Mutations in the TEFM gene cause mitochondrial disease
In this article, you’ll learn more about mitochondria and mitochondrial diseases, the role of the TEFM gene, and how this causes disease. It will also tell you how next-generation sequencing was used to study this disease.
What are mitochondria?
Mitochondria are small particles in a cell, but they are very important. They are often referred to as the powerhouses of the cell, as they are crucial for energy metabolism, but they do so much more! They also play an important role in programmed cell death or apoptosis, cell growth, cell signalling, and more.
Mitochondria have their own DNA, the mitochondrial DNA, which is responsible for thirteen proteins. However, for mitochondria to function, they also need hundreds of proteins whose genetic information is on one of the chromosomes in the nucleus.
What are mitochondrial diseases?
Mitochondrial diseases are a group of genetic disorders characterised by defects in mitochondrial function. They can be caused by mutations in the mitochondrial DNA or, more commonly, mutations in the DNA of the nucleus. Each individual disease is rare. However, mitochondrial diseases are the most common group of inherited neurological disorders. All combined, more children die from mitochondrial disease than from childhood cancer.
The symptoms of mitochondrial disease are very variable. Even in a family with the same mutation in their DNA, the symptoms and age of onset can be very different, so prognosis and life expectancy can be hard to predict.
The most common symptoms are neurological problems and muscle weakness. You can also read our blog about what ChatGTP writes about mitochondrial diseases.
Where does TEFM play a role?
I already mentioned that mitochondria have their DNA. This is not a chromosome but a small circular piece of DNA. For the DNA to form a functional protein, it must first be transcribed into RNA. In mitochondria, this doesn’t happen for each gene individually but for the entire circle, creating one long RNA that needs to be split into pieces. TEFM stands for Mitochondrial Transcription Elongation Factor; the name already explains what it does. It helps the mitochondria to produce those long RNAs. Without TEFM, the mitochondria can only form the first part of the long RNA strand, but it can’t move much further. As a result, patients have a high amount of the first RNAs on this circle, but almost nothing is further away from the start point.
Because the mitochondrial proteins work together to produce ATP, this process is completely disrupted, and the cells can’t make enough energy.
What happens when TEFM doesn’t work well?
Unfortunately, patients with a mutation in the TEFM gene are ill. How ill and what the symptoms are depends on the exact mutation. Some mutations are in a region of the DNA that is more important than others. Some of the patients that have been identified died as an infant, while others are adults now. Most patients have neurological problems, a delay in development, intellectual disability and muscle weakness.
This gene is essential not only in humans. We also showed that removing the tefm gene in zebrafish leads to abnormalities in the neuromuscular junctions and abnormal mitochondrial function.
Here, you can read our paper's more detailed, scientific explanation: “TEFM variants impair mitochondrial transcription, causing childhood-onset neurological disease.”
How was NGS used to study this?
We used RNA-seq to study the effect of TEFM on mitochondrial RNA transcription. With RNA-seq, we could immediately see that the most affected genes are playing a role in the mitochondria (as expected), particularly the OXPHOS genes encoded by the mitochondrial RNA. Further in-depth analysis showed that fewer RNA fragments are located further away from the start point, also called the promotor. This indicates that the mutations found in the patients cause precisely what we predicted based on published papers. As a result, this confirms that the patients are ill because of the mutation we found in their TEFM gene.
Why did we study the role of TEFM?
For many rare diseases, there is no treatment yet. The first step in finding a cure is knowing what exactly causes the disease. Knowing what gene is malfunctioning and the exact DNA mutation in the patient is the first step, but more is needed. If we understand what goes wrong in cells, there is hope for future therapy.