A Genetic Cause of Multiple Sclerosis Discovered

Summary: A new study claims researchers have proven multiple sclerosis can be caused by a single genetic mutation.

Source: University of British Columbia.

Scientists at the University of British Columbia and Vancouver Coastal Health have proven that multiple sclerosis (MS) can be caused by a single genetic mutation – a rare alteration in DNA that makes it very likely a person will develop the more devastating form of the neurological disease.

The mutation was found in two Canadian families that had several members diagnosed with a rapidly progressive type of MS, in which a person’s symptoms steadily worsen and for which there is no effective treatment.

The discovery of this mutation should erase doubts that at least some forms of MS are inherited. The prevailing view has been that a combination of many genetic variations cause a slight increase in susceptibility. In the two families described in this study, two-thirds of the people with the mutation developed the disease.

“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,” said senior author Carles Vilarino-Guell, an assistant professor of medical genetics and a member of the Djavad Mowafaghian Centre for Brain Health.

Although only one in 1,000 MS patients appears to have this mutation, its discovery helps reveal the biological pathway that leads to the rapidly progressive form of the disease, accounting for about 15 per cent of people with MS. The discovery could also provide insight into the more common, fluctuating form of MS, known as “relapsing-remitting,” because in most cases, that disease gradually becomes progressive.

The findings, published today in the journal Neuron, could help in the search for therapies that act upon the gene itself or counteract the mutation’s disease-causing effects. More immediately, screening for the mutation in high-risk individuals could enable earlier diagnosis and treatment before symptoms appear.

Image shows a genetic family tree.
The family trees of the two families with the MS-causing mutation. “M”=individuals with the mutation. Black circles=individuals with MS and age of disease onset. Gray circles or squares=individuals with the mutation whose health is unknown. NeuroscienceNews.com image is credited to Carles Vilarino-Guell/University of British Columbia.

“If you have this gene, chances are you will develop MS and rapidly deteriorate,” said co-author Dr. Anthony Traboulsee, the MS Society of Canada Research Chair at UBC and Director of Vancouver Coastal Health’s MS and Neuromyelitis Optica Clinic. “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.”

Background on MS and this discovery

Signal disruption: Multiple sclerosis results from the body’s immune system attacking myelin, the fatty material that insulates neurons and enables rapid transmission of electrical signals. When myelin is damaged, communication between the brain and other parts of the body is disrupted, leading to vision problems, muscle weakness, difficulty with balance and coordination, and cognitive impairments. Canada has one of the highest rate of MS in the world, for reasons that elude scientists.

Defective protein: The MS-causing mutation discovered by UBC scientists was found on a gene called NR1H3. That gene produces a protein known as LXRA, which acts as an on-off switch on other genes. Some of those other genes stop the excessive inflammation that damages myelin or help create new myelin to repair the damage. A team led by Weihong Song, professor of psychiatry at UBC and the study’s other senior author, found that the mutation of that gene – a substitution of just one nucleotide for another in the DNA – produces a defective LXRA protein that is unable to activate those other critical genes.

Researchers at the University of British Columbia have discovered a rare genetic mutation that causes multiple sclerosis, which should erase doubts that some forms of the neurological disease are inherited.

Early intervention: People with a family history of MS could be screened for this mutation, and if they carry it, could be candidates for early diagnostic imaging long before symptoms appear; or they could opt to increase their intake of Vitamin D (low levels of which have been associated with the disease). If someone diagnosed with relapsing-remitting MS were found to have this mutation, they might be candidates for earlier, more aggressive treatment to delay the onset of the progressive form of the disease.

A more realistic animal model: Vilarino-Guell and his collaborators are now awaiting delivery of the first mice to be genetically engineered with this mutation, enabling examination of the cascade of reactions that leads to MS. Currently, scientists simulate MS in mice by either injecting them with myelin, which triggers an immune response, or by feeding them a drug that destroys myelin directly. Neither one mimics how the disease originates in humans.

Thousands of samples: The families with this mutation had donated to a Canadian-wide collection of blood samples from people with MS, begun in 1993 by 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 – one of the largest such biobanks in the world.

About this genetics research article

Funding: The study was funded by MS Society of Canada, Multiple Sclerosis Scientific Research Foundation.

Source: Brian Kladko – University of British Columbia
Image Source: This NeuroscienceNews.com image is credited to Carles Vilarino-Guell/University of British Columbia.
Video Source: The video is credited to UBC Medicine.
Original Research: Full open access research for “Nuclear Receptor NR1H3 in Familial Multiple Sclerosis” by Zhe Wang5, A. Dessa Sadovnick, Anthony L. Traboulsee, Jay P. Ross, Cecily Q. Bernales, Mary Encarnacion, Irene M. Yee, Madonna de Lemos, Talitha Greenwood, Joshua D. Lee, Galen Wright, Colin J. Ross, Si Zhang, Weihong Song, and Carles Vilariño-Güell in Neuron. Published online June 1 2016 doi:10.1016/j.neuron.2016.04.039

