Friday, 3 June 2016

Progressive MS Gene Discovered.


Zhe Wang, A. et al. Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. Neuron 2016 90:948



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 multiincident 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. 
  • 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 transcriptional dysregulation
  • Common variants in NR1H3 are associated with primary progressive multiple sclerosis
Males are represented by squares and females by circles; the proband is arrowed and a diagonal line indicates deceased subjects. Patients diagnosed with MS have black-filled symbols, and mutation carriers of unknown phenotype have gray-filled symbols.

You ask is there a progressive MS gene and people have looked and so far nothing concrete has surfaced, which doesn't surprise me. Personally I do not believe that progressive and relapsing MS are distinct diseases and are simply part of a spectrum and that is why progression can follow relapsing disease. Likewise I am led to believe that identical twins can have relapsing or primary progressive disease and therefore strikes a blow against genetic progression. 

However will there be genes that increase your risk of progression? Of course there will be!. There genes will influence how your body responds to physical insults. In this study in a family with loads of MS, they have found a gene that appears to be associated with progressive MS. 

Gene hunters have taken different approaches to hunting for genes. One approach is "bigger is better" and people have focussed on collecting as many samples as possible and then hunted for genes. This is a powerful approach and has given us about 150 genes that are involved in the susceptibility. However, I have wondered if I had a couple of rabbits where I knew the genetic cause but put them together with a few other rabbits and ended up with a barnful of rabbits and then I analysed all the rabbits in the barn, would those causal genes be found? 

Another approach is to hunt for informative families and see if you can find the causative genes. This has a risk that what you find is specific for your odd sample. Anyway using this latter approach a gene was discovered in two unrelated families that had multiple members with MS. This gene appears to increase the risk, in some individuals, of developing a severe form of progressive multiple sclerosis.


Other studies have shown so far have found that that the main MS gene is in a region of called the major histocompatibility complex. The gene variant is common in Northern Europeans. There are also between about another 150-450 genes that can contribute to this MS susceptibility. 

In animals it is possible to show that a single gene or single set of genes in the major histocompatibility can render an animal susceptible where it once was not. However, this I believe occurs because the non-susceptible animal already has a number of the other key susceptibility genes and in genetic studies in the beasties this is certainly the case.

That 70% of the people in this study getting this single gene get MS suggests to me that I am hearing the "duelling banjos" in the background :-)[don't understand? watch Deliverance]..as some of the other genes needed for MS are are probably present in within these families, but are not segregating
. This can happen in regions where few people live or where marrying cousins is common and so the gene pool is small. I don't know anything about the families except that they were white.

It was thought that the mutation in the NR1H3 gene came in the two families from a common ancestor. 

In the families studied the people usually developed PPMS or progressive MS within a few year of diagnosis.  Accumulation of disability was rapid, but unfortunately they did not talk about where these people had lesions on their MRI. Was this rapid worsening because they had loads of lesions or were there no MRI lesions and people just got worse. This is important when fuelling thoughts about what is happening

When they looked in the general population, this gene did not pop out and so would be missed by the "rabbit in the barn" approach or should I say genome wide association studies. This gene was not associated with the development of relapsing MS, however genetic variants were more common in people with PPMS (odds ratio at 1.3 meaning its presence does not make that much of an influence).

We have known about genetics that predisposes one to progressive MS, one of these factors is the dreaded Y chromosome genes as males. However age of diagnosis is another risk factor. But if you have progressive disease, I suspect your nerve reserve has been depleted. 

Now what is the gene and what does it do 

The gene is NR1H3 encodes liver X receptor alpha (LXRA) and this is involved in lipid (Fat) metabolism and cholesterol levels. It can also form a complex with retinoid X receptors (RXRs), remember them yes, RXR are associated with myelination, however this genetic variant did not complex with with RXR

The authors believe "that at the outset of disease, damage to myelin sheaths in NR1H3 mutation carriers may produce an intensified inflammatory response due to the inability of the innate immune system and nitric oxide to suppress the expression of pro-inflammatory mediators. In addition, these patients may present impaired remyelination of damaged axons due to the dysregulation of myelin genes, resulting in chronic demyelination, nerve loss and progression"


The Pathogenic mutations in NR1H3 appear to be rare and are unlikely to account for disease in more than one in a thousand people with MS.

