Although multiple sclerosis (MS) is known to run in certain families, attempts to find genes linked to the disease have been elusive. Now for the first time researchers are reporting a gene mutation that can be connected directly to the development of the disease. The results appear June 1 inNeuron.
"This finding is critical for our understanding of MS," says Carles Vilariño-Güell, an Assistant Professor in the Department of Medical Genetics at the University of British Columbia (UBC) in Vancouver and one of the study's senior authors. "Little is known about the biological processes that lead to the onset of the disease, and this discovery has massive amounts of potential for developing new treatments that tackle the underlying causes, not just the symptoms."
MS is a neurodegenerative disease in which the immune system attacks the myelin that protects nerve fibers, upsetting the flow of information between the brain and the body. It affects about 2 million people worldwide, and in its more severe, progressive form, no good treatments are available.
About 10% to 15% of MS cases appear to have a hereditary component, but until now researchers conducting genetic studies have found only weak associations between the risk of developing MS and particular gene variants. In contrast, people who carry the newly discovered mutation have a 70% chance of developing the disease, the team determined.
In the current study, the investigators reviewed materials from the Canadian Collaborative Project on Genetic Susceptibility to MS, a large database that contains genetic material from almost 2,000 families across Canada. They looked at a family that had multiple cases of the disease--five cases over two generations--and did exome sequencing to look for rare coding mutations that were present in all family members who had the disease. After identifying a gene of interest, they went back to the database and found the same mutation in another family with multiple cases of MS. Interestingly, all patients in these families with the mutation presented with the progressive form of MS.
"The mutation we found, in a gene called NR1H3, is a missense mutation that causes loss of function of its gene product, LXRA protein," says neuroscientist Weihong Song, Canada Research Chair in Alzheimer's Disease at UBC and the study's other senior author. Together with other members of the same family, LXRA controls transcriptional regulation of genes involved in lipid homeostasis, inflammation, and innate immunity.
Mice with this gene knocked out are known to have neurological problems, including a decrease in myelin production. "There is clear evidence to support that this mutation has consequences in terms of biological function, and the defective LXRA protein leads to familial MS development," Song says.
"One thing that's important to note is that although this mutation is present in only about 1 in 1,000 people with MS, by doing association analysis we've also found common variants in the same gene that are risk factors for progressive MS," Vilariño-Güell adds. "So even if patients don't have the rare mutation, treatments that target this pathway would likely be able to help them."
The researchers say that the discovery of this mutation will enable them to develop cellular and animal models for MS that are physiologically relevant to human disease--tools that have not previously been available. "These models will provide a good way for us to study the mechanism underlying the disease, as well as to screen for drugs that target it," Song says.
The researchers note that there is already interest in targeting this pathway for drug development in other diseases, including atherosclerosis. "These are still early days and there is a lot to test, but if we are able to repurpose some of these experimental drugs, it could shorten the time it takes to develop targeted MS treatments," Vilariño-Güell says.
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