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] 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.

Labels: ,