A single genetic mutation may increase a person’s risk of developing a rare, severe form of multiple sclerosis (MS) by roughly 60 percent, according to a study published recently in the journal Neuron.
That’s an unusually straightforward result for a complex disease like MS, which has previously been traced to hundreds of mutations that each increases the risk of developing the disease only slightly.
“That’s why our finding is unprecedented,” Carles Vilariño-Güell, Ph.D., an assistant professor of medical genetics at The University of British Columbia and one of the paper’s senior authors, told Healthline.
His team found the mutation by combing through a database of Canadians with MS who had donated blood samples as part of the Canadian Collaborative Project on Genetic Susceptibility to MS.
Some of these samples belonged to a family that was disproportionately diagnosed with the disease. Four first cousins and two parents developed MS.
The team isolated a common mutation from their DNA, and looked for that mutation in other individuals in the database.
That’s how they found a second family similarly afflicted. Three first cousins and two parents were diagnosed with MS.
Having so many cases of MS within a family is rare. The disease is not considered truly heritable, although a person’s risk does increase if a parent or sibling has the disease.
The families shared another rare trait. Most had the more severe version of the disease known as primary progressive MS, which makes up 10 to 15 percent of all MS cases.
Treatments for primary progressive MS have so far eluded scientists, although there are promising clinical trials underway of a drug called Ocrelizumab.
The study found the mutation only in a handful of people, all of whom were diagnosed with a rare form of the disease.
Therefore, the researchers don’t suggest they have found the genetic basis of MS.
But they do think they’ve discovered a way to study how the disease progresses in the body and what drugs could be developed to slow or even stop it
Bruce Bebo, Ph.D., vice president of research at the National Multiple Sclerosis Society, agrees.
“Studying the genetics of a very rare form that is inherited can give us clues about pathways involved in MS in the general population,” he told Healthline.
The mutation appears to disable a regulatory gene called NR1H3, which codes for a protein that helps regulate the inflammation and the metabolism of lipids.
The researchers now plan to engineer a similar mutation in mice so they can study the outcome of a disabled NR1H3 gene and test potential new drugs in an animal model.
And because the NR1H3 pathway has already been implicated in diseases like atherosclerosis and heart disease, there are already drugs in clinical trials for safety that could be repurposed for treating MS, Vilariño-Güell said.
“Understanding the genetics of MS could help us get closer to individualizing therapy to people for better outcomes,” Bebo said.
Getting Personal with Treatment
People with a disease like MS, which appears in so many different ways and can be linked to so many different genetic components, could benefit by personalized medicine.
If the mechanism of each disease causing mutation or group of mutations is pinpointed, scientists could potentially design more effective, targeted treatments rather than the standard one-size-fits-all therapies.
That means tracking down the many different genetic hotspots that are linked to MS.
Overall, genetic predisposition accounts for only about a third of a person’s risk of developing the disease, Bebo said. Within that category only about half the genes responsible can be identified.
Researchers don’t know where the other half of that genetic risk comes from, Bebo said, but it makes sense that it would include rare mutations like this one that help explain risk in a small fraction of MS patients.
And there could be many different versions of these mutations.
“Odds are if you look at a different family the genetic risk would probably be something different than this,” Bebo said.
Speeding Through the Genome
The Canadian database has been available since the late 1990s, but only recently has the team had access to exome sequencing, a powerful, efficient tool that makes searching for tiny genetic changes easier.
This technique sequences only the DNA that codes for proteins — leaving the other 98 percent behind. It’s like speed reading the genome.
Exome sequencing has been particularly helpful for finding so-called “Mendelian” diseases — diseases that can be traced to a single, heritable mutation just like Gregor Mendel’s purple and white pea flowers. Cystic fibrosis and sickle cell anemia are two examples of these diseases.
With this discovery, the researchers say that have found a Mendelian form of MS.
That doesn’t mean the discovery won’t be beneficial for the 85 percent of people diagnosed with relapsing remitting MS. In many of those patients, the disease eventually changes course and becomes progressive.
Whatever is learned about primary progressive MS — a condition that doesn’t respond to treatments for other types of MS — could also potentially help those with secondary progressive MS, the researchers say.