UBC Researchers Discover A Rare Genetic Link May Lead To Multiple Sclerosis

Imagine losing the ability to control your nerve function. You may encounter numbness and weakness in the limbs. Your ability to speak could decline as well as your vision. Tics and tremors might take over certain parts of your body. You even are at risk for depression.
These are just a few of the symptoms of multiple sclerosis, which is better known simply as MS. This condition affects over two million people worldwide and leads to significant reductions in a person’s quality of life. Yet quite possibly the worst aspect of this disease isn’t the range of symptoms, but the culprit causing them.
Our immune system is our natural defense force against pathogens and toxins. Exposure to these invaders leads to a response to clear the threat. Yet, in some cases, the immune system loses its way and turns against us. The troops begin to target and kill our own valued cells. This condition, known as autoimmunity, may lead to several diseases based on the target of immune attack. In the case of MS,  that target is the myelin sheath, which protects nerves and maintains proper signal and function.
Identifying the triggers for autoimmunity is no easy challenge, particularly for MS. Over the years, numerous options have been presented. Most research has focused on exposure to environmental factors such as prior infection or tobacco. Research has shown there are definite correlations yet no actual causal mechanism has been proven.
While environmental exposure does present a compelling argument, a similar amount of work has been devoted to a more internal suspect: our genetic code. Several genes have been examined for their potential role in disease onset. Usually, the results show a single change, better known as a polymorphism, can increase the risk for disease.
There are currently over a dozen genes capable of contributing to disease. Some, such as the human leukocyte antigen and the immunological sensor protein CD45 are not surprising. Others, including the Vitamin D receptor, may not be as evident and yet still play a role.
Now there is another gene to put on the list. It’s officially called nuclear receptor subfamily 1, group H, member 3, but it is better known as NR1H3. The addition comes as a result of recent work from a group at the University of British Columbia, headed by Dr. Weihong Song and Carles Vilariño-Güell. Their discovery, now published in the journal Neuron reveals the increasing complexity of MS and suggests a need to more widely explore the genetic code.
This wider examination was the reason the team conducted the study. The group wanted to gain perspective on an inherited form of the disease, known as familial multiple sclerosis. They acquired samples from nine individuals from one family spanning three generations. Five had already been diagnosed with MS while the others acted as controls.
Once the samples were acquired, the DNA was sequenced for any signs of polymorphisms. This wasn’t an easy task as the team discovered over 47,000 different variants of genes. However, closer examination of these changes allowed the team to figure out which ones would actually have an impact on cell function. This thankfully reduced the number to 37.
The next stage of analysis involved determining if any of the 37 changes associated with disease in the individuals. In this case, 33 did not. That left four possible options, but only one seemed to be more prevalent in those suffering from MS. This was NR1H3.
The team found in the familial cases, there was a mutation in the protein. It was known as p.Arg415Gln. This meant the amino acid at position 415 had changed from arginine to glutamine. Although this change may not appear at first to be troublesome, the team felt this could be the key to numerous troubles.
The group performed assays in the lab to determine if the p.Arg415Gln mutation would cause a change in cellular function. They focused on two roles of the protein. The first was controlling the way genes are expressed, known as transcriptional regulation. The second was the ability to block other proteins from performing their tasks properly, known as transrepression.
The analyses proved to be fruitful and identified the effect of the mutation occurs through the transcriptional regulation mechanism of NR1H3. This dysregulation affects many biological pathways, most notably cholesterol metabolism, which is important for proper development of the protective myelin sheath. The change prevented the formation of genes responsible for transport, breakdown and elimination of cholesterol. This could directly affect myelin homeostasis. The mutation also affected the path involved in the production of immunological proteins, which led to a reduction in the ability of the cell to prevent inflammation. On a larger scale, this effect would lead to worsening of symptoms as the disease progressed.
The outcomes of this study reveal how a single polymorphism can have potentially drastic effects on the entire body. Previously identified genetic variants may raise the risk of developing MS from 1 in 1,000 to about 1.1 to 1.3. However, when this particular mutation in NR1H3 is present, that risk increases to 600-700. Thankfully, this particular change is extremely rare and was only observed in two out of 2,053 families.
For the authors, the identification of this mutation provides an opportunity for treatment. By figuring out how to reverse or deal with the effects of mutation, the team may be able to help improve quality of life for those suffering. Even more promising, the treatment may also have wider use to help individuals with other variants of the protein. While this milestone may be years away, this study shows how genetic analysis in families may help to better understand diseases like MS and determine ways to improve the quality of life for those who suffer.

Read the original research article:

Wang Z, Sadovnick AD, Traboulsee AL, Ross JP, Bernales CQ, Encarnacion M, Yee IM, de Lemos M, Greenwood T, Lee JD, Wright G, Ross CJ, Zhang S, Song W, Vilariño-Güell C. Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. Neuron. 2016 Jun 1;90(5):948-54. doi: 10.1016/j.neuron.2016.04.039.