WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome, 2023 Hwang et al

You can certainly detect significant quantitative differences in expression with this number of samples - it's not like a GWAS as you say. There will still be problems with multiple testing though - they have hopefully corrected for the number of different genes they have looked at, but the NIH intramural study as a whole looks at so many outcomes that it'll be difficult for it to be informative with such a small number of patients.

That said, maybe the expression difference has a huge effect size. Either way replication is the key to these things.

 

Post copied from the NIH news thread

https://twitter.com/user/status/1569754875214405637


https://twitter.com/user/status/1569754885083504640


https://twitter.com/user/status/1569754892570447872


Hopefully not confounded by healthy controls being fitter than ME/CFS patients.

 

https://twitter.com/user/status/1569931177745604608

[ME/CFS News: The @NIH has found that increased expression of the WASF3 protein is associated with abnormal mitochondrial function in the muscles of some #MECFS patients. Credit to @brianvastag. While we wait for the publication of their findings, let's look at the underlying biology:

The endoplasmatic reticulum (ER) is a network of membranes in the cell that produces various proteins and substances. Mitochondria are attached to the ER at special sites called mitochondria-associated ER membrane (MAM).]

https://twitter.com/user/status/1569931187082108928

[ME/CFS News: MAMs do not merely hold the mitochondria in place: they allow communication and exchange of substances between mitochondria and the ER. WASF3 is one of the proteins found in MAMs.

WASF3 also has functions elsewhere in the body but from the information released so far it sounds like the NIH believes that its function as link between ER and mitochondria is most important.]

https://twitter.com/user/status/1569931902106083333

[ME/CFS News: What does all this mean? I am not sure yet. It sounds like it could have something to do with mitophagy (removal of damaged mitochondria) and regulation of metabolism (perhaps part of a "starvation" response). MAMs are important in neurological disorders.]


According to Wikipedia, “[t]he [WASF3] gene product is a protein that forms a multiprotein complex that links receptor kinases and actin. Binding to actin occurs through a C-terminal verprolin homology domain in all family members. The multiprotein complex serves to tranduce signals that involve changes in cell shape, motility or function.[6]”

 

Hi Everyone, Brian here - I appreciate folks picking up the thread. When I tweeted the name of the gene product they were working on back in July, I probaby shouldn't have. But I did, so let me clarify some things since there is a lot of rampant (incorrect) speculation on this thread:

Dr Hwang's lab made a discovery in a patient with another disease he was studying. The discovery involved mitochondria.

Brian Walitt then asked Hwang to look at mitochondria in the muscle biopsies from the patients in the intramural NIH study.

Hwang saw the same finding in about 10 of the ME/CFS patients.

The discovery is unpublished and it is a new mechanism of action of the protein in question - so yes, it's a discovery, nothing in the literature describes it as yet.

Hwang is submitting a paper describing this discovery as a case study in the non-ME/CFS patient but in the paper he is also mentioning the possible connection to ME/CFS.

So, as with anything, caution is certainly warranted. I think it's very interesting but whether it leads to treatment, well we all know how long and winding the road of medical research is.... There's also no way to know right now WHY this gene product is elevated in ME/CFS and what is going on upstream to elevate it. So...proceed with caution.

Edit: This finding was seen in most, but not all, of the intramural patients who had muscle biopsies.

Brian

 

I highly doubt it, especially if the difference is large enough to be observed in a small cohort. I think the two reasons GWASes need so many people is because the effect of individual mutations is tiny and because you need to rule out coincidences from looking at so many genes.

Edit: My reply was redundant. I wrote it before seeing the whole thread. Sorry.

 

Quick search of the literature found that this gene is HIF-1a and hypoxia activated in cancer cells

 

Hey Brian, thank you for the visit! When you say he found "it" in about 10 ME patients, could you estimate out of how many total? just a ballpark ;-)

 

10 out of 17 would appear to be a very high proportion. You'd need to think of the inclusion criteria, i.e. basis the 17 were selected, of course.

