Affinage

THOC6

THO complex subunit 6 · UniProt Q86W42

Length
341 aa
Mass
37.5 kDa
Annotated
2026-06-10
12 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

THOC6 is a WD-repeat subunit of the THO/TREX complex that supports nuclear mRNA biogenesis and is essential for proper mRNA processing in mammalian tissues (PMID:23621916, PMID:38388531). Within TREX, THOC6 is critical for assembly of the higher-order tetramer composed of four six-subunit THO monomers: it physically associates with the THO subunits THOC1 and THOC5 (PMID:30476144), and its loss reduces the binding affinity of ALYREF to THOC5 (PMID:38388531). Rather than impairing bulk nuclear mRNA export, biallelic loss-of-function disrupts TREX tetramer assembly and produces mRNA mis-splicing in neural tissue, defining a processing role distinct from export (PMID:38388531). Disease-associated missense variants (e.g., Gly46Arg, Trp100Arg, Val234Leu, Gly275Asp, Gly190Glu) displace THOC6 from the nucleus to the cytoplasm and disrupt its interactions with THOC1 and THOC5, establishing THOC6 dysfunction as the basis of an inherited intellectual-disability syndrome (TIDS) (PMID:23621916, PMID:30476144, PMID:38388531). In cardiomyocyte models, THOC6 loss reduces proliferation, increases apoptosis, and lowers expression of contractile and structural proteins including type I collagen, cardiac α-actin 1, and β-tubulin, with disrupted sarcomeric organization (PMID:41967792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2013 Medium

    Established that THOC6 normally resides in the nucleus as part of the THO/TREX complex and that a disease mutation mislocalizes it, linking loss of nuclear function to a cellular phenotype.

    Evidence Immunofluorescence localization of wild-type versus p.Gly46Arg mutant and siRNA knockdown with apoptosis readout in cultured cells

    PMID:23621916

    Open questions at the time
    • Did not identify the molecular interactions THOC6 mediates within TREX
    • Mechanism connecting mislocalization to apoptosis not defined
    • No tissue-level or processing phenotype assessed
  2. 2019 Medium

    Defined the molecular consequence of pathogenic variants by showing they disrupt THOC6 interactions with THO subunits THOC1 and THOC5 in addition to altering nuclear localization.

    Evidence Co-immunoprecipitation and localization assays across multiple disease missense variants in a single lab

    PMID:30476144

    Open questions at the time
    • Did not establish the functional output of disrupted THO interactions
    • Effect on mRNA fate (export vs. processing) not tested
    • No higher-order complex assembly characterized
  3. 2024 High

    Resolved the core mechanism by showing THOC6 is required for TREX tetramer assembly and mediates ALYREF–THOC5 binding, and that its loss causes mRNA mis-splicing rather than nuclear export failure.

    Evidence Human and mouse TIDS models with binding affinity assays, RNA nuclear export assays (negative), and RNA-seq mis-splicing analysis in neural tissue, including a biallelic Thoc6 LOF mouse

    PMID:37720017 PMID:38388531

    Open questions at the time
    • Specific mis-spliced transcripts driving neural pathology not enumerated
    • Structural basis of THOC6's role in tetramer formation not resolved
    • How impaired tetramer assembly mechanistically alters splice site selection unclear
  4. 2026 Medium

    Extended THOC6 function beyond neural tissue by showing its loss compromises cardiomyocyte survival and contractile/structural protein expression, implicating sarcomeric integrity.

    Evidence CRISPR/Cas9 knockout in H9C2 and hiPSC-derived cardiomyocytes with RNA-seq and protein validation

    PMID:41967792

    Open questions at the time
    • Whether contractile gene changes arise through TREX-dependent splicing not established
    • Causal link between protein changes and sarcomeric disruption not dissected
    • In vivo cardiac relevance not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how THOC6-dependent TREX tetramer assembly mechanistically governs splice-site selection and which target transcripts mediate tissue-specific phenotypes.
  • No structural model of THOC6 within the TREX tetramer
  • Effector mis-spliced transcripts driving neural and cardiac disease unidentified
  • Mechanistic coupling between tetramer assembly and spliceosome function undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 1
Partners
ALYREFTHOC1THOC5
Complex memberships
THO complexTREX complex

