Genetics: Chromosome 6 BTN2A2 and BTN3A3 (BTN2A1)

[Hoopoe]

According to the AstraZeneca PHEWAS, the variants associated with ME/CFS are near the beginning and the end of the PRY-SPRY domain.

That made me curious because it must have some meaning.

I read up a bit on the topic and something similar occurs in familial mediterranean fever (in the MEFV gene which also has a PRY-SPRY domain). If I have understood this right, these finds suggest altered signalling (rather than mutations that lead to a nonfunctional protein).

The attention here has focused on immune signalling of the PRY-SPRY domain. This could be correct but there might be other kinds of signalling that haven't been discovered yet.

It would be an interesting exercise to make a list of diseases with known mutations in a gene that contains a PRY-SPRY domain.

 

[SugarSquared]

The seem to be involved, like CA10, both in noxious stimuli and synaptic pruning.

I was able to learn a bit about synaptic pruning through the thread started by @chillier , but I know nothing about noxious stimuli. Is there a thread here or does anyone have a suggestion of a short summary I could read?

 

[Jonathan Edwards]

I was able to learn a bit about synaptic pruning through the thread started by @chillier , but I know nothing about noxious stimuli. Is there a thread here or does anyone have a suggestion of a short summary I could read?

We don't have a thread as far as I know. Noxious stimuli coming in through the body are mostly passed to the brain by spino-thalamic neurons, which connect to the thalamus. They carry pain and temperature sensations. But I think touch sensation, coming through other tracts, can also be recognised as noxious if pathways are sensitised by e.g. prostaglandins. Feeling touch as pain is called allodynia. Then there are noxious stimuli coming in through cranial nerves like optic nerve and auditory nerve and also directly through hypothalamic sensors for nausea and so on. It is pretty complicated. James Cox may be able to provide a review but is probably busy writing grants and doing research most of the time!

 

[jnmaciuch]

I was playing around on the human protein atlas entry for BTN2A1 since I realized they have single cell data for bergmann cells.

This plot is showing gene expression on the non-neuronal brain cell types (first row is BTN2A1 expression, lower rows are selected marker genes for the cell types, values for each gene are row-scaled). Microglia and circulating immune cells (just a handful each, probably caught in the vasculature) express BTN2A1 much more highly. So it seems clear that bergmann glia are probably not the source of the high cerebellar expression.



There was one neuronal cell type that matched microglial expression levels: VGLUT1+ cerebellum granular cells. So I think that's probably why the cerebellum is enriched in BTN2A1 expression.

 

[Jonathan Edwards]

I think it could be extremely valuable to have immunohistochemical analysis of brain and cord tissue for BTN2A1 isoforms. I have had a quick look on the net and can only find pictures using immunoperoxidase linked to a rabbit polyclonal antibody that looks very doubtful to me. Several of the images suggest non-specific carbohydrate binding (e.g. mucus). I think there may be a need to check through a panel of monoclonals to try to find one that is clean (this is a big and standard problem for IH). Peroxidase may be good, although I would favour metal enhancement for this, or alkaline phosphatase conjugates. We also need isoform specific reagents.

I suspect the lack of images reflects a general lack of interest in BTNs, because they have not come up as doing anything very important. They likely do but it has been missed. From what I have heard BTNs are quite well expressed and immunogenicity so expression patterns should be demonstrable. RNA studies are more fashionable these days but I find them much harder to interpret.

There may be more stuff on PubMed so I will look further.

 

[jnmaciuch]

Just a note: the more I've dug into BTN2A1 structure the more I see inconsistencies with what was written in the Coppin et al. Schizophrenia paper. For example, they claim the MOG-like domain is only in one isoform, but that feature is actually listed on all the 4 isoforms (Q7KYR7-2, Q7KYR7-4, Q7KYR7-5, Q7KYR7-6) in the Ensembl database.

They also claim in the text:

The W117C mutation occurs within the immunoglobulin V-set domain (Fig. 4c), a conserved structural motif critical for antigen recognition and immune cell-cell interactions (Barclay, 2003; Li et al., 2023).

In contrast, isoform Q7KYR7–5 (466 amino acids) exhibits a completely different domain organization. The W117C mutation in this isoform lies within the N-terminal immunoglobulin V-set domain (residues 30–84), a structurally conserved motif critical for antigen recognition and initial ligand binding in immune receptor function (Barclay, 2003; Li et al., 2023; Ramos-Miguel et al., 2015)

But from the figure from their paper that I showed earlier, it's not in the V-set domain:

In fact both of their identified mutations are in the region that's in every isoform of the protein. Between this and the unfounded speculation about cerebellum/innate immune specific compartmentalization of isoforms (which they could have easily checked the same way I did, given the paper came out in 2026 and this GTEx resource has been available for a while), I don't think this paper is a reliable source of information for anything about BTN2A1 isoforms.

 

[SugarSquared]

Disease-specific associations were found in BTN2A1 , BTN3A2 , and H2BC11 . The BTN2A1 rs1977199A allele was protective in RA (OR = 0.93) but increased r-axSpA risk (OR = 1.23), and was associated with reduced IL22 (p = 0.00016) and elevated HO-1 in obese individuals (p = 6.73×10 −6 ). In contrast, BTN3A2 rs9393716G and H2BC11 rs66462181C increased RA risk but were protective in r-axSpA, linked to decreased HO-1 and IL6 (p = 2.43×10 −5 , 3.287times;10 −4 , 1.18×10 −4 ). These SNPs also acted as eQTLs for immune-related genes such as BTN3A2 , HMGN4 , and TRIM38 .

