Genetics: Chromosome 6 BTN2A2 and BTN3A3 (BTN2A1)

The rs13195402 variant produces distinct amino acid substitutions
in two BTN2A1 isoforms with divergent domain architectures (Fig. 4b,
c). In the canonical isoform Q7KYR7–6 (330 amino acids), the W178C
mutation is positioned within the Butyrophilin subfamily 3 member A2-
like Ig-C domain (residues 145–231), which represents the C-terminal
immunoglobulin constant-type domain involved in immune receptor
stabilization and effector functions (Cano et al., 2021; Le Floch et al.,
2024; Yuan et al., 2023). This full-length isoform contains an N-terminal
immunoglobulin-like domain of myelin oligodendrocyte glycoprotein
(MOG) (residues 30–143) followed by the Ig-C domain where W178C is
located. 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). Notably, this longer isoform also contains a Butyrophilin subfamily 3 member A2-like Ig-C domain (residues 84–170) and an additional C-terminal B30.2/SPRY domain (residues 249–445), a protein-protein interaction module implicated in innate immune signaling (Cano et al., 2021). These immunoglobulin-like domains are essential for T-cell regulation and immune cell recognition (Cano et al., 2021; Le Floch et al., 2024; Yuan et al., 2023), suggesting potential neuroimmune mechanisms in SCZ (Smyth and Lawrie, 2013; Afridi et al., 2021; Feng et al., 2025).
 
I don't understand much of the significance of the above but it looks important and seems to track considerable detail. What I don't understand is why a MOG sequence turns up in a BTN isoform.

My hunch is that this may turn out to be an important clue and BTNs are involved in some brain specific interactions.
 
ME/CFS Science Blog said:
Plotting the two GWAS results on the same graph, looks like this. The DecodeME top SNPs are slightly to the left of BTN genes which start at 26,365 (just below the top anxiety SNPs).
Click to expand...
Do you happen to have the transcript positions for the two sets of top SNPs handy? Or even just top SNP rsIDs? I had a thought about location. If not I can go and find them.
 
BTN2A1's expression pattern revealed a striking dual localization: predominant expression in peripheral immune cells and organs, including granulocytes (94.55), blood (92.79 female, 91.43 male), spleen (92.44 male, 92.20 female), monocytes (90.41), and lymph nodes (90.87), alongside notable cerebellar expression in cerebellar hemisphere (91.92 male, 91.29 female), cerebellum (91.41 female), cerebellar cortex (91.32 female), and right hemisphere of cerebellum (91.28 male, 90.21 female). This distribution suggests BTN2A1 may function both in peripheral immune regulation and within the central nervous system (Savinetti et al., 2021; Yu et al., 2021), supporting potential neuroimmune mechanisms in SC
 
The structural differences between BTN2A1 isoforms suggest potential functional compartmentalization across these tissue sites. Given that the canonical isoform Q7KYR7–6 (330 amino acids) contains the complete domain architecture for immune receptor function (Cano et al., 2021; Le Floch et al., 2024; Yuan et al., 2023), it likely predominates in peripheral immune tissues (granulocytes, monocytes, spleen) where classical T-cell co-regulation occurs. In contrast, the longer isoform Q7KYR7–5 (466 amino acids) with its additional B30.2/ SPRY domain (residues 249–445)—a protein-protein interaction module implicated in innate immune signaling (Cano et al., 2021)—may be preferentially expressed in cerebellar tissues where BTN2A1 shows notable expression. This would suggest that the W178C variant (disrupting the Ig-C domain in Q7KYR7–6) may primarily affect peripheral immune homeostasis and systemic T-cell regulation, while the W117C variant (disrupting the Ig-V domain in Q7KYR7–5) could affect cerebellar neuroimmune signaling relevant to the motor coordination and cognitive deficits observed in SCZ patients (Kang et al., 2024; Yeganeh- Doost et al., 2011). Despite comparable thermodynamic destabilization between variants (ΔΔG − 2.1 to − 2.4 kcal/mol; Table 2), this potential tissue-isoform compartmentalization suggests they may contribute to SCZ pathophysiology through complementary but spatially distinct mechanisms. Experimental isoform-resolved expression profiling in sorted immune cell populations and cerebellar tissue would be valuable to test this hypothesis.
 
Jonathan Edwards said:
I don't understand much of the significance of the above but it looks important and seems to track considerable detail.
Click to expand...
It suggests that BTN2A1 has different splicing and protein forms which might correspond to different compartments (potentially immune vs. brain). Give me one second, I'll see if I can sort out whether the AZ mutations give us a hint here--if they are in a part of the gene that gets spliced out of one isoform, that might tell us which one matters more for ME/CFS susceptibility.

