It’s no secret that genetic mutations can alter the way our bodies – and bodily processes – work. For example, explains Charcot-Marie-Tooth News, GARS gene mutations stop protein production in ribosomes. These particular mutations are found in patients with Charcot-Marie-Tooth disease type 2D (CMT2D). But what is the impact of this protein production complication, and how could researchers utilize this knowledge to improve patient outcomes? Take a look at the study results in Nucleic Acids Research to learn more.
Charcot-Marie-Tooth Disease (CMT)
To begin, let’s first take a closer look at what Charcot-Marie-Tooth disease (CMT) is. Although CMT is rare, it is also one of the most common inherited neurological disorders. CMT affects the peripheral nerves, which sit outside of the brain and spinal cord. There are different forms of CMT, all dependent on specific gene mutations. For example, GARS mutations cause CMT2D; over 30 different genes have been associated with various forms of CMT. Regardless, these mutations cause the degeneration of peripheral nerves, making it difficult for muscles and nerves to communicate. Symptoms often appear in adolescence or early adulthood, and include:
- Foot drop and frequent tripping
- Muscle weakness in the hands, feet, and lower legs
- Lower leg deformities due to muscle loss
- Muscle atrophy in the hands
- High arches and/or hammertoes
- Decreased or absent reflexes
- Difficulty with walking or fine motor skills
GARS Mutations & CMT2D
As explained above, there are over 30 genes associated with the development of CMT. But researchers wanted to focus on a particular set of genes: those which instructed the production of enzymes called aminoacyl-tRNA synthetases. Normally, these enzymes help spur protein production. Proteins are assembled within the ribosome. During this process, aminoacyl-tRNA synthetases perform aminoacylation to link amino acids and form protein bonds. But in patients with CMT, gene mutations affecting these enzymes stop protein production. However, researchers knew that these same genetic aberrations didn’t affect aminoacylation. So why was protein production being stopped?
Thus, researchers sought to understand how gene mutations interrupted a process called translation. In particular, the researchers focused on GARS mutations. Normally, this gene encodes for the glycyl t-RNA enzyme, which is affected in those with CMT2D. After evaluating mutations through ribosome profiling, the researchers found:
- GARS mutations in patients with CMT2D caused glycyl-tRNA deficiency. Because of this, elongation – part of the protein production process – was interrupted.
- When elongation stops, ribosomes halt protein production. This is because glycine cannot join the protein chain. Again, this affects the next step in the process and stops translation from beginning.
Ultimately, this causes a stress response within cells. Researchers still need to understand how this translates into the symptoms seen in patients with CMT2D. However, addressing the stress response and the issues in protein production could be an avenue for researchers to create future therapeutic options for patients.