Multiple sclerosis, or MS, is a disease that has been puzzling neuroscientists and researchers for decades. There is no one specific cause, of all types of MS, but at the University of British Columbia and Vancouver Coastal Health, new information has shown for the first time that a single genetic variant, a very rare mutation in a person’s DNA can result in a high chance that person will develop MS, probably the more severe form of Primary Progressive Multiple Sclerosis, or PPMS.
The mutation was found with the help of some Canadian families that had several members diagnosed with the rapidly progressive type of MS. There are no treatments currently available for this form of MS. Knowing that it can be inherited is a huge advance in looking for treatments for it.
Before this research, it’s been thought that there were several possible genetic variations that could increase a person’s chance of developing the disease, but one one specific mutation could be identified until this study. In a press release, senior author of the study, Carles Vilarino-Guell, an assistant professor of medical genetics and a member of the Djavad Mowafaghian Centre for Brain Health said,
“This mutation puts these people at the edge of a cliff, but something still has to give them the push to set the disease process in motion. The findings, published today in the journal Neuron, could point the way toward therapies that act upon the gene itself or counteract the mutation’s downstream effects. More immediately, screening for the mutation in high-risk individuals could enable earlier diagnosis and treatment before outward symptoms appear.”
MS is occurs when the body’s own immune system attacks the myelin sheath protecting neurons. This protective layer allows for the transmission of electrical signals from the brain to the muscles of the body. When this layer is corrupted, the patient experiences vision problems, muscle weakness, difficulty with balance and coordination, and cognitive impairments. Scientists are not sure why, but Canada has one of the highest rates of MS in the world.
The genetic mutation discovered in the study at UBC is rare, only about on in 1,000 patients have it, but the fact that it’s been identified can help investigators learn more about the biology of the disease and perhaps understand how the less severe form, relapsing and remitting MS, or RRMS, can progress to PPMS.
The mutation was found on the gene known NR1H3, which secretes a protein known as LXRA, which can switch other genes on and off. Some of those genes can slow or stop the inflammation that damages the myelin sheath and in some cases can actually repair damage already done by the disease. With this newly discovered mutation---which isn’t even very large; it’s simply one nucleotide being subbed in for another--- a defective LXRA protein is produced and that protein is unable to help with inflammation or repair of the myelin.
The families that had this mutation had donated to a Canadian-wide collection of blood samples from people with MS, begun in 1993 by study co-author A. Dessa Sadovnick, a UBC Professor of Medical Genetics and Neurology. The 20-year project, funded by the MS Society of Canada and the Multiple Sclerosis Scientific Research Foundation, has samples from 4,400 people with MS, plus 8,600 blood relatives and as a result is one of the largest biobanks in the world.
Now that this mutation has been found, the team at UBC can create genetically altered mice that have it, and study possible treatments. Currently, mice in MS studies have acquired MS by the injection of myelin which causes an immune response and disease symptoms or they have been given a drug that destroys the myelin, but neither of these methods are the same as how humans get MS, so they are not helpful in getting mouse studies to translate to human clinical trials. Having mice that have developed MS in the same way as humans will improve studies and hopefully lead to better treatments.
Co-author Anthony Traboulsee, the MS Society of Canada Research Chair at UBC and Director of Vancouver Coastal Health’s MS and Neuromyelitis Optica Clinic stated, “If you have this gene, chances are you will develop MS and rapidly deteriorate. This could give us a critical early window of opportunity to throw everything at the disease, to try to stop it or slow it. Until now, we didn’t have much basis for doing that.”
Check out the video below to learn more about this significant development in how MS is caused.
Sources: National MS Society
, University of British Columbia
, MS Society Canada