Genetics: Chromosome 17 CA10

V.R.T. said:
Ive just realised I don't know whether CA10 is raised or lowered in DecodeME and the fibro studies
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The GWAS studies found that a mutation near the CA10 gene is associated with risk of these conditions, but that doesn't itself provide much detail on what the mutation does, such as whether it upregulates or downregulates CA10 in the brain.

The mutation that increases risk of ME/CFS seems to be associated with increased CA10 in the prostate, based on a different dataset (GTEx), but I would guess the prostate itself is not relevant in these conditions.

We'll need further study to see if we can find out what is actually different about CA10 in ME/CFS (assuming CA10 is even the relevant protein associated with the mutation, which isn't a guarantee).
 
forestglip said:
I've been reading about CA10, and I thought it would be useful to compile what I was reading into a mini-review, for my own and others' future reference.

This isn't meant to include interpretation of how different CA10 findings may fit together, but rather it's basically a compilation of almost all papers reporting CA10 as a main finding, with a quick summary of each one. It likely includes some findings that are based on very limited or weak evidence. Though I did skip some papers with obvious issues, such as genetic studies that didn't use multiple test correction.

The findings related to CA10 that seem strongest to me:
  • CA10 is part of the alpha-carbonic anhydrase family, a group of genes which catalyze the reversible reaction that converts carbon dioxide to bicarbonate, yet CA10 itself has no ability to catalyze this reaction.
  • CA10 is highly conserved, meaning that its gene sequence has changed very little throughout evolution of different organisms. When a gene is conserved, it suggests that the gene is very important, as mutations which change the gene too much are very detrimental to an organism's ability to pass on its genes.
  • CA10 appears to be a tumor suppressor, based on evidence from a variety of tumor types.
  • Functional experiments show that CA10 likely plays a key role in neural synapse formation, such as through binding to neurexins and thus preventing heparan sulfate from binding to neurexins. Heparan sulfate itself influences which post-synaptic ligands can bind to pre-synaptic neurexins.
  • CA10 may play a role in ME/CFS and pain (GWAS).
  • CA10 may play a role in age at first period in women (GWAS).
  • Absence of CA10 (or at least the versions in zebrafish) causes severe physical defects and early death in zebrafish.
  • Absence or downregulation of a similar gene, CA8, which also has no catalytic activity, is linked to ataxia (problems with muscle coordination and balance) and possibly intellectual disability in humans.
Edit: In case it wasn't clear, the text above is a quick, informal summary. The attached PDF is the review.
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Nice one!
 
Just read back over the thread - great work! Just throwing a question out there for some thoughts. If you were going to focus on a part of the body where CA10 is expressed (e.g. DRG or a particular brain region such as hypothalamus), which region would you focus on that is relevant to the symptoms/pathology in ME/CFS?
 
And to add to that, within those tissues, which particular subpopulations of cells are likely to be relevant (single cell RNAseq databases are helpful here). Just curious because you guys are miles ahead of me with the ME/CFS literature!!!
 
James Cox said:
Just read back over the thread - great work! Just throwing a question out there for some thoughts. If you were going to focus on a part of the body where CA10 is expressed (e.g. DRG or a particular brain region such as hypothalamus), which region would you focus on that is relevant to the symptoms/pathology in ME/CFS?
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Hopefully others provide some ideas, as I'm a beginner in neuroscience, so I don't have a good idea of what areas are most promising in terms of symptoms.

If I was forced to choose an area to study CA10 in, I'd probably look at the cerebellum. It looks to be most highly expressed there, and that seems to be where the similar protein CA8 has its main functions (specifically Purkinje cells), based on the handful of papers about CA8 I read that are cited in the review. I'm not sure if anyone has ruled out that CA10 also interacts with IP3 receptors in those cells in the way CA8 does.
 
forestglip said:
Hopefully others provide some ideas, as I'm a beginner in neuroscience, so I don't have a good idea of what areas are most promising in terms of symptoms.

If I was forced to choose an area to study CA10 in, I'd probably look at the cerebellum. It looks to be most highly expressed there, and that seems to be where the similar protein CA8 has its main functions (specifically Purkinje cells), based on the handful of papers about CA8 I read that are cited in the review. I'm not sure if anyone has ruled out that CA10 also interacts with IP3 receptors in those cells in the way CA8 does.
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Thanks. You might be a beginner in Neuroscience but a pro in Genetics I see!! Have you ever explored in the single cell RNAseq databases? They are quite good fun as you can see exactly which populations of cells express a particular gene. For example, a good one for DRGs is this http://harmonized.painseq.com/
 
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James Cox said:
which region would you focus on that is relevant to the symptoms/pathology in ME/CFS?
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Others, @SNT Gatchaman, @Jonathan Edwards, might have some thoughts (no pressure tho).

This is something I've been wanting to look into more systematically. It would be really nice to have findings organized somewhere by brain region.

I also know no proper neuroscience but two interesting possible things off the top of my head:
  • There's some literature suggesting raised lactate (recently collected by forestglip here) in various areas of the brain (the ventricles are mentioned a lot).
  • We've probably mentioned this already, but there is that preliminary data from the Amsterdam autopsy study where they found "missing" CRH neurons in the hypothalamus. Thread on that here.
 
ScoutB said:
Others, @SNT Gatchaman, @Jonathan Edwards, might have some thoughts (no pressure tho).

