Rare Genetic Mutation Associated with Multiple Sclerosis Development

For the first time, researchers discovered a genetic mutation that could be directly connected to the development of multiple sclerosis (MS).

MS affects approximately 2 million people globally, and about 10% to 15% of cases seem to have a hereditary component. Previous research to find genes linked to the disease had inconclusive results, until the current study published in Neuron found a mutation in the gene NR1H3.

“This finding is critical for our understanding of MS,” said senior study author Carles Vilariño-Güell. “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.”

The study gathered information from a large database called the Canadian Collaborative Project of Genetic Susceptibility to MS. In one particular family who had 5 cases of MS over 2 generations, researchers performed exome sequencing to look for rare coding mutations present in each family member with MS.

Once a gene of interest was identified, researchers looked back through the database, only to find that the same mutation was in another family who also had several cases of MS. Researchers noted that all the patients in these families who had the mutation suffered from 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,” said senior study author Weihong Song.

Mice that have the gene knocked out are known to have neurological issues, 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 said.

Authors concluded that individuals who carry this newly discovered mutation have a 70% chance of developing MS. However, the mutation is only present in a small portion of MS patients.

“One thing that's important to note is that although this mutation is present in only about 1 in 1000 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 said. “So even if patients don't have the rare mutation, treatments that target this pathway would likely be able to help them.”

Researchers believe the findings will enable them to develop cellular and animal models of MS that are physiologically relevant to human disease.

“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.