Variations in two genes could significantly increase the odds of developing multiple sclerosis, according to a new study by a team of Duke researchers.
The scientists discovered a new interaction between a gene called IL7R—which past studies have demonstrated contributes to the likelihood of developing MS—and a gene that plays an important role in regulating it, called DDX39B. They hypothesized that a variation in these genes would produce a different protein—one more likely to cause MS.
“If you happen to be an individual that has the variants of both genes, you have a much higher chance of developing MS,” said Mariano Garcia-Blanco, co-lead author of the study and chair of the department of molecular biology and biochemistry at the University of Texas Medical Branch at Galveston.
Garcia-Blanco explained that the study's research focused on controlling the expression of "soluble IL7R," or the soluble form of a receptor that is important in activating the immune cells causing the neural damage associated with MS.
The difference between soluble IL7R and the standard IL7R protein is a portion of a gene known as an exon, which is the sequence of a gene's DNA that contains information about the coding for a protein sequence. Garcia-Blanco explained that the same gene could produce multiple versions of a protein in a process known as alternative splicing.
“What alternative splicing does is akin to what an editor in the film industry can do,” he said.
Just as a film editor can select which scenes of a movie to include in the final cut, proteins can control which pieces of a gene are used to make the final protein product. Garcia-Blanco noted that cutting out an additional piece of the IL7R gene is what produces the soluble IL7R protein, which causes MS.
This is where the DDX39B plays its role. DDX39B produces the enzyme responsible for ensuring that the soluble form of IL7R is produced, Garcia-Blanco explained.
“It’s not that the enzyme is defective or that there is a change in where the enzyme is,” he said. “What happens in those individuals is that they make less of the enzyme—they have lower levels.”
Simon Gregory, co-lead author of the study and director of genomics and epigenetics at the Duke Molecular Physiology Institute, explained that because the two genes work so closely together, a variant in one can profoundly affect the protein produced by the other.
Before more advanced research can be undertaken, Garcia-Blanco noted that a much more accurate animal model of the disease must be created. Mice do not produce the same type of soluble IL7R as humans, so normal mice cannot be used in these types of studies. One focus, therefore, is to breed mice capable of creating more human-like IL7R proteins.
Both Garcia-Blanco and Gregory said that they were hopeful that the research on these genes would help in the diagnosis and treatment of MS.
“If we start identifying these sorts of relationships at a genetic level, then we can figure out what’s happening at a functional level,” Gregory said.
However, the implications of these findings could extend far beyond multiple sclerosis.
“What we’re talking about is not only applicable to multiple sclerosis, but we actually believe that it may be important for several other autoimmune disorders,” Garcia-Blanco said.
Get The Chronicle straight to your inbox
Signup for our weekly newsletter. Cancel at any time.