Could ME/CFS be associated with NFAT5 dysfunction?

Hello all,

During my research, I've become interested in a specific protein, which is called NFAT5 (or also TonEBP) and which I think might be linked to ME/CFS.

Here is why I think it could be the case:

Response to osmotic stress

Ronald Davis developed a test that works by submitting cells from a patient to osmotic stress and observing their caracteristics:

A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

The transcription factor NFAT5 is known, among other, for its role in the adaptation to osmotic stress, especially by increasing the influx of osmolytes or the production of proteins (Heat Shock Proteins) that can protect the structure of other proteins from the destructuring effect of osmotic stress.

Osmolytes are small molecules (for example betaine, aka trimethylglycine) that can help counter osmotic stress without disturbing the normal processes of the cell.

Could the abnormalities observed in cells of CFS patients, when an osmotic stress is set up, be the consequences of a dysfunction of NFAT5 and of the ability to accumulate osmolytes to prevent the damage done by osmotic stress?

Immune system

NFAT5 is also known to be tightly linked to the immune system:

Not enough by half: NFAT5 haploinsufficiency in two patients with Epstein-Barr virus susceptibility

Thus, a dysfunction of NFAT5 could be a cause of EBV reactivation. Some patients suffering from CFS are also suffering from EBV reactivation.

It was also found that Coxsackievirus B3 could act against the NFAT5 protein (cleaving it) as it's inhibiting its replication. So we can wonder whether other pathogens would seek to eliminate NFAT5 from the cells they infect.

Glymphatic system

NFAT5 could also be linked to CFS as it has been hypothesized that the glymphatic system, which could be related to NFAT5 via the aquaporin AQP4, could be involved in CFS:

The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy

A dysfunction of NFAT5, having for consequences an impaired glymphatic flow, could cause some cases of the CFS.

Inflammatory Bowel Disease (IBD)

CFS seems to be associated with digestive troubles called Inflammatory Bowel Disease (because IBD could be associated with intestinal permeability and thus leak of pathogens and inflammatory substances like LPS?). A study had the following conclusion:

Increased risk of chronic fatigue syndrome in patients with inflammatory bowel disease: a population-based retrospective cohort study

It is interesting to note that NFAT5 could also be involved in IBD:

Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency

Could NFAT5 dysfunction be a common root cause of CFS and IBD?

Water homeostasis

Some studies demonstrated that CFS patients could have issues with water homeostasis. In particular, they seem to suffer from drastically lowered vasopressin (an antidiuretic hormone) compared with controls:

Chronic fatigue disorders: an inappropriate response to arginine vasopressin?

Another publication found that NFAT5 (aka TonEBP in the literature), seemed to be necessary for vasopressin production.

Transcription Factor TonEBP Stimulates Hyperosmolality-Dependent Arginine Vasopressin Gene Expression in the Mouse Hypothalamus

Thus, an NFAT5 dysfunction in the area of the brain in charge of vasopressin production could lead to lowered levels of vasopressin, which is associated with CFS.

Post-exertional malaise

After physical exertion, muscles themselves could be a part of the cause of PEM as inflammation can happen after physical activity and could, if not properly controlled, cause a sickness feeling. NFAT5 seems to play a role in muscles' recovery as it allows cells to take osmolytes so that they help fight the stress:

A combinatorial role for NFAT5 in both myoblast migration and differentiation during skeletal muscle myogenesis

Induction of Osmolyte Pathways in Skeletal Muscle Inflammation: Novel Biomarkers for Myositis

Could an issue with NFAT5 activation after physical activity lead to an inflammatory reaction which would be a cause of PEM?

Do you think it could be a credible hypothesis?
Thanks.

 

The apparent dysregulation of blood volume and water in ME/CFS is interesting. However NFAT5 is probably just one of hundreds of genes that could have something to do with that. As far as I know, altered muscle regeneration has not yet been reported in ME/CFS (but since I'm going from memory, this could easily be wrong). There doesn't seem to be any specific link between NFAT5 and ME/CFS.

