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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
TUSC3
tumor suppressor candidate 3
Chromosome 8 Β· 8p22
NCBI Gene: 7991Ensembl: ENSG00000104723.21HGNC: HGNC:30242UniProt: D6RA37
70PubMed Papers
21Diseases
0Drugs
20Pathogenic Variants
FUNCTIONAL ROLE
Transporter
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
magnesium ion transportoligosaccharyltransferase complexprotein N-linked glycosylationcognitionautosomal recessive non-syndromic intellectual disabilitydengue diseaseIntellectual disabilitygenetic disorder
✦AI Summary

TUSC3 is a multifunctional protein operating at the intersection of protein glycosylation and magnesium homeostasis with significant implications for both developmental and neoplastic disease. As an accessory subunit of the endoplasmic reticulum oligosaccharyl transferase (OST) complex, TUSC3 catalyzes N-linked glycosylation of specific protein substrates 1, particularly those with acceptor sites near cysteine residues where it forms transient mixed disulfides to facilitate glycosylation 1. Beyond its oxidoreductase function, TUSC3 critically regulates ER magnesium homeostasis through complex formation with ERMA, a mechanism essential for neuronal function and synaptic integrity 2. Dysfunction of TUSC3 manifests distinct phenotypes depending on tissue context. Loss of TUSC3 causes autosomal recessive intellectual disability through ER Mg²⁺ depletion and PERK-eIF2α pathway activation, leading to impaired learning, memory, and social behavior 2. In hepatocellular carcinoma, TUSC3 downregulation paradoxically promotes epithelial-mesenchymal transition and tumor progression via the LIPC/AKT axis 3, whereas in colorectal cancer, increased TUSC3 expression drives oncogenic signaling through WNT/β-catenin and MAPK pathways 4. Biliary atresia susceptibility involves TUSC3 variants affecting ciliogenesis 5. These tissue-specific roles suggest TUSC3 represents a functionally dual gene with context-dependent tumor suppressive and tumor-promoting activities. Magnesium supplementation shows therapeutic promise for TUSC3-associated intellectual disability 2, and epigenetic activation of TUSC3 may treat XMEN disease 6.

Sources cited
1
TUSC3 possesses an ER-luminal thioredoxin domain that forms transient mixed disulfides with substrates and increases glycosylation efficiency for specific glycoproteins
PMID: 24685145
2
TUSC3 is essential for ER Mg²⁺ homeostasis through complex formation with ERMA; loss causes ER Mg²⁺ depletion, PERK-eIF2α activation, and ID-like phenotypes including learning/memory impairment
PMID: 41203647
3
TUSC3 downregulation in hepatocellular carcinoma promotes EMT and tumor progression through the LIPC/AKT signaling axis
PMID: 36274132
4
TUSC3 overexpression in colorectal cancer drives EMT, proliferation, migration, and invasion through MAPK, PI3K/Akt, and Wnt/Ξ²-catenin signaling
PMID: 27071482
5
TUSC3 variants are associated with biliary atresia susceptibility through effects on ciliogenesis and planar polarity
PMID: 37572794
6
Epigenetic activation of TUSC3 expression by decitabine and panobinostat rescues immune and metabolic deficiencies in XMEN disease models
PMID: 37086924
Disease Associationsβ“˜21
autosomal recessive non-syndromic intellectual disabilityOpen Targets
0.64Moderate
dengue diseaseOpen Targets
0.50Moderate
Intellectual disabilityOpen Targets
0.50Moderate
genetic disorderOpen Targets
0.49Moderate
Abnormality of the skeletal systemOpen Targets
0.44Moderate
COVID-19Open Targets
0.37Weak
conduction system disorderOpen Targets
0.32Weak
intelligenceOpen Targets
0.30Weak
ovarian neoplasmOpen Targets
0.29Weak
Abnormality of the nervous systemOpen Targets
0.27Weak
body weight gainOpen Targets
0.26Weak
kidney diseaseOpen Targets
0.26Weak
placenta praeviaOpen Targets
0.25Weak
self-injurious ideationOpen Targets
0.25Weak
asthmaOpen Targets
0.24Weak
HypercalcemiaOpen Targets
0.24Weak
nervous system benign neoplasmOpen Targets
0.24Weak
spinal cord injuryOpen Targets
0.24Weak
squamous cell carcinomaOpen Targets
0.23Weak
