Researchers discover gene mutation that causes progressive MS

For the first time, researchers have identified a gene mutation that’s directly linked with the development of multiple sclerosis (MS), a difficult-to-diagnose neurodegenerative disease that affects about 2.3 million people worldwide. Those findings, published Wednesday in the journal Neuron, may enable earlier diagnosis and intervention, as well as aid the search for therapies that act upon the gene itself or counteract the mutation’s disease-causing effects.

“Genes are like lighthouses to tell you what you should be looking at, what is causing the disease,” study senior author Carles Vilariño-Güell, an assistant medical genetics professor at the University of British Columbia (UBC), in Vancouver, told “A lot of treatments are for clinical symptoms and don’t tackle the underlying biology of the disease because we don’t know a lot about how disease develops. Knowing the genes highlights a previous state before clinical symptoms, I think that’s really critical— the tools they provide for analysis are unbelievable.”

Multiple sclerosis results from the immune system’s attack on the myelin that protects nerve fibers, disrupting the flow of information between the brain and the body. Previous research has identified only weak associations between genetics and MS, but about 10 to 15 percent of cases appear to have a hereditary component. MS has no cure, and treatment usually focuses on recovery and management.

“For a long time, genetics was never associated with [MS]. People felt it was all immune or environment, and never really thought about the role of genetics,” study co-author Dessa Sadovnick, a UBC professor of medical genetics and neurology, told “When we started doing these data, it was almost like you’re going against the grain.”

For their research, the UBC team reviewed genetic material from almost 2,000 families that are part of the Canadian Collaborative Project on Genetic Susceptibility to MS database, which began in 1993. They condensed their data set to families with four or more members diagnosed to study 100 families total. Researchers found that individuals with the newly discovered genetic mutation had a 70 percent chance of developing MS.

“In these families, when they have such a strong incidence of MS, it’s more likely that there is one strong genetic component that is responsible for it,” Vilariño-Güell said. “The majority of people have MS because of a combination of genetic and environmental factors.”

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Researchers used exome sequencing to identify the gene mutation on the NR1H3 gene in a family that had five cases of MS over two generations. Next, they confirmed the mutation in a second family with multiple cases of MS. All patients in these two families had primary progressive MS (PPMS), which is characterized by worsening neurologic symptoms and a highly devastating and untreatable course of the disease. PPMS occurs in 15 percent of people diagnosed MS, for which there is no treatment or cure.

“It’s very gratifying; it’s validation of what we’ve been thinking for a long, long time,” Sadovnick said. “We’re not saying all MS is purely genetic. In general, there may be a lot of families that are a mix of genes and some that are purely environmental [causes]. The first step is identification.”

The gene mutation causes loss of function of its gene product, LXRA protein. LXRA acts as an on-off switch on other genes, some of which stop the excessive inflammation that damages myelin or help create new myelin to repair the damage.

Their research is distinct, Vilariño-Güell said, because not many MS patients have families and because of advances in genetic technology and exome sequencing. Traditionally, researchers would need to study massive families to find genetic links, but with MS, some relatives don’t have the disease from the same cause, which complicates the analysis. With exome sequencing— which has improved in quality and decreased in price since its inception eight years ago— researchers could collect available information from a nuclear family and sequence from there.

The University of British Columbia team is currently analyzing 20 other qualifying families. While these families are rare and it may seem unusual to focus on this population, looking at the gene mutation will allow researchers to find the common, small changes that increase the likelihood of developing primary MS, study authors said.

It’s possible that primary progressive MS develops by different pathways than the one discovered in their research, and treatment for one patient may not work with another, but it’s a step toward personalized medicine, as drugs that affect this pathway may help patients with other diseases such as Alzheimer’s and atherosclerosis, Vilariño-Güell said.

“Developing treatment for these families is very likely going to help a large group of patients that have primary progressive MS and potentially also secondary progressive MS,” he added.

Another potential impact of their research is the ability to screen for the MS gene mutation, which Vilariño-Güell likened to BRCA screening for breast cancer. Doctors could use MRI scans to monitor those with the mutation, which may reveal lesions before the onset of clinical symptoms.

For the minority of families with severe and progressive MS, identifying the gene could help them tackle the disease from the onset, before the disease moves quickly downhill.

Also, because the NR1H3 gene is involved in atherosclerosis and Alzheimer’s disease, it’s possible that MS research can take advantage of the huge push in drug development for these diseases, he added. These drugs have already gone through phase 1 clinical trials, saving as much as half the time for MS researchers to repurpose an existing drug.

The team plans to introduce the genetic mutation into a mouse model, which will allow them to study the biomechanics that cause the disease in people. If the mice show clinical symptoms, such as a myelin defect and gait problems, they’ll characterize the phenotype then test new corrective treatments. This work is at least a year away, study authors said.

“It’s an impressive opportunity not available before because we didn’t have the mechanisms of human disease in an animal,” Vilariño-Güell said. “What’s really exciting about this finding is it will open so many doors to research and hopefully new treatments for patients.”