Genetics: ARFGEF2, CSE1L

[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.