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