Quote from abstract of New overlapping and disease-specific genetic risk factors for rheumatoid arthritis & ankylosing spondylitis, 2026, Cabrera-Serrano et al

 

[hotblack]

Thanks @SugarSquared I’ve also posted a few recent papers around mechanisms of gamma delta T cell activation by butyrophilins here which seemed interesting.

 

[SugarSquared]

Thanks @SugarSquared I’ve also posted a few recent papers around mechanisms of gamma delta T cell activation by butyrophilins here which seemed interesting.

Thanks! Lots of interesting papers there.

Has anyone kept tabs of which BTN researchers have been reached out to? There's a lot of researchers on that thread. It could be useful to have a list and go through emailing each one (or at least the corresponding author of each thread). Hopefully we'll land on someone interested in discussing the connection with ME/CFS and potentially even in doing research.

 

[Axel]

I don't think this paper is a reliable source of information for anything about BTN2A1 isoforms.

In any case, thank you for breaking it all down.
It’s helpful to visualise the different isoforms.

Figures for the different BTN2A1 isoforms and their tissue-specific transcript expression. As a reminder, most of the ME/CFS-associated mutations fell in the PRY-SPRY domain, which is only present in 2/4 isoforms (the two on the left in the figure).

Would the idea for us, perhaps, be that as long as nothing triggers the "defective" isoforms, everything would work more or less fine?

 

[jnmaciuch]

Would the idea for us, perhaps, be that as long as nothing triggers the "defective" isoforms, everything would work more or less fine?

I think there are too many unknowns here unfortunately. We don’t know if the mutated proteins cause an additional problem, or are just one part of some regulatory mechanism that might be less efficient without BTN2A1. We also don’t know if BTN2A1 is always carrying out some homeostatic function, or if it only becomes important under certain circumstances like an active immune response. We know that BTN2A1 does have a role with sporadic gdT cell signaling, but can’t assume that’s the only relevant function (or that it’s the function relevant to ME/CFS). Long story short we just need a lot more information on what this protein does generally

 

[V.R.T.]

I think there are too many unknowns here unfortunately. We don’t know if the mutated proteins cause an additional problem, or are just one part of some regulatory mechanism that might be less efficient without BTN2A1. We also don’t know if BTN2A1 is always carrying out some homeostatic function, or if it only becomes important under certain circumstances like an active immune response. We know that BTN2A1 does have a role with sporadic gdT cell signaling, but can’t assume that’s the only relevant function (or that it’s the function relevant to ME/CFS). Long story short we just need a lot more information on what this protein does generally

On the subject of that, did anyone contact this guy?

https://www.virologie.uni-wuerzburg...oup-prof-dr-thomas-herrmann-senior-professor/ look in publications list of this guy

I have drafted an email to the two key note speakers of last years Gamma Delta T Cell Conference. I will be sending it out when capacity allows, and may send it to more people on the programme who seem to be involved in relevant areas of study after that.

 

[Jonathan Edwards]

Now we have this weird claim that BTN2A1 variants are linked to intelligence or executive function. I have f9ound it quite hard to get background on this. The spiel is that BTN2A1 is involved in lipid metabolism, apart from its immune role and since myelin is full of lipid you need good BTN2A1 to be clever. Oh yeah? Sounds pretty dumb to me. Why are common variants still around if they make you dumb? Since when was intelligence just a matter of neurons being snug in some nice myelin?

I sense a rabbit is loose.

 

[Jonathan Edwards]

Unless of course the downside of neurons being snug and clever is a risk of getting ME/CFS.

 

[Kilian_M]

On the subject of that, did anyone contact this guy?

I did but did not hear something back. Feel free to try again.

 

[V.R.T.]

I did but did not hear something back. Feel free to try again.

Ah that's disappointing. Thank you for trying though!

 

[hotblack]

Looking at more papers on BTNs and gamma delta I came across an interesting trove of papers by people at the Francis Crick Institute and the Hayday Lab at KCL, we also have a mention of Prof Adrian Hayday in relation to needing to take LC seriously.

We investigate how tissue integrity is maintained and restored by T lymphocytes resident within sites such as skin, gut, and reproductive tract.

Our focus is gamma-delta T cells, discovered following our identification of T cell receptor (TCR) gamma-chain genes. We have shown that the gamma-delta TCR uses a germline (innate) motif to engage butyrophilin-like molecules (of hitherto unknown function) expressed by healthy epithelial cells. Upon cell dysregulation, the TCR switches to adaptive recognition of “stress antigens”. We are now asking how this unique capacity to bridge innate and adaptive immunity relates to disease, and may be exploited in cancer immunotherapy.

@Jonathan Edwards I wonder if you’ve ever crossed paths or have any contacts?

 

[Jonathan Edwards]

@Jonathan Edwards I wonder if you’ve ever crossed paths or have any contacts?

I was aware of Hayday but have not met him. I may be able to contact him via the Crick.

 

[hotblack]

Here’s all the Hayday Lab papers from the Crick https://www.crick.ac.uk/research/find-a-researcher/adrian-hayday

A lot of interesting looking research. As well as gamma delta T cell and butyrophilin research and a chunk of covid stuff, there’s papers like this which looks at a mechanism where NMDAR antibodies in the brain cause microglia to destroy certain glutamate receptors, this gives rise to psychosis like behaviour in their model. It shows that clozapine reduces this, it modulates immune response via an unknown mechanism, reducing circulating autoantibodies so reducing microglial action. So the drugs antipsychotic effects may be partially immunomodulatory rather than simply due to its action on dopamine and serotonin receptors. Maybe the mechanisms aren’t directly relevant here (although microglia, glutamate, a dopamine modifying drug….) but they’re not averse to looking at interesting immune and brain things!