. It consists of 79 exons, which are smaller segments of DNA that each carry part of the code for making dystrophin.
Everyone has a DMD gene, but it becomes mutated in patients with DMD or Becker muscular dystrophy (BMD), which is typically milder than DMD. This leads to the absence of dystrophin in DMD or the production of a shorter, partially functional protein in BMD. With both diseases, progressive muscle weakness and damage occurs.
What are the types of DMD gene mutations?
There are three main genetic variants that occur in patients with DMD: Deletions, duplications and point mutations.
Deletion mutations
Around 70% of individuals with DMD have deletion mutations. Deletions can impact just one exon, or multiple. Exons 45 to 55, for example, are considered a “hotspot” region, meaning mutations are especially common in this area. However, people can also have deletion mutations beyond these exons.
Duplication mutations
Duplication mutations occur in about 10% of individuals with DMD. As the name suggests, these mutations occur when one or more exons of the DMD gene are doubled.
Just like deletion mutations, duplication mutations can occur anywhere in the DMD gene. Some studies have shown that duplications are more common near the beginning of the gene, particularly exons 2 to 23.
Point mutations
About 20% of those with DMD have point mutations. Point mutations consist of very small deletions, duplications or changes in individual DNA bases. Even though point mutations are on a much smaller scale than exon-level deletion or duplication mutations, this doesn’t mean they cause a milder form of the disease.
One type of point mutation commonly seen in DMD is a nonsense mutation, which forces the protein to stop production too early. This usually leads to a shortened, nonfunctional version of the protein.
What are in-frame and out-of-frame mutations?
Every gene has a reading frame, which is the way that the DNA sequence is grouped so that it can be read correctly by the cell’s machinery to produce a protein.
When in-frame mutations occur, a certain number of DNA bases are duplicated or deleted in a way that doesn’t disrupt the overall reading frame; this means the cell can still make functional dystrophin, though it may be shorter than normal. With out-of-frame mutations, on the other hand, the grouping of DNA bases is altered and the reading frame is disrupted.
In general, in-frame mutations are associated with BMD, while out-of-frame mutations tend to cause DMD.
How is a patient’s gene variant identified?
Genetic testing can examine a patient’s DNA and pinpoint the exact mutation in their DMD gene. A genetic counselor or geneticist can help; a blood sample is all that’s needed.
Sign up here to get the latest news, perspectives, and information about DMD sent directly to your inbox. Registration is free and only takes a minute.