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]University of British Columbia. “A Genetic Cause of Multiple Sclerosis Discovered.” NeuroscienceNews. NeuroscienceNews, 1 June 2016.
<https://neurosciencenews.com/multiple-sclerosis-genetics-4349/>.[/cbtab][cbtab title=”APA”]University of British Columbia. (2016, June 1). A Genetic Cause of Multiple Sclerosis Discovered. NeuroscienceNews. Retrieved June 1, 2016 from https://neurosciencenews.com/multiple-sclerosis-genetics-4349/[/cbtab][cbtab title=”Chicago”]University of British Columbia. “A Genetic Cause of Multiple Sclerosis Discovered.” https://neurosciencenews.com/multiple-sclerosis-genetics-4349/ (accessed June 1, 2016).[/cbtab][/cbtabs]


Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

•An arginine to glutamine mutation in NR1H3 causes multiple sclerosis in families
•The clinical phenotype is consistent with rapidly progressive multiple sclerosis
•This mutation results in loss of function leading to transcriptional dysregulation
•Common variants in NR1H3 are associated with primary progressive multiple sclerosis

Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss and neuronal dysfunction. Despite the aggregation observed in some families, pathogenic mutations have remained elusive. In this study, we describe the identification of NR1H3 p.Arg415Gln in seven MS patients from two multi-incident families presenting severe and progressive disease, with an average age at onset of 34 years. Additionally, association analysis of common variants in NR1H3 identified rs2279238 conferring a 1.35-fold increased risk of developing progressive MS. The p.Arg415Gln position is highly conserved in orthologs and paralogs, and disrupts NR1H3 heterodimerization and transcriptional activation of target genes. Protein expression analysis revealed that mutant NR1H3 (LXRA) alters gene expression profiles, suggesting a disruption in transcriptional regulation as one of the mechanisms underlying MS pathogenesis. Our study indicates that pharmacological activation of LXRA or its targets may lead to effective treatments for the highly debilitating and currently untreatable progressive phase of MS.

“Nuclear Receptor NR1H3 in Familial Multiple Sclerosis” by Zhe Wang5, A. Dessa Sadovnick, Anthony L. Traboulsee, Jay P. Ross, Cecily Q. Bernales, Mary Encarnacion, Irene M. Yee, Madonna de Lemos, Talitha Greenwood, Joshua D. Lee, Galen Wright, Colin J. Ross, Si Zhang, Weihong Song, and Carles Vilariño-Güell in Neuron. Published online June 1 2016 doi:10.1016/j.neuron.2016.04.039

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  1. Daniel MacArthur2016 Jun 13 09:41 a.m. (4 days ago) 8 of 8 people found this helpful

    This paper reports that an NR1H3 variant, rs61731956, encoding p.Arg415Gln, causes familial multiple sclerosis (MS) (Wang Z, 2016). We have some major concerns about the evidence for the effect of the R415Q variant on risk for MS, which rests on two pedigrees with imperfect segregation with disease.

    The reported data allows us to provide an estimate of penetrance for the R415Q variant. This variant was found in 1 out of 2053 individuals in a multiple sclerosis case series, but is also seen (as the authors note in passing) in 21 individuals among the 60,706 present in the Exome Aggregation Consortium (ExAC) collection (11-47290147-G-A). Enrichment in cases over controls is one important criterion for establishing pathogenicity of sequence variants (MacArthur DG, 2014, Richards S, 2015).

    The ancestry distribution of the case series reported in Wang Z, 2016 is not stated, but the series was collected in Canada and appears to be of predominantly European ancestry (Sadovnick AD, 1998, Traboulsee AL, 2014). The 21 individuals with this variant in ExAC are all of non-Finnish European ancestry, with 66,738 non-Finnish European chromosomes having genotype calls for this variant. Thus, the variant is not significantly enriched in cases over ExAC population controls (P = .56) – indeed, its allele frequency is lower in MS cases (0.02%) than in ExAC European population controls (0.03%).

    A review of lifetime risk estimates for MS found the best estimates of lifetime risk of MS to be 0.25% for women and 0.14% for men (Alonso A, 2008, see Table 1). Using the allele frequencies observed in ExAC and in the case series, along with these estimates of lifetime risk, we can apply formulae for calculating the penetrance or lifetime risk, and confidence intervals thereof, for reportedly Mendelian variants as described in (Kirov G, 2014, Minikel EV, 2016). The upper bound of the 95% confidence interval is 1.7% for women and 0.9% for men, indicating that this variant contributes extremely weakly, if at all, to MS risk.

    The functional characterization of the effects of the p.Arg415Gln variant on gene function, while potentially interesting, does not provide independent support for a role of this gene in MS risk.

    We urge the community to consider rigorous statistical approaches and independent replication before making strong claims of pathogenicity. In this case, publicly available data (and indeed data that are actually noted in the paper) are sufficient to strongly suggest that this variant has little or no effect on MS risk. Independent analyses of this variant in large case-control studies of MS are needed, and we look forward to seeing the results of such analyses from the MS community in the near future.

    Eric Vallabh Minikel and Daniel MacArthur, Broad Institute of MIT and Harvard

  2. I am 60 years old and have been diagnosed with MS since I was 21 years old. I have 5 children , 2 of my kids have been diagnosed with MS. Too. I would be willing to under testing to see if I have the gene

  3. I have two children ages 45and 50 boy and girl both have ms, no ms in either my wifes or my family.
    terrible sickness, maybe some day there will be a cure

  4. Still has to an environmental trigger. I know identical twins. One has MS & the other one doesn’t. I know this is only the first step in solving this mystery but it does leave other questions unanswered.

  5. Not an opinion, but a question, you a rapid decline, how rapid? 5 years 10 years, the reason I ask is my husband has PPMS and has had it for 9 years !

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