intracerebral hemorrhageOpen Targets
0.20Weak
Intellectual developmental disorder, autosomal recessive 7UniProt
Pathogenic Variants20
NM_006765.4(TUSC3):c.529C>T (p.Gln177Ter)Pathogenic
Inborn genetic diseases|Intellectual disability, autosomal recessive 7
β˜…β˜…β˜†β˜†2025β†’ Residue 177
NM_006765.4(TUSC3):c.420dup (p.Gln141fs)Pathogenic
Intellectual disability, autosomal recessive 7
β˜…β˜…β˜†β˜†2025β†’ Residue 141
NM_006765.4(TUSC3):c.992C>A (p.Ser331Ter)Pathogenic
not provided|Intellectual disability, autosomal recessive 7|Intellectual disability|Intellectual disability, autosomal recessive 24|Inborn genetic diseases
β˜…β˜…β˜†β˜†2025β†’ Residue 331
NM_006765.4(TUSC3):c.279dup (p.Gln94fs)Pathogenic
not provided|Intellectual disability, autosomal recessive 7
β˜…β˜…β˜†β˜†2025β†’ Residue 94
NM_006765.4(TUSC3):c.220C>T (p.Arg74Ter)Likely pathogenic
Intellectual disability, autosomal recessive 7|not provided
β˜…β˜…β˜†β˜†2023β†’ Residue 74
NM_006765.4(TUSC3):c.286C>T (p.Gln96Ter)Likely pathogenic
Intellectual disability, autosomal recessive 7
β˜…β˜†β˜†β˜†2025β†’ Residue 96
NM_006765.4(TUSC3):c.199C>T (p.Arg67Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2024β†’ Residue 67
NM_006765.4(TUSC3):c.567+1G>CPathogenic
Intellectual disability, autosomal recessive 7
β˜…β˜†β˜†β˜†2024
NM_006765.4(TUSC3):c.55_69delinsGC (p.Tyr19fs)Likely pathogenic
Intellectual disability, autosomal recessive 7
β˜…β˜†β˜†β˜†2022β†’ Residue 19
NM_006765.4(TUSC3):c.244C>T (p.Arg82Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2022β†’ Residue 82
NM_006765.4(TUSC3):c.568-2A>GLikely pathogenic
Intellectual disability, autosomal recessive 7
β˜…β˜†β˜†β˜†2022
NM_006765.4(TUSC3):c.1028G>C (p.Ser343Thr)Pathogenic
Intellectual disability, autosomal recessive 7|not provided
β˜…β˜†β˜†β˜†2021β†’ Residue 343
NM_006765.4(TUSC3):c.163C>T (p.Gln55Ter)Likely pathogenic
Intellectual disability, autosomal recessive 7|Abnormality of the nervous system
β˜…β˜†β˜†β˜†2021β†’ Residue 55
Single allelePathogenic
Intellectual disability, autosomal recessive 7
β˜…β˜†β˜†β˜†2018
NM_006765.4(TUSC3):c.938-8_939delLikely pathogenic
Inborn genetic diseases
β˜…β˜†β˜†β˜†2017
NM_006765.4(TUSC3):c.327T>A (p.Tyr109Ter)Likely pathogenic
Intellectual disability, autosomal recessive 7
β˜…β˜†β˜†β˜†β†’ Residue 109
NM_006765.4(TUSC3):c.119dup (p.Gly41fs)Likely pathogenic
Intellectual disability, autosomal recessive 7
β˜†β˜†β˜†β˜†2023β†’ Residue 41
NM_006765.4(TUSC3):c.225del (p.Lys75fs)Pathogenic
Intellectual disability, autosomal recessive 7
β˜†β˜†β˜†β˜†2022β†’ Residue 75
NM_006765.4(TUSC3):c.786dup (p.Asn263fs)Pathogenic
Intellectual disability, autosomal recessive 7
β˜†β˜†β˜†β˜†2008β†’ Residue 263
NM_006765.4(TUSC3):c.714A>G (p.Ile238Met)Likely pathogenic
Intellectual disability
β˜†β˜†β˜†β˜†β†’ Residue 238
View on ClinVar β†—
Related Genes
MOGSProtein interaction100%PDGFRLProtein interaction96%DOLPP1Protein interaction95%ALG10BProtein interaction94%CRBNProtein interaction92%ALG10Protein interaction90%
Tissue Expression6 tissues
Heart
100%
Ovary
66%
Brain
49%
Lung
16%
Liver
8%
Bone Marrow
1%
Gene Interaction Network
Click a node to explore
TUSC3MOGSPDGFRLDOLPP1ALG10BCRBNALG10
PROTEIN STRUCTURE
Preparing viewer…
PDB4M91 Β· 1.10 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
1.31LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF1.01 [0.79–1.31]
RankingsWhere TUSC3 stands among ~20K protein-coding genes
  • #6,774of 20,598
    Most Researched70
  • #2,193of 5,498
    Most Pathogenic Variants20
  • #13,774of 17,882
    Most Constrained (LOEUF)1.31
Genes detectedTUSC3
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
TUSC3: a novel tumour suppressor gene and its functional implications.
PMID: 28272772
J Cell Mol Med Β· 2017
1.00
2
TUSC3: functional duality of a cancer gene.
PMID: 28929175
Cell Mol Life Sci Β· 2018
0.90
3
Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes.
PMID: 37572794
J Hepatol Β· 2023
0.80
4
PMID: 20301507
0.70
5
Downregulation of TUSC3 promotes EMT and hepatocellular carcinoma progression through LIPC/AKT axis.
PMID: 36274132
J Transl Med Β· 2022
0.60