Key genetic concepts that explain how changes in DNA lead to DM1 and DM2. Understanding the genetics behind myotonic dystrophy (DM) can help explain why symptoms vary so widely, why different body systems are affected, and why DM can look so different from one person to another.
Common genetics terms
Below are genetics terms you may encounter when learning about DM or talking with healthcare providers.
- DNA (deoxyribonucleic acid)
The molecule that carries genetic instructions for how the body develops and functions. - RNA (ribonucleic acid)
A molecule that copies instructions from DNA to help cells make proteins and regulate how genes are used. - Proteins
Large molecules that perform most of the work in cells. Proteins support muscle movement, digestion, heart rhythm, and many other essential functions. - Gene
A specific section of DNA that contains instructions for making a protein or RNA. - Nucleotides
The basic building blocks of DNA and RNA. In DNA, they are represented by the letters A, T, C, and G. In RNA, T is replaced by U. - RNA splicing
A process where RNA is edited before it is used, allowing cells to make different proteins from the same gene. - Mutation
A change in the DNA sequence.
(Definitions adapted from the National Human Genome Research Institute)
How genetic instructions are used in the body
A helpful way to think about genetics is to imagine as a cookbook full of recipes.
- DNA is the master cookbook that holds every recipe and is safely stored in the cell.
- Each gene is a recipe for making specific proteins.
- When a cell needs a protein, it makes a copy of the recipe called RNA.
- Before the RNA is used, it is edited through RNA splicing, similar to adjusting a recipe.
- The spliced RNA is then used to create a protein, the “finished dish” that performs a specific job in the body.
Proteins play many roles. Some help build muscle and maintain strength. Others help digest food, regulate hormones and heart rhythm, or support brain function.
When changes in DNA affect health
Sometimes, the DNA cookbook contains errors, like repeated sections, missing instructions or spelling mistakes. These changes are called mutations.
Not all mutations cause health problems. For example, humans have hundreds of genes related to smell, so losing one usually has little effect. Some mutations may even provide benefits.
In myotonic dystrophy, the mutation interferes with how RNA and proteins behave inside cells, leading to the symptoms of DM.
The myotonic dystrophy type 1 (DM1) gene
At the core of DM1 is a mutation in the DMPK (Dystrophia Myotonica Protein Kinase) gene.
Normally, the DMPK gene contains a short repeated DNA sequence made up of the letters CTG.
- People without DM1 typically have 5 to 37 CTG repeats.
- People living with DM1 have 50 to more than 4,000 CTG repeats.
When this expanded CTG sequence is copied into RNA, it creates abnormally long RNA molecules.
The myotonic dystrophy type 2 (DM2) gene
At the core of DM2 is a mutation in the CNBP (CCHC-Type Zinc Finger Nucleic Acid Binding Protein) gene, which is also known as ZNF9 or CNBP1.
Normally, the CNBP gene contains a short repeated DNA sequence made up of the letters CCTG.
- People without DM2 typically have fewer than 75 CCTG repeats.
- People living with DM2 may have 75 to more than 11,000 CCTG repeats.
When this expanded CCTG sequence is copied into RNA, it creates abnormally long RNA molecules.
How RNA toxicity disrupts cells in DM
In both DM1 and DM2, the extra-long RNA strands created by the expanded repeats create a problem known as RNA toxicity. Instead of being processed by the cell, the RNA strands:
- Clump together inside the cell’s nucleus.
- Trap proteins needed for RNA splicing.
- Disrupt normal cell processes.
Over time, the loss of these proteins and ongoing cellular disruption contribute to the wide range of symptoms seen in myotonic dystrophy, including muscle weakness, myotonia, pain, fatigue, and effects across multiple body systems.
Why DM symptoms can vary across the body
Over time, CTG repeats in DM1 and CCTG repeats in DM2 can continue to change within a person’s body over time. This is called somatic mosaicism.
Because each cell carries its own copy of DNA, the number of repeats can vary between cells throughout the body. For example, a blood cell may have a different repeat length than a muscle cell. This variation may help explain why DM symptoms can differ in severity across different parts of the body.
Exact repeat size in each cell or tissue is not required for diagnosis or most clinical care.
How DM is passed through families
Both DM1 and DM2 are inherited in an autosomal dominant pattern:
- If one parent has DM, each child has a 50% chance of inheriting the mutation.
- DM is not related to sex chromosomes, so males and females are equally affected.
- DM does not skip generations.
- A person who inherits the mutation will eventually develop symptoms, although they may appear later in life.
How DM can change across generations
In DM1, symptoms may appear earlier or become more severe in successive generations. This pattern is called genetic anticipation and occurs because CTG repeats can expand when passed from parent to child.
The most severe form of DM1, Congenital myotonic dystrophy (CDM), is most often inherited from the mother. Researchers believe this may be due to greater repeat expansion during egg cell formation, although more research is ongoing.
Learn more on Congenital Myotonic Dystrophy
In DM2, genetic anticipation is not clearly observed. Disease severity does not appear to correlate with repeat length, and repeat size does not consistently increase across generations. Some studies continue to explore whether anticipation may occur in specific circumstances, particularly when DM2 is inherited from the mother.