The patient with immunodeficiency due to NFAT5 haploinsufficiency had a clinical presentation that seems different from ME/CFS.

I should add that I'm just an interested amateur. So far the only described clinical presentations of genetic defects that I've found that resembled ME/CFS where mitochondrial (and maybe hormonal).

 

I can't really add much, as I'm not medically trained but I'm interested in anything that may explain my fluctuating water weight issues. I'm really really tiny in every way but managed to gain 3 kg in 4 days last week for example, all water. That's huge. And that's on top of my already bad water retention of at least 5 kg. It fluctuates so much that I have to keep clothes of different sizes. Pretty horrible and I've never had this before my EBV infection and it started very suddenly back then, literally one evening. I swelled up so quickly and to such an extent that I rushed to the hospital in panic.

Several doctors examined me since, all of them said it is not edema, despite my rapid weight fluctuations and the fact that its distribution is really weird. I met with a lot of disbelief despite the fact that it has totally changed my normal body shape and I do look really oddly shaped with it when it is very bad. In the evenings I have elephant legs and a pregnant-looking belly, in the mornings my face looks distorted due to the amount of water ending up on it at night after sleeping lying down. It is not just a little bit puffy, it is abnormal looking, even my nose is visibly bigger. I really only look myself when there is very little extra water in me during some exceptionally good period (so extremely rarely). It can affect my looks so much that I tend to wear sunglasses outside even in rain to hide my weird puffy eyes and when my body looks really oddly disproportionate then I just prefer not to be seen by people.

The swelling can feel really uncomfortably tight in my mid-section, at other times it just feels like my mid-section is falling apart to pieces, almost like my organs are going to just fall out (this feeling must be due to the expansion of the tissue?).

So anyway, it sucks and doesn't seem to be common, so I'm interested in anything that might explain it. This might actually just be something I was unknowingly predisposed to regardless of ME/CFS and maybe the disease has affected me in a way that it brought it out. I don't know but whatever it is it is strictly connected to the fluctuation and start of my other symptoms.

So anyway, I cannot really address the hypothesis but I'm interested in anything that might explain why this weird fluid imbalance is happening to me.

 

It is really odd, @Wyva, I've heard of people getting severe oedema with lupus before, but not with ME.

It's frustrating that no-one will take it seriously. I know strange symptoms can occur without any explanation being found, but they can also be a sign of an underlying issue. You'd think they'd want to check that out.

I used to get what felt like severe bloating premenstrually, but my weight only increased by 1kg (and at 5' 8", I'm not exactly tiny either). I can't imagine gaining 3kg in a few days!

 

Wasn't there talk about aquaporins during the latest Invest in ME conference? They function to allow water to move in and out of cells.

 

Indeed, it doesn't necessitate a gene defect. I also think a NFAT5 dysfunction wouldn't be (if it's really associated in the first place) the root cause of the disease as you noted. I wonder if stress (in a broad sense) and infections that can be stemming from it, nutritional deficiencies, metabolic issues and toxicity could be it.

Indeed, it's probably not the only gene involved. I also believe it's a quite important gene, be it regarding water homeostasis or the immune system.

@Wyva It doesn't really explain variations of edema but according to the study on water homeostasis, ME/CFS seems to be associated with water retentions.

Thanks all for your replies and consideration for this hypothesis

 

Any reasonable idea is worth discussing but the above seems like a series of circumstantial associations.

It seems fair to say something is dysregulating homeostasis in ME, it doesn't mean that NFAT5 is causal and its association with these processes may be symptomatic not causal. The causal mechanism remains obscure.

My immediate thought is that specific gene associated causation of ME is the kind of question Decode ME will help answer even if a SNP is not required to get ME, as the presence of an SNP may change the predisposition to developing ME relative to the general population. That is why n=25k.

 

Indeed and that's why I'm rather cautious (I hope I am) when I'm talking about it, mentioning associations. See also my last message where I say I don't think it could be causal.

But even if it's not the root cause (in the case there is a confirmed association in the first place, but it's absolutely not proven), I believe it would be something valuable to know, because it would bring the focus on water homeostasis, which could be an important factor in the disease.