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Genetic Mutation Tied to Multiple Sclerosis Development in Study

NEW YORK (GenomeWeb) – A Canadian research team has found a gene mutation that can be directly connected to some patients' development of multiple sclerosis.

MS is a neurodegenerative disease in which the myelin that protects nerve fibers are attacked by the body's immune system, upsetting the flow of information between the brain and the body. It affects 250,000 to 350,000 people in the United States, according to the National Institutes of Health, and there are few treatments available to patients diagnosed with the more severe and progressive form of the disease.

Approximately 15 percent of MS cases are estimated to be hereditary, according to the NIH, but until now researchers conducting genetic studies have found only weak associations between the risk of developing MS and particular gene variants. 

The findings, published this week in the journal Neuron, verify that at least some cases of MS are inherited and that there is at least one gene associated with genetic risk factors for the disease.

"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," senior author Carles Vilariño-Güell, assistant professor in the department of medical genetics at the University of British Columbia in Vancouver, said in a statement.

The researchers looked at exome sequencing and Sanger sequencing data from almost 2,000 families across Canada — including 2,053 MS patients and 799 unrelated healthy control subjects — provided by the Canadian Collaborative Project on the Genetic Susceptibility to Multiple Sclerosis. They then identified variants and analyzed them to determine if there were shared gene signatures.

"The mutation we found, in a gene called NR1H3, is a missense mutation that causes loss of function of its gene product, LXRA protein," senior author Weihong Song, the research chair in Alzheimer's disease at UBC, said in a statement.

Previous studies have shown mice with NR1H3 knocked out are known to have neurological problems, including a decrease in myelin production. "This 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 said.

The research team determined that people who carry the mutation in NR1H3 have a 70 percent chance of developing MS. While the mutation is only found in about 1 in 1,000 people with MS, performing a stratified association analysis, the researchers also found common variants in the same gene that are risk factors for progressive MS, Vilariño-Güell noted. "So, even if patients don't have the rare mutation, treatments that target this pathway would likely be able to help them," he said.

The researchers believe that the discovery of this gene mutation will enable them to develop cellular and animal models for MS that are physiologically relevant to human disease, which has not been possible before now. "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 said.

While research into MS is still considered at an early stage, there is already interest in targeting this pathway for drug development in other disease, including atherosclerosis. "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 said.