‘Breakthrough’ study links gene mutation to MS
UBC scientists believe clues to disabling disease found in two families with disease
When Canadian scientist Dessa Sadovnick started her career, the idea that genes played a role in multiple sclerosis was almost heretical and her PhD supervisor even urged her to abandon her research on the topic.
Four decades later, it is widely accepted that genetics are important in MS, partly because of Sadovnick’s pioneering work.
On Wednesday, she and her team published their latest genetic discovery: a single mutation linked to severe MS in seven members of two Canadian families.
The study authors believe they have found the first gene mutation to cause a rare and inherited form of MS, though this finding needs to be replicated by further studies.
The research, published in the journal Neuron, reveals an exciting new clue for understanding the severest form of MS, which affects 15 per cent of patients, and this could, perhaps, pave the way for new treatments.
For Sadovnick, the study feels like a personal victory.
“You pursue this topic your whole life and you reach a point where you think, ‘Are you just being stubborn or is there something there?’ ” said Sadovnick, a professor of medical genetics and neurology at the University of British Columbia. “It’s sort of a vindication, because I put up with a lot of ridicule over many, many years.”
Scientists now understand MS to be a complex disease caused by an accumulation of several factors — both of a genetic kind, which make certain people more vulnerable to MS, and an environmental sort, such as smoking — that cause an inflammatory immune response that triggers the disease.
While no single gene mutation has previously been found to cause MS — and some scientists doubt that such a gene exists — more than 100 genes have been linked to the disease.
But they only slightly increase a person’s risk and the prevailing belief is that many genetic mutations need to occur simultaneously for a person to develop MS.
But, in the mid-’70s, when Sadovnick was still a PhD student, genetics was a burgeoning field and MS research was dominated by immunologists, many of whom dismissed the role of DNA.
A handful of studies hunted for genes that might cause MS, but they turned up empty-handed. But Sadovnick had grown up around MS — her family was heavily involved in MS advocacy and a close friend had the disease — and she always suspected that genes played a role.
“I did know families where more than one person had MS. It didn’t seem off-the-wall to me,” she said. “But it sounded very off-the-wall . . . when I came to UBC. “It was like a heretic suggestion.” Sadovnick remembers speaking at an immunology conference in the mid-’80s, when an organizer told her to wrap things up because he considered her research nonsense.
But she stuck to her hunch and, in 1993, she launched a 20-year effort to collect blood samples and clinical information from 4,400 Canadians with MS, as well as 8,600 relatives.
The biobank has since yielded some 100 research papers, including a 1995 study where she and her collaborators found a genetic basis in families in which more than one person has MS.
This latest paper also mines Sadovnick’s biobank, now housed at UBC.
This time, she and her team focused on families where at least four members had MS. The goal was to tease out genetic mutations that might be causing their disease.
The genetic analysis was spearheaded by Carles Vilarino-Guell, another professor of medical genetics at UBC, who honed in on a gene called NR1H3, a region that plays a role in regulating inflammation, a trigger for MS.
He found one Canadian family where several members carried a specific mutation on this gene; five developed primary progressive MS and a sixth relative, who carries the mutation, has an unknown health outcome.
(The samples were collected in the 1990s and researchers have since lost track of the subjects, according to Vilarino-Guell).
Researchers then located a second family with the gene mutation. This family had two relatives with MS and another three who carried the mutation, but had not been diagnosed with MS at the time they participated in the study. In Canada, there is about a 1-in-1,000 chance of developing MS and people who carry known risk factors have about a 3-in-1,000 chance, he said. The risk to people in these families is dramatically higher.
“The mutation that we have identified has at least two-thirds chance of developing the disease,” he said. “That’s why this is really a big breakthrough here.”
Researchers who were not involved with this study say its results are “very interesting,” because, for the first time, it points to a biological pathway that could lead to primary progressive MS, said Michael Demetriou, an MS researcher and professor of neurology at the University of California, Irvine.
The study also identified other mu- tations on the NR1H3 gene that might be associated with primary progressive MS, which is much more poorly understood than the more common form of the disease, known as relapsing-remitting MS, and still lacks any available treatments.
“This is, I think, a unique and important study,” Demetriou said. “It may lead to targeting of this particular pathway for therapies.”
He cautioned that there are caveats. While Sadovnick and her co-authors are confident this gene mutation caused MS in these families, other researchers caution it’s too early to make this claim.
This gene mutation is extremely rare — the study estimates it occurs in just 1 in 1,000 MS patients — and some family members didn’t get MS, suggesting another factor must be involved in triggering the disease.
The paper also looked at just two families who share a common ancestor, meaning they are probably distantly related — so while these are “intriguing” findings, more studies are needed before the link can be verified, according to Dr. Philip De Jager, an MS researcher with Brigham and Women’s Hospital and Harvard Medical School in Boston.
“Gene (mutations) that are relatively rare in the population can appear to be disease related — or, they are actually just rare and happen to be in that family by chance,” said De Jager, who was not involved with the study.
“That’s actually a bigger problem than is generally appreciated.”
Vilarino-Guell says this is just the beginning of this chapter in his MS research and he’s already identified 100 other Canadian families with multiple MS sufferers who have yet to be analyzed.
If this gene mutation is validated by further research, perhaps scientists could eventually develop genetic tests for predicting people at risk of developing severe MS, said neurologist Dr. Anthony Trablousee, another co-author.
He suspects there are other gene mutations waiting in Sadovnick’s biobank, perhaps holding more clues that could help unravel the complicated mystery that is MS.