So what happens in mice that don't have the gene and there is clearly a lipid metabolism problem notably in the cholesterol pathway and probably related to this is a sex hormone problem such that testosterone and oestrogen levels are affected and when we look in the family tree the females are affected.

Neuropathological examination of LXRA-LXRB double knockout mice has shown several brain abnormalities, including axonal and neuronal loss and lipid accumulation.

Research Idea


However, again we find that progressive nerve damage has something to do with cholesterol. Time and time again the cholesterol pathway comes up in nerve damaging disease such as Alzheimers Disease. It is one of the major pathways that we have found to be affected in beasties with progressive (EAE) disease, as you will soon see when it is published. 

Is this why simvastatin has an effect on progressive MS? I not would be surprised.

20 comments:

  1. One might think they look at RRMS as well. I know some twins where they and mom also have RRMS.

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    1. They did look at RRMS and found no association.
      If you have a parent with MS you have a higher risk of developing MS I think about 1-5% verses 0.001% in the general population. This is not surprising as your parent has enough of the MS genes to have MS.
      You get half your genes from one parent and half from the other. If both parents have ms your risk is higher but still about 95% chance you don,t get ms.

      If you are a twin you have 25-30% risk of getting MS. In the families above it looks like the gene was dominant I.e. one copy of the gene variant is enough to give you the risk of disease with high penetrance (most but not all of people with gene get the condition). However I will bet that people in these families carry some of the other MS risk genes. A high percentage of northern Europeans carry the MHC gene variant associated with MS, I don't. Neither does MD2 who has arisk gene for something else that has not appeared...yet.

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    2. They will make a mouse with this gene variant, I bet it will not get ms like disease, that because you will need other genes to trigger ms but the mouse will do badly once it gets disease. I believe this because the gene variant blocks protein production and the gene knockout study in mice has already been done

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    3. They did look at RRMS and found no association.
      If you have a parent with MS you have a higher risk of developing MS I think about 1-5% verses 0.001% in the general population. This is not surprising as your parent has enough of the MS genes to have MS.
      You get half your genes from one parent and half from the other. If both parents have ms your risk is higher but still about 95% chance you don,t get ms.

      If you are a twin you have 25-30% risk of getting MS. In the families above it looks like the gene was dominant I.e. one copy of the gene variant is enough to give you the risk of disease with high penetrance (most but not all of people with gene get the condition). However I will bet that people in these families carry some of the other MS risk genes. A high percentage of northern Europeans carry the MHC gene variant associated with MS, I don't. Neither does MD2 who has arisk gene for something else that has not appeared...yet.

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  2. don't understand they hype with this study- they need to replicate their findings.

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    1. It's a very rare genetic variant, how would you replicate it?
      As MD says though it may be telling us something in MS generally about the importance of the cholesterol pathway in progression which we have also identified in our progressive mice.
      I don't think its pants!

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    2. MD2,

      Is cholesterol good or bad this week? It feels like the message has been switching a lot over the past year.

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    3. Aidan,
      It's complicated! Remeber that the simvastatin trial showed a neuroprotective effect. cholesterol is a precursor for many lipid mediators. Still much to find out.

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    4. If the authors of the study are reading this Blog about looking at the gut microbiome related mutation, and the use of contraceptives in women also linked to mutation HR1N3...
      The gut bacteria seem to act on the production of cholesterol.

      And maybe Prof. G like this: EBV infection appears to act via the concentration of Cholesterol...

      http://www.ncbi.nlm.nih.gov/pubmed/20594556

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    5. Just a heads up that there is a lot of very sceptical commentary on this paper (Wang, Neuron, 2016) on twitter right now among some of the top human genomics researchers:
      https://twitter.com/dgmacarthur/status/738709741514424320

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    6. Told you this study is garbage- not replicated already

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    7. An MS paper that doesn't reproduce, now there's a new one:-).
      Reproduce in a larger data set I'm hearing but these families are unusual and rare.