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Wild-type THOC6 localizes to the nucleus as part of the THO/TREX complex, while the disease-associated p.Gly46Arg mutant is predominantly cytoplasmic, indicating the mutation disrupts normal nuclear import or retention. siRNA knockdown of THOC6 increased apoptosis in cultured cells. Cellular localization studies (immunofluorescence), siRNA knockdown with apoptosis readout Orphanet journal of rare diseases Medium 23621916
2019 Disease-associated missense variants in THOC6 (including Trp100Arg, Val234Leu, Gly275Asp, Gly190Glu) alter the physiological nuclear localization of the THOC6 protein and disrupt its interaction with at least two THO complex subunits, THOC1 and THOC5. Co-immunoprecipitation (interaction studies), cellular localization assays, protein expression analysis Human molecular genetics Medium 30476144
2024 THOC6 is critical for mammalian TREX tetramer formation (composed of four six-subunit THO monomers). Biallelic loss-of-function THOC6 variants reduce the binding affinity of ALYREF to THOC5 without affecting overall TREX member protein expression or localization, implicating impaired TREX tetramer assembly. Defects in RNA nuclear export were not detected; instead, mRNA mis-splicing was observed in human and mouse neural tissue, revealing a THOC6-mediated TREX role in mRNA processing distinct from nuclear export. Human and mouse TIDS model systems, co-immunoprecipitation/binding affinity assays (ALYREF–THOC5 interaction), RNA nuclear export assays (negative for export defects), RNA-seq mis-splicing analysis in neural tissue, germline biallelic Thoc6 LOF mouse model Nature communications High 38388531
2023 Biallelic THOC6 LOF variants do not influence expression or localization of TREX members in human cells but reduce ALYREF binding affinity. Nuclear mRNA export is not impaired; instead, mRNA mis-splicing occurs in neural tissue, indicating THOC6-mediated TREX tetramer function is primarily in mRNA processing rather than export. Human cell LOF models, co-immunoprecipitation (ALYREF binding), RNA nuclear export assays, RNA-seq splicing analysis Research squarepreprint Medium 37720017
2026 THOC6 knockout in H9C2 cardiomyocytes reduces cell proliferation and increases apoptosis. THOC6 KO alters expression of type I collagen (COL1A1, COL1A2) and cardiac α-actin 1. In hiPSC-derived cardiomyocytes, THOC6 KO leads to hypertrophic and dilated cardiomyopathy phenotypic features including disrupted sarcomeric organization and reduced COL1A2 and β-tubulin expression. CRISPR/Cas9 knockout in H9C2 cardiomyocytes and hiPSC-CMs, RNA-seq, protein-protein interaction analysis, experimental validation of target protein expression Experimental cell research Medium 41967792

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Intellectual disability associated with a homozygous missense mutation in THOC6. Orphanet journal of rare diseases 46 23621916
2016 Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping. Clinical genetics 26 27102954
2019 Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. Human molecular genetics 21 30476144
2024 TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome. Nature communications 9 38388531
2022 Biallelic THOC6 pathogenic variants: Prenatal phenotype and review of the literature. Birth defects research 8 35426486
2020 The first reported case of Beaulieu-Boycott-Innes syndrome caused by two novel mutations in THOC6 gene in a Chinese infant. Medicine 8 32282736
2019 First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India. European journal of medical genetics 7 31421288
2022 A truncating variant in the THOC6 gene with new findings in a patient with Beaulieu-Boycott-Innes syndrome. American journal of medical genetics. Part A 4 35084103
2024 THOC6 is a novel biomarker of glioma and a target of anti-glioma drugs: An analysis based on bioinformatics and molecular docking. Medicine 1 38728502
2026 THOC6 deficiency leads to cardiomyopathy by reducing myocardial contractile proteins in cardiomyocytes. Experimental cell research 0 41967792
2025 Expanding the phenotypic spectrum of Beaulieu-Boycott-Innes syndrome: A case report of a novel THOC6 gene mutation associated with ambiguous genitalia and disorders of sexual development. Medicine 0 40760536
2023 Mechanisms of mRNA processing defects in inherited THOC6 intellectual disability syndrome. Research square 0 37720017

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