Interesting to see what the increase was (e.g. clearly distinguishing patients from activity matched controls ---) and whether it's a potential biomarker e.g. which could add a further filter to genetic studies ----.

EDIT - I've only glanced at a few posts.

 

Wouldn't that make it potentially significant i.e. if it were found in a high proportion of the study population?

 

I think I should have mentioned that a gene being "upregulated" basically means that it's making more of whatever protein it codes for. Basically, without checking, it's an MRNA that controls the gene ---telling it to make more/less of the protein. If you've an illness then upregulating the gene may be a (downstream) consequence --- and thus a potential therapeutic (drug) target.

MRNA levels aren't a genetic fingerprint/cause/pre-disposing gene they are upregulated/downregulated as a (downstream) consequence of an illness --- so everyone with the illness (regardless of their genetic makeup) is likely to have this signature upregulation. So a high proportion of a (disease) population demonstrating upregulation might indicate a common pathology but it wouldn't tell us anything about their genes.
Check out Alain Moreaus work on MRNAs in ME/CFS - here's a random example - https://pubmed.ncbi.nlm.nih.gov/33184353/

Yip me too!

I've corresponded with Dr Nath a couple of times - e.g. highlighting technology (stuff highlighted on this website) like Aaron Ring (Yale) autoantibody/antigen work --- he was already in touch with Aaron! My impression is that he's knowledgeable and cares --- I only wish that was the norm! I come from one of the lands of BPS bullshit [EDIT - think I should mention that the UK has funded GWAS/Chris Ponting's project] - UK.
Can't recall Walitt.

 

I believe Hwang looked at 14 muscle biopsies from ME/CFS patients and found the abnormality in "about 10".

 

DOCKopathies: A systematic review of the clinical pathologies associated with human DOCK pathogenic variants

The family of DOCK proteins are involved in intracellular signalling, including "Rho GTPases like RAC1, RHOA, WAVE/WASF1, and N‐WASP". Many of these pathways are involved in the rearrangement of the actin cytoskeleton, metabolism, and cell migration.

It sounds like these could have something to do with the abnormal expression of WASF3 found by the NIH.

 

Merged thread

Conference talk "ER [endoplasmic reticulum] Stress Induction of WASF3 May Underlie CFS"

Dr. Paul Hwang of the NIH's National Heart, Lung, and Blood Institute, is giving a talk on March 27 entitled "ER [endoplasmic reticulum] Stress Induction by WASF3 May Underlie CFS".

It's at a Keystone Symposium, which is closed to the public and discourages reporters from directly reporting on results presented. But this tells me Dr. Hwang is confident in his findings (which remain unpublished).

The backstory: As part of the NIH's ME/CFS intramural study, patients had muscle biopsies. Dr. Hwang, through a somewhat seredipitous route, was looking at muscle tissue of a patient with a cancer syndrome who also had ME/CFS-like symptoms. With the tissue of this patient, he discovered a problem with this gene WASF3, and when he looked at the ME/CFS patient samples, he saw the same problem in most.

This work remains unpublished but some of us who were in the intramural study returned to NIH last year to take part in Dr. Hwang's spin-off study.

 

C'mon, publish it!

 

I second that @RedFox

It's taking an awfully long time to see the published results of the NIH intramural study.

 

Exercise is listed as one of the causes of ER stress. My understanding is that ER stress can lead to the unfolded protein response. If exercise can induce the unfolded protein response in ME/CFS, could that lead to a marked reduction of metabolites in urine as we've seen in Hanson's recent study?

My understanding is that as part of the unfolded protein response, the production of new proteins is stopped.

And if the response fails to restore the cell to good condition, the cell dies. Would many cells dying off some time after exercise fit with PEM?

 

I know science takes time but they are really taking the piss at this point. People need this research to come out yesterday!

 

Dr. Whittemore of the NINDS said this on 2/13/23 of the ME/CFS Intramural Study (fwiw): “I just checked and they are finalizing the figures and then it will go for final internal review before being submitted. I’m told they are very close!”