      It appeared in neuron and maybe the authors were sick of negative comments they were getting from the genetics community controlling the medicial genetic papers. I dont know, people will do work but making a transgenic mouse is not going to move us more than the knockout if it is a loss of function mutant. Lets wait and see genetics in MS has yet to give us a treatment in 20 years and millions of dollars spent, we will have to wait few more years to know if this pans out

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    8. seems some the science argument is that in some data base where there are X number of people with this variant and they don't have MS, but come on there are thousands of people with HLADRB1*1501 and they dont have MS. It will be a question of what other genese these families have. It is clear not a gene determining cause, at least in the majority of people

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    9. seems some the science argument is that in some data base where there are X number of people with this variant and they don't have MS, but come on there are thousands of people with HLADRB1*1501 and they dont have MS. It will be a question of what other genese these families have. It is clear not a gene determining cause, at least in the majority of people

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    10. As MD said may be the interaction of this gene with other genes, and perhaps interaction with environmental factors, but research isn't a "garante", actually the people who gave the impression and the wrong interpretation of it...

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    11. MacArthur and Minikel just posted a detailed critique of this paper on pubmed commons see: http://www.ncbi.nlm.nih.gov/pubmed/27253448#cm27253448_16159

      Their analysis suggests that the data supports a maximum penetrance of 1.7% for this mutation rather than the 70% that the authors claimed (and which gained this paper all the media attention).

      It will be interesting to see if the original authors post a response.

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  3. MD so I found interesting comment about this research here on the Blog. First they came because friends tell me: "Cinara found the cause of MS," and I said: "What? I don't heard anything so far!"
    I even saw in news here in Brazil saying that with this "research" the MS "would be an autoimmune disease to become a genetic disease".
    Then I stop to read the survey in full and I saw it was not so, in fact the authors at no time said that.
    As the media when either is well sensationalist, biased and "bad" of textual interpretation.

    In fact, at least to me said more research raised "questions, questions" than it provided answers.
    Even I commented on them in a group:

    PPMS would be a subtype of different MS?
    It would then be why people with PPMS and with this particular genetic mutation, do not respond to disease-modifying treatments, including the most effective DMTs and even to own transplant, just be a problem in the way of Cholesterol Homeostasis?
    If a mutation is with phenotypic background (genetic interaction with the environment) who have RRMS and SPMS went to then had change in this haplotype NR1H3 gene, and therefore began to present the components of the neurodegenerative disease? And that environmental factors could be these?
    What would be the NRH1H3 relationship with HLA DRB1 * 1501?
    And what environmental factors could affect this gene, providing this mutation? And a poor diet high in saturated fats and rich in polyunsaturated fats then help the body in this deficient via cholesterol regulation, or would not have any relationship?
    Why just have problems in this homeostasis of lipids and the constant inflammation, this problem is that would be overloading the mitochondria and even interfering with the intestinal microbiome?
    What is the role of this mutation in those who have RRMS, as this, at least in the studied samples d and q ho had RRMS, it has not been found?
    And precisely indicate a deregulation of the Cholesterol contraceptive use could be interfering with this cholesterol regulation in women?
    By interfering in the way of Innate Immunity and coagulation could be employed acetylsalicylic acid as adjunctive treatment?
    And what viral infections and vitamin D deficiency would have to do with all this, with this gene?

    As I said I got a lot more questions than answers ...

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    1. Much of what is in the media is a load of rubbish, I best not say more as it gets me in too much trouble:-(

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  4. The MS Society added it to their website under News on the 1st June.

    Rare genetic mutation associated with rapidly progressive form of MS
    https://www.mssociety.org.uk/ms-news/2016/06/rare-genetic-mutation-associated-rapidly-progressive-form-ms

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  5. Ok found it thanks.

    Regards as always.

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