Genetics: CA10

[Hutan]

DecodeME candidate ME gene
From the Candidate Genes document

In DecodeME, we attempted to link GWAS variants to target genes. Here we discuss the top two tiers of predicted linked genes that we are most confident about –‘Tier 1’ and ’Tier 2’.

We defined genes as Tier 1 genes if: (i) they are protein-coding genes, (ii) they have GTEx-v10 expression quantitative trait loci (eQTLs) lying within one of the FUMA-defined ME/CFS-associated intervals, and (iii) their expression and ME/CFS risk are predicted to share a single causal variant with a posterior probability for colocalisation (H4) of at least 75%. For this definition, we disregarded the histone genes in the chr6p22.2 HIST1 cluster, as their sequences and functions are highly redundant (1). This prioritisation step yielded 29 Tier 1 genes.

For the intervals without Tier 1 genes, three Tier 2 genes were defined as the closest protein-coding genes without eQTL association: FBXL4 (chr6q16.1), OLFM4 (chr13q14.3), and CCPG1 (chr15q21.3).

CHROMOSOME 17
Chr17 contained one Tier 1 gene.

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CA10 (Tier 1)

• Protein: Carbonic anhydrase-related protein 10. UniProt. GeneCards.
Note that this gene encodes a protein that lacks catalytic activity. The allele that increases the risk of ME/CFS is associated with increased CA10 expression in prostate.

• Molecular function: CA10 binds both α- and β-neurexins, a major class of presynaptic cell adhesion molecules, and enhances their surface transport (62). CA10 is most highly expressed in the cerebellum, followed by the spinal cord and cerebral cortex, and is localised to synapses (62). CA10 inhibits the addition to neurexins of heparan sulfate (HS) glycosaminoglycan, a post-translation modification that controls the binding of presynaptic neurexins to postsynaptic neuroligins (63,64). This trans-synaptic interaction is crucial for synaptic transmission and plasticity.

In a rat model of nerve injury (spinal nerve ligation [SNL]-associated allodynia in the ipsilateral hind paw), inhibition of such Nrx1b-Neuroligin-1 interactions prevents pain (65). Nrx1β/Nrx1b contributes to neuropathic injury–induced nociceptive hypersensitivity by interacting with neurologin-1 (NL1), which subsequently activates the spinal NL1/PSD-95/pNR2B cascade. Neurexin 2 appears to be involved in pain processing (66,67).

• Cellular function: CA10 is thought to play a role in the central nervous system, especially in brain development.

• Link to disease: Tissue injury-induced synaptic redistribution of NLGN1 appears to be involvedin the development of pain hypersensitivity (68). NLGN1 in the spinal cord dorsal horn (a key site for processing pain signals) is involved in the processing of nociceptive signals. Peripheral inflammation rapidly enhances the synaptic localisation of NLGN1. Peripheral inflammation induces synaptic accumulation of the NMDA receptor. NLGN1 knockdown attenuates this accumulation and alleviates pain hypersensitivity (68).

• Potential relevance to ME/CFS: Altered CA10 expression modulates addition of heparan sulfate to presynaptic neurexins. This changes their affinity for post-synaptic neurologins, cell-cell signalling across the synapse and individuals’ pain sensitivity.


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References

62 Sterky FH, Trotter JH, Lee SJ, Recktenwald C V, Du X, Zhou B, et al. Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand. Proc Natl Acad Sci US A. 2017 Feb 14;114(7):E1253–62.

63 Montoliu-Gaya L, Tietze D, Kaminski D, Mirgorodskaya E, Tietze AA, Sterky FH. CA10 regulates neurexin heparan sulfate addition via a direct binding in the secretory pathway. EMBO Rep. 2021 Apr 7;22(4):e51349.

64 Zhang P, Lu H, Peixoto RT, Pines MK, Ge Y, Oku S, et al. Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships. Cell. 2018 Sep 6;174(6):1450-1464.e23.

65 Lin TB, Lai CY, Hsieh MC, Jiang JL, Cheng JK, Chau YP, et al. Neuropathic Allodynia Involves Spinal Neurexin-1β-dependent Neuroligin-1/Postsynaptic Density-95/NR2B Cascade in Rats.Anesthesiology. 2015 Oct;123(4):909–26.

