A new study reports a mutation in the gene EGR2 that caused Charcot-Marie-Tooth disease type 2 (CMT2) in an Italian family.
The study, “A novel family with axonal Charcot-Marie-Tooth disease caused by a mutation in the EGR2 gene,” was published in Journal of the Peripheral Nervous System.
The research focused on an Italian family in which five people across three generations showed symptoms of CMT. Using neurological tests and biopsies, investigators confirmed the diagnosis of CMT. Specifically, they determined that the patients had CMT2, where the axons — the long, wire-like parts of nerve cells — are damaged.
However, when the researchers tested the patients for mutations commonly associated with CMT2, such as changes in the genes MFN2 and GDAP1, they didn’t find anything out of the ordinary. This prompted them to do a broader experiment in which they sequenced 117 genes, known for their roles in demyelinating and axonal Charcot-Marie-Tooth disease and other related peripheral neuropathies, leading them to identify the mutation in the EGR2 gene.
This mutation, p.E412G, was present in everyone in the family with CMT and in no one else. Moreover, no other likely disease-causing mutations were identified. Therefore, the investigators declared, with confidence, that this mutation was responsible for causing the disease.
The protein encoded by EGR2 is a transcription factor, meaning it helps control whether genes in a cell are turned “on or off.” It’s particularly important for regulating the production of myelin, the protective layer in neurons that helps ensure that electrical signals are transmitted quickly and efficiently.
In this sense, it’s somewhat intuitive that a change in this gene might lead to CMT. In fact, this same mutation was previously reported to have caused CMT in a Czech family.
However, exactly how this particular mutation leads to disease is still not clear. When the researchers used computer programs to predict what effect this mutation would have on the function of the EGR2 protein, they found conflicting results: some programs predicted that this mutation would damage the protein, while others predicted it would have little to no effect.
Also, the disease didn’t progress the same way for everyone with this mutation even within this family: “Age at onset was variable, ranging from childhood to the 5th decade of life, and disability ranged from mild to moderate,” the researchers stated in the paper.
Despite these questions, the study provides solid evidence that this EGR2 mutation can cause CMT2. Further research may provide clues as to the mechanism of disease development and how knowing this genetic information might help improve prognoses and treatments for patients.