Chromosomes are like chapters in a book and our genes are the sentences in our book.
Mutations are like a misspelled word or a disruption in one of those sentences. There are various types of mutations responsible for the symptoms of Duchenne.
Below describes what different types of mutations would look like if the DMD gene where sentences in a book:
Imagine the above sentence “THE CAR WAS RED” was the DMD gene of an individual without Duchenne. The different mutations of Duchenne would look like the following:
Deletion Mutation: THE ___ WAS RED. (subtracting a word) or THE _AR WAS RED. (subtracting a letter)
Insertion/Duplication Mutation: THE CAR WAS RED RED. (add one word) or THE CAR WAS ERED. (add one letter)
Missense Mutation: THE CAR WAS HAT. (changed one word) or THE CAR WAS RDD. (changed one letter)
Nonsense Mutation: THE CAR. (ends the instructions too soon)
The DMD gene is constructed like our example of sentences shown above. However, each three-letter word is an exon. The DMD gene is very large and contains 79 exons or 79 three letter words. Below is a picture of the DMD gene with all 79 exons perfectly fitting together like a puzzle.
When a Duchenne diagnosis is suspected, genetic testing will be able to show whether it’s an in-frame deletion or out-of-frame. Why does this matter? Because an in-frame mutation is more common in milder forms of Becker muscular dystrophy whereas the out-of-frame mutations cause the more severe Duchenne muscular dystrophy. Becker muscular dystrophy is typically less severe, has a later age of onset and a slower rate of progression.
The picture below shows our dystrophin puzzle once again. Here we have exons 23 to 42 missing, but the puzzle pieces still fit together. Dystrophin is produced but a much shorter version of the protein.
With an out-of-frame deletion, the production is completely disrupted and, therefore, no dystrophin can be produced, indicted by the grey exons below.
The above image demonstrates why Duchenne tends to be one of the more severe forms of muscular dystrophy. However, there are always exceptions to these rules, and it is possible for an individual to have an in-frame mutation with Becker with signs and symptoms consistent with Duchenne. Research is ongoing to help us better understand why this is.
Large deletions occur in 60 – 70% of Duchenne cases, and 80-85% of Becker cases.
Example: The ____ was red (subtracting a word) or The _ar was red. (subtracting a letter)
Exons are sections of DNA (or our three letter words as described above). They are responsible for creating proteins, including dystrophin. If one or more exons are missing, the sequence no longer makes sense because our puzzle no longer fits together, and the protein cannot be made. Alternatively, a non-functional protein is made but is then quickly broken down by our bodies.
While many different exon deletions can occur, there are some that geneticists have found to be the most common or called “hot spots”. For example, in the diagnosis of Duchenne, deletions of the exons 44-55 are frequently detected and considered one of these hot spots. Understanding if this type of mutation is responsible for your child’s symptoms is important because, if so, they may be eligible for exon skipping therapy.
Large Duplications occur in 10% of Duchenne cases and 5-10% of Becker.
Example: The car was red red. (add one word) or The car was ered. (add one letter)
A duplication or insertion mutation occurs when one or more exons are copied or a letter of part of the word is doubled (also called point mutations). The result has the same effect as a deletion in that the sentence no longer makes sense and the dystrophin protein is either not produced or a non-functional protein is made. A duplication can occur in any one or any number of the 79 exons.
Occurs in 15-30% of Duchenne cases and 10-15% of Becker cases.
These mutations differ from those listed above because they do not involve changes to an entire exon. Instead of the whole codon being duplicated or deleted, point mutations occur when only one single component of the exon or in our word example a single letter is affected. The most common of these mutations is referred to as a “nonsense mutation,” which causes the gene to prematurely signal a stop in the production of the dystrophin protein. The result however is the same as all the other mutations in that no functional dystrophin is made.
Understanding which type of mutation is responsible for your child’s diagnosis of Duchenne can enhance your treatment journey.
Some treatments, such as exon skipping therapies, are based on the specific genetic change your child may have. Therefore, it’s important you know what your mutation is, as it may determine your eligibility for a clinical trial and/or future access to a treatment once approved in Canada.
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