66 Xu L, Feng Q, Deng H, Zhang X, Ni H, Yao M. Neurexin-2 is a potential regulator of inflammatory pain in the spinal dorsal horn of rats. J Cell Mol Med. 2020 Dec;24(23):13623–33.

67 Xu L, Zheng S, Chen L, Yang L, Zhang S, Liu B, et al. N4-acetylcytidine acetylation of neurexin 2 in the spinal dorsal horn regulates hypersensitivity in a rat model of cancer-induced bone pain. Mol Ther Nucleic Acids. 2024 Jun 11;35(2):102200.

68 Zhao JY, Duan XL, Yang L, Liu JP, He YT, Guo Z, et al. Activity-dependent Synaptic Recruitment of Neuroligin 1 in Spinal Dorsal Horn Contributed to Inflammatory Pain. Neuroscience. 2018Sep 15;388:1–10.

69 Kutay U, Bischoff FR, Kostka S, Kraft R, Görlich D. Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor. Cell. 1997 Sep 19;90(6):1061–71.

 

[hotblack]

Other s4me threads mentioning this gene

W

Thread 'Genome-wide association study of multisite chronic pain in UK Biobank, 2019, Johnston'

Jul 6, 2025

Genome-wide association study of multisite chronic pain in UK Biobank, 2019, Johnston

Abstract

Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype ‘chronic pain grade’, have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual’s overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for...

• wigglethemouse
• ca10 pain
• Replies: 7
• Forum: 'Conditions related to ME/CFS' news and research

• 

 

[Jonathan Edwards]

A role for this gene in brain as a target tissue in terms of pain sensitisation and potentially all sorts of intolerances, fatigue and ineffective sleep/rest is maybe the easiest one to propose. The question then would be what shifts at the time of onset of ME/CFS to make this a problem in someone previously healthy. But that would presumably be a different part of the story.

 

[Hutan]

Figure 4 suggests that the particular allele found in the ME/CFS cohort is associated with increased expression in the prostate. It isn't recorded as having increased expression anywhere else, although perhaps that is just that no one has looked.

The SNPID, the particular allele, is 17:52183006:C:T.
I think the RS ID is rs34626694

Four of the eight loci (RABGAP1L, FBXL4, OLFM4,CA10) were associated at p < 0.05 with cases ascertained using post-exertional malaise and
fatigue in the UK Biobank and the Netherlands biobank Lifelines. We found no evidence of sex-bias among discovered associations, and replicated in males two genetic signals (ARFGEF2, CA10) discovered in females. The ME/CFS association near CA10 colocalises with a known association to multisite chronic pain.

It seems like quite a robust finding, showing up with some degree of strength in the UK Biobank/Lifelines replication and the male subset.

 

[Yann04]

The interesting anecodotal thing I’ve noticed, atleast with me and my mum (who has mild ME) and a couple ME friends online, is that we generally saw ourselves as having high pain tolerance before onset.

 

[Hutan]

Yes, same, and even after. For a cut, child birth... I don't get the impression that a particular allele of CA10 means that a person was born with, or even has, a global low pain tolerance, although the BPS people may latch onto that idea.

I suspect the idea that CA10 is all about nociception is too limited. After all, the risk allele is recorded as being highly expressed in the prostate, and it seems unlikely it is there to sense pain.

 

[forestglip]

It isn't recorded as having increased expression anywhere else, although perhaps that is just that no one has looked.

My understanding is that it's based on a project (GTEx) that tested expression of all genes in 54 different tissues to see where mutations affect expression. So I think they would have looked at CA10 in all tissues.

Paper about GTEx

 

[Hoopoe]

The question then would be what shifts at the time of onset of ME/CFS to make this a problem in someone previously healthy.

I think increased pain sensitivity (along with anxiety, feeling fragile, etc.) are often misunderstood. They're often a survival strategy by a brain that is sensing illness or vulnerability. Having increased pain sensitivity changes the behaviour of a person in a way that reduces certain risks.

A person with increased pain sensitivity will more motivated to avoid conflict, fights, falls, further injuries, etc. These things, in combination with the existing illness or vulnerability, are much more dangerous than they normally would be, and that's why they are upregulated.

