A novel mutation in the PMP22 gene was found in a family with Charcot-Marie-Tooth Disease (CMT) disease, and has been detailed in the study “A Novel Missense Mutation in Peripheral Myelin Protein‑22 Causes Charcot-Marie-Tooth Disease,” published in the Chinese Medical Journal.
Most CMT1 patients (70-80 percent) have a duplication of the PMP22 gene, which codes for the Peripheral Myelin Protein-22, a protein required for conducting nerve signals. Some patients who also display clinical signals of CMT1 may have different alterations in this gene and others.
In this study, researchers used a new DNA-sequencing technology (next-generation sequencing, or NGS) to identify PMP22 mutations in a CMT Chinese family. In the family, patients’ ages ranged from 31 to 65 years. Reaching the second decade of their lives, they started to feel muscular weakness after standing or walking for a long time. Although the disease progressed slowly, one of the family members displayed severe muscle disability and became wheelchair-dependent.
The team obtained DNA for sequencing from peripheral blood cells. They started by looking for the PMP22 gene duplication, the most common in CMT1 patients. However, no gene duplication was found in these patients. Then, researchers completely sequenced genes known to be associated with CMT, including the PMP22. They identified a single nucleotide change in PMP22 gene of CMT family patients that was absent in the unaffected family members or other healthy individuals.
To gain insight into the mutation effect in myelin protein function, researchers performed a set of experiments in the lab. They introduced the mutated gene in cells to study the behavior of the resultant mutated protein. While the non-mutated protein form was mainly in the cellular membrane, the “sick” variant concentrated inside the endoplasmatic reticulum (ER), a cell compartment involved in protein synthesis. Moreover, it caused cells to die, suggesting the mutated form is toxic.
In patients with a copy of the mutated gene, the mutated myelin may be toxic for neurons and even interfere with the non-mutated myelin. “All of these studies confirmed that mutant PMP22 possess a toxic gain-of-function feature. In addition, mutant PMP22 could form heterodimers with the Wt PMP22 and then impair Wt [non-mutated] protein transport through the ER to the cell surface, suggesting a dominant‑negative mechanism,” the authors wrote. A toxic effect of this mutation also may explain why these patients always have more severe disease manifestations than patients with a PMP22 duplication mutation.