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One Genetic Cause Found for Progressive Multiple Sclerosis

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Some cases of multiple sclerosis can be explained by a single DNA mutation. (YouTube)

One of the most severe form of multiple sclerosis (MS) is sometimes caused by the malfunction of a single gene, NR1H3, a group of researchers from the University of British Columbia reports in the journal Neuron. Some 60-70% of people with a certain type of mutation in this gene will end up with primary-progressive MS (PPMS), a particularly nasty form of the disease.

This is by far the strongest connection ever found between any single genetic mutation and MS.

Fortunately, mutations in this gene are very rare, meaning that only something on the order of 1 in 1,000 cases of MS can be directly linked to them. But this discovery is a bigger deal than these numbers make it sound.

Identifying NR1H3 uncovers a new pathway in the cell to explore to find new treatments for PPMS. This will obviously help the 15% of MS patients suffering from PPMS but it may also help even more patients than this.  Since many cases of MS eventually progress to PPMS, these new treatments could help many MS patients in the later stages of their disease.


Short-Circuited Nervous System

Multiple sclerosis (MS) is a disease in which a person's immune system attacks the outer covering of nerve cells. The slow loss of this myelin sheath causes nerves to short-circuit, which can cause problems ranging from vision loss, fatigue, loss of coordination, and trouble walking, to paralysis and even death for the 400,000 or so Americans who have the disease.

The wide range of symptoms comes about because what happens to a particular patient depends on which nerves happen to have been attacked.

The most common form of MS is relapsing-remitting MS (RRMS). With this form, disease progression comes in spurts. There are periods where the symptoms become more severe and periods where symptoms lessen or even disappear.

PPMS is the more disabling form, where the disease progresses without periods of remission. The gene these researchers identified helps to explain this second form of the disease.

In multiple sclerosis, the myelin that covers nerve cells becomes inflamed, swollen, and detached. It is then destroyed, forming a scar over the axons (nerve fibers). Sclerosis means scar.
In multiple sclerosis, the myelin that covers nerve cells becomes inflamed, swollen, and detached. It is then destroyed, forming a scar over the axons (nerve fibers). Sclerosis means scar. (NIH/Patient Education Institute)

It makes sense that the NR1H3 gene might be involved in PPMS, because this gene plays a role in both the immune system and in repairing the myelin sheath around nerve cells. The study suggests that when this gene isn’t working right, the immune system sometimes overreacts to something in the environment, causing it to attack the myelin sheath. The sheath can’t then be repaired once the attack happens. Symptoms continue to get worse as the immune system attacks again, and again.

Now that scientists know NR1H3 plays a role in MS, they can focus their energies on finding treatments that balance the gene's malfunction.

Finding a Disease-Causing Variant

The researchers discovered this gene was involved in MS by studying two Canadian families who had many members with the disease. Even so, the gene was not easy to find.

The first step was to sequence and compare every gene in two first cousins, both of whom had the PPMS form of the disease. Researchers were looking for genetic differences the two shared that might explain why they both had MS.

This type of sequencing is called “exome sequencing,” and it looks only at the 2% of our DNA that is genes. The reports for the two cousins found 48,333 variants in one cousin and 47,681 variants in the other.

A variant is simply a difference from the DNA scientists use as a reference, called the reference genome. It is simply a set of DNA that scientists have agreed that they will compare the DNA they are studying to.

Most of these tens of thousands of variants are silent and have little or no effect, while others might give us traits that make us unique, such as eye color or the shape of our toes.

Researchers winnowed down the number of variants that might be responsible for the MS that ran in this family to 37, by looking for variants that the two cousins shared, that were rare (if a disease causing variant is common then lots of people would have the disease), and that might be predicted to affect how a gene works.

The team next compared 185 people without the disease to all nine family members with the disease, to find which of these 37 was in the MS patients but not the group without MS. This eliminated another 33 variants.

Researchers then took the remaining four and looked for them in 2,053 MS patients and 799 people without MS. This eliminated three more, leaving a single variant in the NR1H3 gene as the only candidate left.

This approach of comparing people with and without a disease is a common way to find DNA differences that can lead to a certain disease. What made it work in this case was that lots of people in a single family had the disease, and it has become much less expensive to look at every gene a person has.

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