In ME/CFS the program that is activated in response to the illness maybe involves a lot of fatigue, general pain sensitivity, and malaise in response to small overexertion so that we do very little and only the essential things and avoid anything that might hurt.

 

[Hutan]

Carbonic Anhydrase-related protein 10 - alternative names are CA10 and CA-RP X

cDNA sequence of human carbonic anhydrase-related protein, CA-RP X: mRNA expressions of CA-RP X and XI in human brain (paywall)

Northern blot analysis demonstrated an approx. 2.8 kb transcript in the human brain and kidney. RNA dot blotting showed significant signals for CA-RP X and XI mRNA expressions in the adult total brain and almost all parts of the central nervous system

It's a 2001 paper, so I'm not sure why the expression findings haven't been picked up in the gene database

 

[Jonathan Edwards]

It isn't recorded as having increased expression anywhere else, although perhaps that is just that no one has looked.

When we were students a friend of mine called David Hawson invente the clorate gland. It is the vestigial equivalent of the prostate in women and is the cause of all sorts of trouble. I am pretty sure nobody has looked for CA10 in the clorate.

 

[forestglip]

It's a 2001 paper, so I'm not sure why the expression findings haven't been picked up in the gene database

The database (and figure 4 above) are about how the DecodeME's (and other) specific mutations affect the amount of CA10 produced, not how much CA10 there is in general. So it's saying that having this ME/CFS mutation leads to more CA10 in the prostate.

Maybe it's possible the effect in other parts exists but was too small to detect. I'm not sure.

For total abundance, you'd look at something like the Human Protein Atlas. It seems to show high expression in oligodendrocyte precursor cells, neurons, and germ cells.

 

[Hutan]

Thanks @forestglip. Apologies for my blundering about. I think I knew that about Figure 4 at one point, but my knowledge isn't solid enough to remember that when I find something else.

So, we don't actually have evidence of the variant being over-expressed anywhere other than the prostate, or causing particular issues.


CA10 is associated with HBV-related hepatocarcinogenesis

In addition, CA10 overexpression resulted in dysregulation of apoptosis-related proteins, including Mcl-1, Bcl-2, Bcl-xL and Bad.

There's a suggestion that miR-27b downregulates CA10 expression. Of course, it's in the abnormal environment of cancer. The authors suggest

These results suggested that CA10 could inhibit apoptosis but couldn't induce ER stress.

 

[forestglip]

So, we don't actually have evidence of the variant being over-expressed anywhere other than the prostate, or causing particular issues.

Good chance you know this since your first sentence where you posted figure 4 above was right, but I wanted to correct the wording here.

The variant isn't overexpressed anywhere. The variant is just a different letter at a particular point in the DNA, and all cells in the body have the same DNA and thus the same variant. The question is, within the significantly mutated region of the DNA in ME/CFS (since we don't know which specific variant in the region is the important one), what do the variants there do.

And what we have good evidence of so far is that the mutations cause more CA10 to be made in the prostate. So the protein CA10 is overexpressed in the prostate because of this variant. Maybe the variant causes differential expression of CA10 or even other genes in other parts of the body. But apparently the only good evidence so far is increased CA10 in the prostate.

I think the closest gene to this mutated DNA region is CA10 as well (based on UCSC Genome Browser), which provides some more evidence that CA10 is what it's affecting.

 

[Hutan]

Yes, for sure, short cut wording. The genetic variant of the CA10 gene is associated with higher levels of the protein CA10 in the prostate than other variants of the CA10 gene.

I think people do talk about genetic expression in a part of the body.

I think I saw this genetic variant involves just a T instead of a C in one place.

 

[forestglip]

The genetic variant of the CA10 gene

To be clear, this variant/location isn't within the CA10 gene. It's just nearby in DNA that doesn't code for any proteins. Just trying to make sure we know to be cautious in that we don't know that CA10 is for sure what this variant is mainly affecting in ME/CFS.

The genetic variant of the CA10 gene is associated with higher levels of the protein CA10 in the prostate than other variants of the CA10 gene.

I think you got it, but in other words: Everyone's got this region of DNA on chromosome 17 near CA10. People with ME/CFS tend to have different letters in this region. At the specific position 17:52183006, they tend to have T, while healthy people tend to have C. Other nearby positions are also different in ME/CFS. And we also know from the GTEx database that mutations in this region are known to increase how much CA10 there is in the prostate.