This is something I've been wanting to look into more systematically. It would be really nice to have findings organized somewhere by brain region.

I also know no proper neuroscience but two interesting possible things off the top of my head:
  • There's some literature suggesting raised lactate (recently collected by forestglip here) in various areas of the brain (the ventricles are mentioned a lot).
  • We've probably mentioned this already, but there is that preliminary data from the Amsterdam autopsy study where they found "missing" CRH neurons in the hypothalamus. Thread on that here.
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Yes I agree! The CRH neuron autopsy findings look a very interesting lead. Thanks for putting a link to the thread - very helpful.
 
James Cox said:
Just read back over the thread - great work! Just throwing a question out there for some thoughts. If you were going to focus on a part of the body where CA10 is expressed (e.g. DRG or a particular brain region such as hypothalamus), which region would you focus on that is relevant to the symptoms/pathology in ME/CFS?
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@jnmaciuch and @hotblack might have some thoughts about this
 
James Cox said:
which region would you focus on that is relevant to the symptoms/pathology in ME/CFS?
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That's probably quite tough, because we don't know what the pathology is or how the symptoms are generated.

Bodies seem to have quite a limited repertoire when it comes to symptoms, so all kinds of things can cause muscle pain, fatigue, nausea, headache etc. When some of the causes are found, they turn out to be surprising or unintuitive.

People with more knowledge might be able to make suggestions, but another way to look at it is to ask what a hypothesis needs to explain. The 24–48 hour delay in PEM onset is quite odd and must rule out quite a lot of phenomena. The data look good on ME/CFS having two age peaks, so that's another thing to consider. And of course there's a strong female predominance, but males are able to develop it too.
 
Thanks @V.R.T.
I’m a bit caught up in projects at the moment so can’t write as much as I would like, but I would start with neuron populations implicated in propagating peripheral immune signals to the brain during active infection. There’s a TRPV1+ subset that’s been described in fever response/thermal regulation via IL-1B/prostaglandin signaling (covering both peripheral nerves and hypothalamic neurons). Also DRG neurons that interact with a local population of macrophages, I believe. I will try to link the studies I’m thinking of when I have a chance.

Another idle possibility ive been tossing around is whether ME/CFS is perpetuated by one of the many intracellular signaling cascades that get activated by calcium flux (and would be triggered by repeated neuron firing). In which case, I’d be interested in whether the CA10 variant associated with ME/CFS just generally increases neuron excitability. There are some cytokines that also have that effect (example here), so that seemed to be a way to tie a persisting neurological problem to an initial infection. Some folks on the forum also report that benzodiazepines/drugs-that-work-via-GABA help substantially, which might support that line of thought. The most promising population to explore this might just be some neuron types in the sensory cortex, since sensitivity to light and sound is a widely reported symptom.

Nice to meet you @James Cox , I’m a PhD student in computational biology with a personal interest in ME/CFS. Happy to chat more
 
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Kitty said:
That's probably quite tough, because we don't know what the pathology is or how the symptoms are generated.

Bodies seem to have quite a limited repertoire when it comes to symptoms, so all kinds of things can cause muscle pain, fatigue, nausea, headache etc. When some of the causes are found, they turn out to be surprising or unintuitive.

People with more knowledge might be able to make suggestions, but another way to look at it is to ask what a hypothesis needs to explain. The 24–48 hour delay in PEM onset is quite odd and must rule out quite a lot of phenomena. The data look good on ME/CFS having two age peaks, so that's another thing to consider. And of course there's a strong female predominance, but males are able to develop it too.
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Good points - thanks.
 
jnmaciuch said:
Thanks @V.R.T.
I’m a bit caught up in projects at the moment so can’t write as much as I would like, but I would start with neuron populations implicated in propagating peripheral immune signals to the brain during active infection. There’s a TRPV1+ subset that’s been described in fever response/thermal regulation via IL-1B/prostaglandin signaling (covering both peripheral nerves and hypothalamic neurons). Also DRG neurons that interact with a local population of macrophages, I believe. I will try to link the studies I’m thinking of when I have a chance.

Another idle possibility ive been tossing around is whether ME/CFS is perpetuated by one of the many intracellular signaling cascades that get activated by calcium flux (and would be triggered by repeated neuron firing). In which case, I’d be interested in whether the CA10 variant associated with ME/CFS just generally increases neuron excitability. There are some cytokines that also have that effect (example here), so that seemed to be a way to tie a persisting neurological problem to an initial infection. Some folks on the forum also report that benzodiazepines/drugs that work via GABA help substantially, which might support that line of thought. The most promising population to explore this might just be some neuron types in the sensory cortex, since sensitivity to light and sound is a widely reported symptom.

Nice to meet you @James Cox , I’m a PhD student in computational biology with a personal interest in ME/CFS. Happy to chat more
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Super helpful and great to meet you. Very insightful - yes let’s definitely chat more!!!
 
James Cox said:
Thanks. You might be a beginner in Neuroscience but a pro in Genetics I see!! Have you ever explored in the single cell RNAseq databases? They are quite good fun as you can see exactly which populations of cells express a particular gene. For example, a good one for DRGs is this http://harmonized.painseq.com/
Click to expand...
Ha, I'd consider myself a beginner in everything. Just picking things up as I go. Thanks for the suggestion, I will definitely explore that site. I've only played around with https://www.proteinatlas.org/ which seems to have a decent variety of tissue and cell types.
 
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