Genetics: Chromosome 12: SUDS3, TAOK3

Hutan

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CHROMOSOME 12 (GWAS-2)
Chr12 contained three Tier 1 genes.

Image of the 2025 DecodeME results by @ME/CFS Science Blog:
1758826778973.png


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SUDS3 (Tier 1)

• Protein: SIN3A corepressor complex component, also known as SDS3. UniProt. GeneCards.
The allele that increases the risk of ME/CFS is associated with increased SUDS3 expression.7

• Molecular function: Regulatory protein that represses transcription and augments histone deacetylase activity of HDAC1 (UniProt). SUDS3 alters expression of the upstream kinase, ASK1, in the p38 MAPK pathway cascade (44).

• Cellular function: Chromatin remodeling and transcriptional regulation. Depletion of mouse Suds3 reveals an essential role in early lineage specification (45).

• Link to disease: Proposed to contribute to the microglial inflammatory response (44).

• Potential relevance to ME/CFS: Unclear, but potentially to neuroinflammation.

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References
7. Johnson BS, Farkas D, El-Mergawy R, Adair JA, Elhance A, Eltobgy M, et al. Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses. Nat Commun. 2024 Dec 1;15(1).

44. Shen J, Lai W, Li Z, Zhu W, Bai X, Yang Z, et al. SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway. Inflamm Res. 2024 Sep;73(9):1547–64.
(note SDS3 is an earlier name for SUDS3)

45. Zhang K, Dai X, Wallingford MC, Mager J. Depletion of Suds3 reveals an essential role in early lineage specification. Dev Biol. 2013 Jan 15;373(2):359–72.
 
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No mentions of SUDS3 or SDS3 on the forum as yet, however

Other mentions of HDAC1 on the forum





 
HDAC1 was a significant hit in the Zhang study, no?

[Edit: ah sorry that was already mentioned above. I think it's interesting to see a few hits between studies on general epigenetic regulation, which might provide hints for findings in cultured cells, which are more likely to be reflective of epigenetic changes that persist in culture]
 
Copying @ME/CFS Science Blog's post on this region and TAOK3 here and also into the first post:
A gene that hasn't been disucssed much is TAOK3 on chromosome 12 (it wasn't a Tier 1 gene). It has been previously been associated with Lupus at around the same region as in DecodeME. The vertical dotted line in the graph below shows the location for the Lupus hit (12:118244946) with the SNP summary data from DecodeME.


1758826778973.png


The Lupus GWAS said this about it:
We also identified a missense variant in TAOK3 (the gene for tau kinase 3) as the top association signal in this locus. The risk allele (rs428073-T) substitutes the 47th amino acid of TAOK3 fromserine to asparagine (S47N), whose functional role remains unknown. S47 is located at the loop region between strands β2and β3, and the substitution should not change the overall strucure of the protein, despite being well conserved among orthologous proteins during evolutionary courses (SupplementaryFigure 10, on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42021). Taok3 plays animportant role in DNA damage–induced activation of the p38/MAPK14 stress-activated MAPK cascade. It enhances T cell receptor signaling by regulating its negative feedback by SH2domain–containing phosphatase 1 (44), and Taok3 deficiency in mice was found to cause defects in the development of marginalzone B cells but not follicular B cells (45).
Identification of Shared and Asian-Specific Loci for Systemic Lupus Erythematosus and Evidence for Roles of Type III Interferon Signaling and Lysosomal Function in the Disease: A Multi-Ancestral Genome-Wide Association Study - PubMed
In this study both shared and Asian-specific loci for SLE were identified, and functional annotation provided evidence of the involvement of increased type III IFN signaling and reduced lysosomal function in SLE.
pubmed.ncbi.nlm.nih.gov
pubmed.ncbi.nlm.nih.gov
 
"It enhances T cell receptor signaling by regulating its negative feedback by SH2domain–containing phosphatase 1 (44), and Taok3 deficiency in mice was found to cause defects in the development of marginalzone B cells but not follicular B cells (45)."

Intriguing. An influence on SHIP1 would make some sense. Marginal zone B cell behaviour is odd in lupus too.
 
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Interesting, so it seems like this is another case where the final annotation for DecodeME was chosen based on high number of color tissues. The top SNP is within an intronic region in DecodeME, and seems to be quite a long deletion. The mutation in the lupus paper you posted was in a protein-coding region which might explain stronger effect of the mutation.

Also, interesting that 3 proteins in that whole region that looks to be in LD have well-established links to MAPK signaling (SUDS3, TAOK3, and PEBP1)
 
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