I'm not actually sure if that specific variant is what increases CA10. I didn't see that connection in the GTEx database. I think it's a nearby variant. But assuming it was this one, then having a T at this location would lead to more prostate CA10 than having a C at this location.

I think people do talk about genetic expression in a part of the body.

By genetic expression, they mean how much mRNA of a gene is made (which might eventually get turned into the finished protein for the gene). It's not about mutations in the DNA. So more like the data in the Human Protein Atlas I linked. (Though that's levels of the finished proteins, I think. Not the intermediate mRNA step.) If you have higher expression of CA10, then your cells are making more mRNA of CA10, which might then lead to more of the protein CA10.

I think I saw this genetic variant involves just a T instead of a C in one place.

Yes, people with ME/CFS are more likely to have a T than a C at this particular location. But this is just the most significant variant/location in the region, and the causal variant could be one of the slightly less significant variants/locations nearby.

 

[Hutan]

To be clear, this variant/location isn't within the CA10 gene.

Thank you. Again, that is something I think I have understood at various times and then sometimes forgotten.

So, the variant is in DNA that doesn't code for a protein, and it's near the CA10 gene. And there is one piece of evidence suggesting that the variant results in more CA10 in the prostate. But it could be affecting other nearby genes.

And other variants were found in the identified region in chromosome 17. The DecodeME team chose the variants to report on for each genetically different region partly based on how much information there was about the impact of the variant.

Do I have that right?

 

[forestglip]

So, the variant is in DNA that doesn't code for a protein, and it's near the CA10 gene. And there is one piece of evidence suggesting that the variant results in more CA10 in the prostate. But it could be affecting other nearby genes.

Exactly. CA10 being the protein that is changed and causing issues in ME/CFS due to these mutations is an educated guess based on the things we know, which you said, but we can't be positive about that yet.

And other variants were found in the identified region in chromosome 17. The DecodeME team chose the variants to report on for each genetically different region partly based on how much information there was about the impact of the variant.

So looking at the manhattan plot they gave:


Every dot is a location on the DNA. The higher a dot is, the more significant, meaning we can be more sure that people with ME/CFS tend to have a different letter at that location. You'll notice that where it says CA10, it's not just one dot high up. It's a whole tower of dots. That's because if people are born with a different letter at one location, they tend to have a different letter at the nearby locations as well. (This effect of nearby locations tending to all be changed together is called linkage disequilibrium or LD.) The dots in the tower are in LD.

So people with ME/CFS tend to have different letters from healthy people at all these dots in the tower (a whole little stretch of DNA). We don't know which specific dot(s) is the location that plays a part in causing ME/CFS. The dot they reported (17:52183006:C:T which means chromosome 17, position 52183006, T instead of C) is just the tallest dot in that tower, or the most significant. But not definitely the problem dot.

And one or more of the dots in this tower is known to cause higher prostate CA10, plus this tower is near [edit: the dots that are the genetic code for the protein] CA10, so they labeled it CA10.

The tower in chromosome 1 on the left says RABGAP1L, but they know that dots in that tower cause different expression (more or less of the gene made) of 11 different genes, so it'll take some more work to figure out which specific gene is causing issues due to that tower of mutations.

 

[jnmaciuch]

Great explanation @forestglip

 

[hotblack]

Thank you. Again, that is something I think I have understood at various times and then sometimes forgotten.

Very much how I feel about a lot of this! There are points when part of a topic seems to makes sense, but other times…
So really useful to read this discussion and have the important nuances gone over. Thank you both!

Some of this uncertainty is the result of looking at SNPs rather than performing full genome analysis, is that right?

 

[jnmaciuch]

Some of this uncertainty is the result of looking at SNPs rather than performing full genome analysis, is that right?

Whole genome sequencing would still be looking at SNPs—the main difference is that GWAS arrays look at a finite amount of locations in the genome and then the rest is inferred, whereas whole genome sequences are (ideally) capturing everything. But whole genome analysis would have similar limitations of trying to infer which SNPs are impacting which genes.

It’s a complicated subject! I’ve had quite a bit of GWAS exposure and still am learning a lot from this paper and discussion.