Good find @Axel
 
jnmaciuch said:
It suggests that BTN2A1 has different splicing and protein forms which might correspond to different compartments (potentially immune vs. brain).
Click to expand...

Yes, I got that far but was puzzled by the MOG bit.

jnmaciuch said:
Give me one second, I'll see if I can sort out whether the AZ mutations give us a hint here--if they are in a part of the gene that gets spliced out of one isoform, that might tell us which one matters more for ME/CFS susceptibility.
Click to expand...

That would be good.
 
Screenshot 2026-08-19 at 16-04-46 AstraZeneca PheWAS Portal.webp
Already been shared previously, but just for reference: the locations of the ME/CFS-associated mutations in BTN2A1

Screenshot 2026-08-19 at 16-05-28 Multi-level computational analysis identifies schizophrenia...webp
From the schizophrenia paper, the two identified isoforms. It is a bit tricky to compare the two because there seem to be multiple rearrangements. The AZ version is probably just the reference isoform. But what's telling is that 4/6 mutations are in the B30.2/SPRY domain, which is not present in the Q7KYR7-6 isoform.

This is what the paper says
The structural differences between BTN2A1 isoforms suggest potential functional compartmentalization across these tissue sites. Given that the canonical isoform Q7KYR7–6 (330 amino acids) contains the complete domain architecture for immune receptor function (Cano et al., 2021; Le Floch et al., 2024; Yuan et al., 2023), it likely predominates in peripheral immune tissues (granulocytes, monocytes, spleen) where classical T-cell co-regulation occurs. In contrast, the longer isoform Q7KYR7–5 (466 amino acids) with its additional B30.2/SPRY domain (residues 249–445)—a protein-protein interaction module implicated in innate immune signaling (Cano et al., 2021)—may be preferentially expressed in cerebellar tissues where BTN2A1 shows notable expression.
Click to expand...
Unfortunately, I can't really get behind their interpretation here. This is complete hand waving for why either isoform should be preferentially expressed in either tissue. I don't understand why their analysis didn't differentiate between the localization of the two different BTN2A1 mutations.

Sadly I am in the middle of grant-related things so can't spare the time right now to see if that answer can be found in some databases. If someone else wants to try their hand at figuring out organ-specific alternative splicing frequency please feel free to step in
 
Thanks. It all seems quite counterintuitive. Particularly that schizophrenia should be linked to defects in the same segment of protein sequence but in two separate proteins only one of which may be brain related?

And it seems that the AZ mutations are somewhere quite different.
 
So to clarify -

The form of BTN2A1 found by AZ in MECFS has 4 mutations that are only found on the BTN2A1 variant that is theorised by the authors of this paper to be more present in brain/CNS tissues and be involved in neuroimmune innate immunity (as opposed to the one they theorise is involved in T cell signalling in peripheral tissues).

However @jnmaciuch thinks the author's interpretation of these variants roles and where they are most strongly expressed makes unwarranted logical leaps and may be innacurate.

Have I got that right?
 
Pulled out these two quotes from JEs extracts about this Q7KYR7–5 variant that stuck out to me.


Jonathan Edwards said:
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). Notably, this longer isoform also contains a Butyrophilin subfamily 3 member A2-like Ig-C domain (residues 84–170) and an additional C-terminal B30.2/SPRY domain (residues 249–445), a protein-protein interaction module implicated in innate immune signaling (Cano et al., 2021).
Click to expand...

Jonathan Edwards said:
the W117C variant (disrupting the Ig-V domain in Q7KYR7–5) could affect cerebellar neuroimmune signaling relevant to the motor coordination and cognitive deficits observed in SCZ patients
Click to expand...

So whilst acknowledging Jnm's reservations, if there's any accuracy to the way the authors categorise this BTN2A1 variant, it sounds very much like something that could be relevant to ME/CFS.

Is it just the roles these varients play that is in question or is the tissues they are most expressed in - e.g. brain, peripheral immune etc - also in question? I notice the authors use a lot of 'may be expressed' type phrases.
 
At least we have established that BTN2A1 codes two very different proteins with likely different functions.
V.R.T. said:
Have I got that right?
Click to expand...

I think so and I think jnm may be right that there isn't any direct case for the isoforms being that way around in terms of expression. It would be odd if schizophrenia was linked to a mutation not affecting the brain version. But then It seems odd that the mutations should be in both versions anyway.
 
Independently, the flagging up of cerebellum may be something to watch. The cerebellum is always relegated to a boring role by neurologists but it is always a mistake to think that a part of the brain has a function in isolation.
 
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