Human study identifies the genetic cause of familial multiple sclerosis.


Multiple sclerosis (MS) is a neurodegenerative disease in which the immune system attacks the myelin that protects nerve fibers, upsetting the flow of information between the brain and the body. It affects about 2 million people worldwide, and in its more severe, progressive form, no good treatments are available.  Although MS is known to run in certain families, attempts to find genes linked to the disease have been elusive. Now, a study from researchers at University of British Columbia identifies the gene mutation connected directly to the development of the disease.  The team state that little is known about the biological processes that lead to the onset of the MS, and their findings have massive amounts of potential for developing new treatments that tackle the underlying causes, not just the symptoms.  The opensource study is published in the journal Neuron.

Previous studies show that about 10% to 15% of MS cases appear to have a hereditary component, however, until now genetic studies have found only weak associations between the risk of developing MS and particular gene variants. The current study shows that 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 current study reviews materials from the Canadian Collaborative Project on Genetic Susceptibility to MS, a large database that contains genetic material from almost 2,000 families across Canada. A family was selected who exhibited multiple cases of the disease, five cases over two generations, with exome sequencing performed to isolate rare-coding mutations that were present in all family members who had the disease. Results show that after a gene of interest was identified, the same mutation was found in another family with multiple cases of MS.  Data findings show that all patients in these families with the mutation presented with the progressive form of MS.

Results show that the mutation identified in a gene called NR1H3, is a missense mutation that causes loss of function of its gene product, the LXRA protein. The lab explain that together with other members of the same family, LXRA controls transcriptional regulation of genes involved in lipid homeostasis, inflammation, and innate immunity.  They go on to add that mice with this gene knocked out are known to have neurological problems, including a decrease in myelin production.

The researchers note that although this mutation is present in only about 1 in 1,000 people with MS, by doing association analysis they’ve also found common variants in the same gene that are risk factors for progressive MS.  They state that this means even if patients don’t have the rare mutation, treatments that target this pathway would likely be able to help them.  The group conclude that there is clear evidence to support that this mutation has consequences in terms of biological function, and the defective LXRA protein leads to familial MS development.

The team surmise that the identification of this mutation will enable the global medical community to develop cellular and animal models for MS that are physiologically relevant to human disease, tools that have not previously been available.  For the future, the researchers state that patients 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. They go on to add that 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.

Source: University of British Columbia 

 

Scientists find genetic cause of multiple sclerosis - neuroinnovations

2 comments

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  • 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

    Like

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