Their findings also provide new insights into the biological processes and gene interactions at play in CMT, further expanding the current knowledge and understanding of the molecular and biological mechanisms underlying this group of inherited disorders of the peripheral nervous system.
The study, “Identification of Candidate Genes Associated with Charcot-Marie-Tooth Disease by Network and Pathway Analysis,” was recently published in the journal BioMed Research International.
To date, dozens of genes implicated in a variety of biological functions have been associated with CMT. Studies in cell and animal models have provided some insights into the biological mechanisms by which a given mutation causes the disease. However, these studies may fail to grasp the role CMT-associated genes play on a global scale.
Now, researchers combed through the published scientific literature and identified 100 genes that have been reported to be associated with CMT. Then, they used computer-based analyses — bioinformatics — to better understand their biological functions on a broad scale.
Bioinformatics uses computer programs for a variety of applications, including determining gene and protein functions, establishing evolutionary relationships, and predicting the three-dimensional shapes of proteins. It examines the patterns that exist across DNA and protein sequences to figure out what their functions are.
Here, the scientists first performed gene ontology (GO) enrichment analysis. Simply put, this type of bioinformatics assessment aims to identify the biological functions that are associated with a given group of genes (CMT-associated genes, in this case) based on what is already known about each individual gene in that group.
The analysis indicated that many of these genes were involved in the regulation of axons, or nerve fibers, and/or the production of myelin, which forms an insulating sheath around nerves. The axons are the nerve fibers responsible for transmitting electrical signals between nerve cells. Meanwhile, the myelin sheath is a fatty substance that protects and insulates nerve fibers.
“These results were consistent with the clinical classification of CMT, which is generally divided into demyelinating and axonal,” the researchers wrote. Axonal CMT is characterized by axon impairment, whereas demyelinating forms of the disease are distinguished by myelin degradation.
The enrichment analysis also suggested some of these genes could be implicated in the regulation of various aspects of cell metabolism, or in autophagy — the process by which cells degrade or recycle components that are damaged or no longer needed.
Subsequent biological pathway analyses confirmed some of these candidate genes played key roles in the regulation of cell metabolism. These analyses also revealed some of the genes were involved in a pathway controlling the production of transfer RNAs (tRNAs) — molecules that help cells “decode” other RNA molecules they use as templates to produce proteins.
The researchers then looked for “crosstalk,” or interactions between the different biological processes they identified earlier. For their analysis, any two biological processes that shared at least three of the previously identified genes were said to have such crosstalk.
This analysis revealed CMT-associated genes were implicated in a total of 83 biological processes, of which all but two had crosstalk with at least one other process.
Crosstalk analyses also showed that the biological mechanisms identified could be roughly divided into three groups: one large group related to nervous system function, metabolism, and immunity, and two smaller groups. Of the two smaller groups, one was related to autophagy and the other to the production of tRNA.
Finally, the investigators conducted an analysis to identify genes that might interact with the 100 CMT-associated genes they studied earlier. After performing this analysis, they identified 30 genes that had never been associated with CMT. But due to their interactions with CMT-related genes, the researchers argued these new genes might also be involved in the disease.
These findings provide a direction for further investigation.
“We have comprehensively collected genes potentially genetically related to CMT in our study, which provided a valuable resource for further analysis,” the scientists wrote.
However, they added that, since computer analyses are at best an imperfect reflection of biological reality, additional biological experiments will be needed to verify the study’s findings.
“By integrating the information from GO [Gene Ontology analyses], pathways, and biological process crosstalk analysis, the conclusions of this study may help to update the new understanding of the pathogenesis [disease mechanisms] of CMT and expand the potential genes of CMT for further exploration,” they concluded.
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