Genetics: Chromosome 20: ARFGEF2, CSE1L, STAU1

[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 20

Chr20 contained seven Tier 1 genes.

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CSE1L (Tier 1)

• Protein: Chromosome segregation 1-like (also known as exportin-2). UniProt. GeneCards.
The allele that increases the risk of ME/CFS is associated with increased or decreased CSE1L expression depending on tissue.

• Molecular function: CSE1L mediates importin-alpha re-export from the nucleus to the cytoplasm after import substrates (cargos) have been released into the nucleoplasm (69). In the nucleus it binds cooperatively to importin-alpha and to the GTPase Ran in its active GTP-bound form. Docking of this trimeric complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the importin-alpha from the export receptor.

CSE1L/XPO2 then return to the nuclear compartment and mediate another round of transport. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. CSE1L is a microtubule-associated protein (UniProt).

• Cellular function: Shuttles between the nucleus and the cytoplasm (69).

• Link to disease: Cellular apoptosis susceptibility protein that is expressed highly in cancer (70).

• Potential relevance to ME/CFS: Inflammation: knockdown of CSE1L in macrophages decreases release of TNF-α (71).


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ARFGEF2 (Tier 1)

• Protein: ARF (ADP- [Adenosine diphosphate-] ribosylation factors) guanine nucleotide exchange factor 2; also known as BIG2. UniProt. GeneCards.
The allele that increases the risk of ME/CFS is associated with increased or decreased ARFGEF2 expression depending on tissue.

• Molecular function: Guanyl-nucleotide exchange factor activator for ARF-like small GTPases. ARFGEF2 is required for membrane association of the AP-1 complex and GGA1. Seems to be involved in recycling of the transferrin receptor from recycling endosomes to the plasma membrane. Probably is involved in the exit of GABA(A) receptors from the endoplasmic reticulum. Involved in constitutive release of tumour necrosis factor receptor 1 via exosome-like vesicles; the function seems to involve PKA and specifically PRKAR2B. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways (UniProt).

• Cellular function: Involved in vesicle trafficking from the trans-Golgi network; neuronal guidance.

• Link to disease: ARFGEF2 is mutated in microcephaly and periventricular heterotopia (72).

• Potential relevance to ME/CFS: Inflammation: regulates the release of TNFR1 exosome-like vesicles (73). TNFR1 acts as a decoy receptor, binding to TNF and preventing it from interacting with cell surface TNFR1, thus modulating inflammation and cell death (74).

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References

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.

70 Tai CJ, Hsu CH, Shen SC, Lee WR, Jiang MC. Cellular apoptosis susceptibility (CSE1L/CAS) protein in cancer metastasis and chemotherapeutic drug-induced apoptosis. J Exp Clin Cancer Res. 2010 Aug 11;29(1):110.

71 Gao CL, Song JQ, Yang ZN, Wang H, Wu XY, Shao C, et al. Chemoproteomics of Marine Natural Product Naamidine J Unveils CSE1L as a Therapeutic Target in Acute Lung Injury. J Am Chem Soc. 2024 Oct 16;146(41):28384–97.

72 Sheen VL, Ganesh VS, Topcu M, Sebire G, Bodell A, Hill RS, et al. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet. 2004 Jan;36(1):69–76.

73 Islam A, Shen X, Hiroi T, Moss J, Vaughan M, Levine SJ. The brefeldin A-inhibited guanine nucleotide-exchange protein, BIG2, regulates the constitutive release of TNFR1 exosome-like vesicles. J Biol Chem. 2007 Mar 30;282(13):9591–9.

74 Hawari FI, Rouhani FN, Cui X, Yu ZX, Buckley C, Kaler M, et al. Release of full-length 55-kDa TNF receptor 1 in exosome-like vesicles: a mechanism for generation of soluble cytokine receptors. Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1297–302.

 

[Jonathan Edwards]

These seem to be quite obscure genes. In both cases there is a suggestion in the text of a link to ME/CFS via inflammation and TNF. But, as said, there is no obvious role for inflammation. Moreover, I suspect that almost any cellular housekeeping gene will have some effect on TNF production.

If TNF production was important why is there no link to polymorphisms in genes more closely linked to TNF itself? Maybe TNF receptor variants or NFkappaB pathway proteins.

I wonder if the first one might have something to do with epigenetic processes in neurons, or even glia.

It may be that the reasons for genes like this coming up are so obscure and coincidental that it is not worth trying too hard to owrk out what they are. But it may also be that obscure genes like these can provide the missing links in the theory building process.

 

[chillier]

From the candidate gene list it seems the locus on chromosome 20 is associated with many other interesting looking genes. For instance ZNFX1, where the eQTL data suggests expression of this gene is increased in brain and pancreas. There was an EMBO paper I saw that argues that ZNFX1 inhibits formation of the NLRP3 inflammasome by binding to and sequestering NLRP3. Could prevent things like macrophages or microglia from secreting IL1 etc.

This paper: https://www.embopress.org/doi/full/10.1038/s44318-024-00236-9

 

[wigglethemouse]

wonder if the first one might have something to do with epigenetic processes in neurons, or even glia.

Yes, the CSE1L RNA is found all over the brain. LINK to Protein Atlas.

I reviewed AI answers on tissue function and the most likely answer based on what we know of ME/CFS is:

Cell Proliferation and Apoptosis: CSE1L plays a role in cell proliferation and apoptosis, and is often associated with cancer development and progression.
Cell Cycle Regulation: CSE1L is involved in regulating cell division and mitosis.

I checked in GeneCards and it has this sentence :
"In addition, the encoded protein may play a role both in apoptosis and in cell proliferation."

