Genetics: RABGAP1L

Hutan

Hutan

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From DecodeME Candidate Genes:

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 1

Chr1 contained 11 Tier 1 protein-coding genes.
Click to expand...

RABGAP1L (Tier 1)

• Protein: RAB GTPase-activating protein 1-like, also known as TBC1D18. UniProt. GeneCards.
The allele that increases the risk of ME/CFS is associated with decreasing RABGAP1L gene expression.

• Molecular function: GTP-hydrolysis activating protein (GAP) for small RAB-like GTPases.

• Cellular function: Contributes to endocytosis and intracellular protein transport, and endosome maturation.

• Link to disease: Suppresses endolysosomal trafficking and autophagy induction during bacterial infection and promotes expulsion of the bacterium Streptococcus pyogenes from cells via endocytosis (2). RABGAP1L expression limits influenza A virus entry at or prior to virus-host membrane fusion and limits replication of several viruses (3).

• Potential relevance to ME/CFS: RABGAP1L inhibits the entry and/or promotes the expulsion of bacteria or viruses. It is a viral restriction factor. Reduction in RABGAP1L expression would be expected to enhance susceptibility to bacterial and viral infection, which often precedes initial ME/CFS symptoms.
 
Note from above. Decreased expression in ME/CFS.

Summary from Google AI

RABGAP1L: A Rab GTPase-activating protein 1-like protein with diverse roles

RABGAP1L, also known as TBC1D18, is a member of the TBC domain-containing protein family involved in the regulation of small membrane-bound GTPases, called Rab proteins. Rab proteins are key regulators of intracellular membrane trafficking, impacting processes such as endocytosis, recycling, and exocytosis. RABGAP1L acts as a GTPase-activating protein (GAP) for specific Rab proteins, meaning it facilitates the hydrolysis of GTP to GDP, effectively switching the Rab protein from an active (GTP-bound) to an inactive (GDP-bound) state.

Functions
* Endocytosis and intracellular protein transport: RABGAP1L has been shown to play a role in endocytosis and the intracellular transport of proteins.
* Regulation of protein localization: It also acts upstream or within the process of regulating protein localization within the cell.
* Antiviral activity: Research indicates that RABGAP1L can potentiate the antiviral action of interferon (IFN) against various viruses, including influenza A virus (IAV), by disrupting endosomal function and limiting viral entry into cells.
* Cell-autonomous immunity: RABGAP1L plays a role in cell-autonomous immunity by modulating the activity of Rab7A and Rab10 during Group A Streptococcus (GAS) infection, thereby influencing both selective autophagy and bacterial expulsion from infected cells.
* Polarized trafficking and cell migration: In conjunction with ANK2, RABGAP1L is involved in the polarized recycling of the fibronectin receptor ITGA5 ITGB1 to the plasma membrane, a process crucial for continuous directional cell migration.

Localization
RABGAP1L is found in several cellular compartments, including the Golgi apparatus, cilium, and early endosomes.

Associated diseases and conditions
* Cholesteatoma: RABGAP1L has been associated with congenital cholesteatoma.
* Systemic lupus erythematosus (SLE): Deletion variants of RABGAP1L have been linked to SLE in Korean women, suggesting a potential role in immune cell regulation and disease susceptibility.
* Alzheimer's disease (AD): Reduced expression of the KIAA0471 gene (now recognized as RABGAP1L) has been observed in the brains of patients with advanced AD, suggesting a potential involvement in neuroprotection and neuronal integrity.
* Cancer: RABGAP1L is also associated with certain types of cancer, including neuroblastoma, pancreatic cancer, and sarcoma.

Related pathways
RABGAP1L is connected to various signaling pathways, including those involving p38MAPK, interleukin 12 complex, and nuclear factor-kappaB. It also plays a role in pathways related to endosomal sorting, maturation, and trafficking.

In conclusion, RABGAP1L is a crucial protein involved in diverse cellular processes, including membrane trafficking, immune responses, and potentially neuroprotection. Its dysregulation has been implicated in various diseases, including cholesteatoma, SLE, Alzheimer's disease, and certain cancers. Further research into RABGAP1L could lead to a deeper understanding of these conditions and the development of novel therapeutic strategies.
 
Other s4me threads mentioning this gene
forestglip

Thread 'Immunological drivers and potential novel drug targets for major psychiatric, neurodevelopmental, and neurodegenerative conditions, 2025, Dardani+'

Immunological drivers and potential novel drug targets for major psychiatric, neurodevelopmental, and neurodegenerative conditions

Christina Dardani, Jamie W. Robinson, Hannah J. Jones, Dheeraj Rai, Evie Stergiakouli, Jakob Grove, Renee Gardner, Andrew M. McIntosh, Alexandra Havdahl, Gibran Hemani, George Davey Smith, Tom G. Richardson, Tom R. Gaunt & Golam M. Khandaker

[Line breaks added]

Abstract
Immune dysfunction is implicated in the aetiology of psychiatric, neurodevelopmental, and neurodegenerative conditions, but the issue of causality remains unclear impeding...
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I am sceptical of implicating these genes in handling the trigger infection. Many of us have had nasty infections of one sort or another. I had very bad EBV, needing oral steroids. But long term I was fine. I don't get the impression that people with ME/CFS have a particularly unusual history in relation to infections. Some people have infections that nearly kill them and do fine, some have rather trivial infections and get ME/CFS.

My guess is that it is much more likely that a gene like this is relevant to some ongoing signalling process once the ME/CFS has got started, and like the transferrin receptor it seems to be something that gets busy when immune cells are primed to sniff around a bit more.
 
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