Scientists find first gene mutation for multiple sclerosis

Scientists on Wednesday reported for the first time that a single genetic mutation can cause multiple sclerosis (MS), a major finding that they said should erase doubts that at least some forms of MS are inherited.

The mutation was found in two Canadian families that had several members diagnosed with a rapidly progressive type of MS, in which a person's symptoms steadily worsen and for which there is no effective treatment, they reported in the U.S. journal Neuron.

"This finding is critical for our understanding of MS," said Carles Vilarino-Guell, assistant professor in the Department of Medical Genetics at the University of British Columbia (UBC) 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 two million people worldwide, and in its more severe, progressive form, no good treatments are available.

Although multiple sclerosis (MS) is known to run in certain families, attempts to find genes linked to the disease have been elusive and researchers have found only weak associations between the risk of developing MS and particular gene variants.

Generally, the prevailing view has been that a combination of many genetic variations cause a slight increase in the disease's susceptibility.

But the new study determined that people who carry the newly discovered mutation have a 70 percent chance of developing the disease.

In the 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 found seven individuals from two unrelated families who showed symptoms of rapidly progressive MS carried a mutation in the gene NR1H3 which regulates inflammation and immunity.

Mice with this gene knocked out are known to have neurological problems, including a decrease in myelin production, said neuroscientist Weihong Song, Canada Research Chair in Alzheimer's Disease at UBC and the study's other senior author.

"The mutation we found, in a gene called NR1H3, is a missense mutation that causes loss of function of its gene product, LXRA protein," Song said.

"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."

Although only one in 1,000 MS patients appears to have this mutation, its discovery helps reveal the biological pathway that leads to the rapidly progressive form of the disease, accounting for about 15 per cent of people with MS, they said.

The researchers noted 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," Vilarino-Guell said.

While noting that the new study only identified one contributing factor rather than an MS cause, Professor Michael Demetriou at the University of California, Irvine, said that it may provide an excellent strategy for treating progressive multiple sclerosis.

"As we currently don't have any drug therapies for progressive MS, this would be a very big deal," said Demetriou, director of the university's National Multiple Sclerosis Society Designated Comprehensive Care Clinic, who was not involved in the study.

"There are some treatments in the pipeline but this represents a potentially new therapy for progressive MS," he said. "Drug treatments may be many years away but this study suggests that targeting this pathway may have some benefit." Endit