A newly discovered genetic mutation gives people who carry it a whopping 70 percent chance of developing multiple sclerosis, potentially opening the way toward new therapies for a debilitating neurological disorder whose ultimate cause has stumped researchers for decades.
But because the mutation was discovered in only two families and 11 people (seven with MS), outside experts were skeptical that it is really involved in the disease, rather than just a statistical fluke.
“I would be very surprised if it turns out to be true,” said Dr. Nikolaos Patsopoulos, a neurologist and MS geneticist at Brigham and Women’s Hospital in Boston.
The mutation, reported by scientists in Canada on Wednesday in the journal Neuron, is unusual for its power. The 70 percent chance of developing MS compares to a 0.1 percent risk in the general population, and the 100 or so previously known genetic variants increase the chance of MS to only about 0.3 percent at most, with no single gene packing much of a punch.
The idea that MS had only these incremental heritable factors was so entrenched that, when one of the scientists involved in the new discovery began pursuing genetic causes of MS, “people thought I was nuts,” said medical geneticist Dr. Dessa Sadovnick of the University of British Columbia.
Although she tracked down many people who said the disease ran in their family, many experts dismissed that as a result of relatives all being exposed to the same environmental factors.
Sadovnick eventually got funding from the MS Society of Canada to collect DNA from 4,400 patients and 8,600 relatives, starting in 1993. Her UBC colleague Carles Vilariño-Güell, a senior author of the new study, and his colleagues combed this biobank for families with at least four MS patients.
There were 25 such families.
The researchers then pulled the patients’ DNA samples, sequenced the genes, and there it was: a rare mutation, in two families, that confers a 70 percent risk of developing MS.
MS develops when the immune system can’t tell friend from foe. T cells, which are supposed to attack only virus-infected cells, instead destroy the fatty sheath, called myelin, around fibers that carry electrical signals from one neuron to another. As a result, those signals peter out or are too weak to keep muscles and other systems running properly, and both neurons and their connecting fibers wither away.
The consequences can include tremors, dizziness, slurred speech, numbness or weakness in the arms and legs, partial or total blindness, and loss of bowel or bladder control.
Why T cells go after myelin remains a mystery, though studies have implicated everything from viruses to smoking to too little vitamin D. If the UBC team’s findings are right, a gene called NR1H3 could be involved, too.
The mutation found in NR1H3 consists of a one-letter “misspelling,” a biological typo sufficient to hobble the protein made by the gene. The protein is a transcription factor, the molecular equivalent of a 19th-century lamplighter who walked the streets turning gas lamps on. Transcription factors roam the genome turning genes on.
NR1H3’s transcription factor activates several genes, including those that control inflammation or are involved in other aspects of immunity. Without that activation, those genes stay as “off” as a gas lamp whose lighter is AWOL, with the result that inflammation runs amok and the immune system destroys myelin.
The specific misspelling Vilariño-Güell and his colleagues initially found in NR1H3 is present in only about 1 in 1,000 people with MS, however — raising doubts about how relevant it will be for most patients, cautioned Dr. Brian Weinshenker of the Mayo Clinic.
“It accounts for only a very, very small proportion of MS cases,” he said.
Its role in MS more broadly could become clearer with studies of mice genetically engineered to carry the risk-increasing mutation, which the UBC team plans to conduct in a few weeks. Such mouse studies, Weinshenker said, could “give us a better sense of what pathways are important in MS,” from genes not being activated to T cells devouring myelin to neurons carrying signals as poorly as a string between two tin cans.
The NR1H3 transcription factor is also involved in the metabolism of blood lipids like cholesterol and triglycerides. “Drugs are being developed that target this gene and its pathways,” Vilariño-Güell said, “so we could save a lot of time” in developing an MS drug by piggybacking on those efforts.
Patsopoulos maintains that the discovery is so unlikely to be right that claims about it leading to drug discoveries “shouldn’t even be made,” he said.
But Vilariño-Güell is more optimistic: “Now there is real hope for stopping this disease.”
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