 

[Jonathan Edwards]

"In addition, the encoded protein may play a role both in apoptosis and in cell proliferation."

But there seems little reason to think that proliferation or apoptosis are relevant in the brain context. I was thinking more in terms of epigenetic changes altering responsiveness to stimuli.

 

[Kitty]

It's also involved in transport processes:

The ARFGEF2 gene provides instructions for making a protein involved in vesicle trafficking within cells. Specifically, it acts as a guanine nucleotide exchange factor (GEF), which means it facilitates the conversion of a molecule called GDP to GTP, activating ADP-ribosylation factors (ARFs).These ARFs are crucial for the movement of vesicles, small sacs that transport molecules within the cell and to its surface.

 

[chillier]

Vesicle trafficking at the region around the endosome once again, just like RABGAP1L. The eQTL data would suggest that the effect of both would be to reduce recycling of endosome contents back to the plasma membrane / reduced exocytosis.

ARFGEF2 acts to promote recycling from endosome to plasma membrane - eQTL suggests lower expression in the majority of tissues.
RABGAP1L acts to deactivate Rabs that inhibit recycling from endosome to plasma membrane - eQTL suggests lower expression of RABGAP1L, which if you can parse all of the double and triple negation I think would again result in a reduction of transport from endosome to plasma membrane.

Both of these highly expressed in neurons. I think a plausible role for these would be in the transport of neurotransmitter receptors at the post-synapse to and away from the synapse membrane. This process appears to be key in the ability of synapses to dynamically modulate their sensitivity. So maybe you could imagine a period of high firing (physical or cognitive activity) leads to a downscaling of synapse sensitivity, but an inability to scale back up synapse sensitivity after a period of low activity.

 

[wigglethemouse]

So maybe you could imagine a period of high firing (physical or cognitive activity) leads to a downscaling of synapse sensitivity, but an inability to scale back up synapse sensitivity after a period of low activity.

I asked AI how down regulation of the two genes could play a role. I thought this particular response was interesting, that is it could be a protective mechanism that contributes to disease.

Potential Link to Diseases: Lower expression of RABGAP1L has been observed in the brains of Alzheimer's disease patients and has also been linked to systemic lupus erythematosus (SLE) in some populations. This suggests potential roles in neuroprotection and immune cell regulation, where its lower expression could contribute to disease progression.

 

[forestglip]

Looking at some of the 25 'critical SNPs' in the first PrecisionLife study on ME/CFS from, I see that one of them, rs237475 which was mapped to the gene KCNB1, is very near this most significant locus in DecodeME.

This is the significance plot for DecodeME, showing the ARFGEF2 locus just a little to the left. Kind of hard to see, but the location of the PrecisionLife SNP is the black diamond labeled with the ID near the middle-right on the bottom.

 

[Hutan]

Coincidentally, I've just been looking at gene STAU1, which is in that cluster of hits (middle of @forestglip's chart). It's a gene that is activated by STAT3 (which is activated by molecules including interferons and cytokines). I don't think we've talked about STAU1 much yet?

Staufen is a member of the family of double-stranded RNA (dsRNA)-binding proteins involved in the transport and/or localization of mRNAs to different subcellular compartments and/or organelles. These proteins are characterized by the presence of multiple dsRNA-binding domains which are required to bind RNAs having double-stranded secondary structures. The human homologue of staufen encoded by STAU, in addition contains a microtubule- binding domain similar to that of microtubule-associated protein 1B, and binds tubulin. The STAU gene product has been shown to be present in the cytoplasm in association with the rough endoplasmic reticulum (RER), implicating this protein in the transport of mRNA via the microtubule network to the RER, the site of translation. [provided by RefSeq, Apr 2020]

Staufen1 (STAU1) is a multifunctional double‐stranded RNA–binding protein that plays a central role in post‐transcriptional gene regulation. It recognizes complex RNA duplexes within messenger RNA 3′ untranslated regions—structures that can arise from intramolecular base–pairing or by imperfect pairing of Alu elements brought together through interactions with long noncoding RNAs—and triggers STAU1‐mediated mRNA decay (SMD) by recruiting factors such as UPF1 (and adaptors like PNRC2). In addition, STAU1 contributes to proper mRNA maturation by facilitating processes such as the replacement of the nuclear cap–binding complex with eIF4E, thereby ensuring efficient translation. These functions have been documented in studies showing its binding to specific RNA secondary structures, its influence on transcript stability during differentiation, and its targeting of a broad set of physiologic mRNAs.

STAU1 also functions as a critical host factor during the replication cycles of diverse RNA viruses. It directly binds structured regions in viral genomic RNAs and associates with viral proteins—such as the nucleocapsid domain of HIV-1 Gag—to facilitate RNA encapsidation, multimerization, and ultimately proper virion assembly. Similar roles have been observed in infections by hepatitis C virus, influenza virus, enterovirus 71, and Ebola virus, where STAU1 modulates viral RNA stability and translation efficiency. This multifaceted involvement underscores its importance in orchestrating a balance between host RNA regulation and viral genome utilization.

Aberrant expression or altered regulation of STAU1 is increasingly linked to disease pathogenesis. In neurodegenerative disorders such as myotonic dystrophy type 1 and spinocerebellar ataxia type 2, elevated STAU1 levels contribute to misregulated splicing and disturbed RNA homeostasis. In the cancer arena, STAU1-mediated decay and its interplay with long noncoding RNAs have been shown to affect signaling pathways that control cell proliferation, apoptosis, and metastasis in colorectal, gastric, cervical, and glioblastoma cases. Thus, STAU1 not only governs routine mRNA metabolism but also emerges as a potential disease modifier and promising therapeutic target.

It also seems to have something to do with stress granules in cells.