TUSC3

Summary

TUSC3 (tumor suppressor candidate 3, HGNC:30242) is a protein-coding gene on chromosome 8p22, encoding Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit TUSC3 (Q13454). Acts as accessory component of the N-oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains.

This gene encodes a protein that has been associated with several biological functions including cellular magnesium uptake, protein glycosylation and embryonic development. This protein localizes to the endoplasmic reticulum and acts as a component of the oligosaccharyl transferase complex which is responsible for N-linked protein glycosylation. This gene is a candidate tumor suppressor gene. Homozygous mutations in this gene are associated with autosomal recessive nonsyndromic mental retardation-7 and in the proliferation and invasiveness of several cancers including metastatic pancreatic cancer, ovarian cancer and glioblastoma multiform.

Source: NCBI Gene 7991 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 337 total — 13 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 6
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_006765

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30242
Approved symbol	TUSC3
Name	tumor suppressor candidate 3
Location	8p22
Locus type	gene with protein product
Status	Approved
Aliases	MGC13453, N33, OST3A, MRT7, MagT2, SLC58A2
Ensembl gene	ENSG00000104723
Ensembl biotype	protein_coding
OMIM	601385
Entrez	7991

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 10 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000382020, ENST00000503191, ENST00000503731, ENST00000506802, ENST00000507316, ENST00000507400, ENST00000508446, ENST00000509177, ENST00000509380, ENST00000510836, ENST00000511342, ENST00000511783, ENST00000515859, ENST00000877722, ENST00000928815, ENST00000947282, ENST00000947283

RefSeq mRNA: 27 — MANE Select: NM_006765 NM_001356429, NM_001413583, NM_001413669, NM_001413670, NM_001413671, NM_001413672, NM_001413673, NM_001413674, NM_001413675, NM_001413676, NM_001413677, NM_001413678, NM_001413679, NM_001413680, NM_001413681, NM_001413682, NM_001413683, NM_001413684, NM_001413685, NM_001413686, NM_001413687, NM_001413688, NM_001413689, NM_001413690, NM_001413691, NM_006765, NM_178234

CCDS: CCDS5993, CCDS5994

Canonical transcript exons

ENST00000503731 — 11 exons

Exon	Start	End
ENSE00001795990	15730666	15730729
ENSE00002074386	15764203	15766638
ENSE00002086163	15540263	15540568
ENSE00003482270	15623080	15623249
ENSE00003486036	15659507	15659647
ENSE00003530913	15673747	15673836
ENSE00003583188	15650697	15650814
ENSE00003584450	15662156	15662296
ENSE00003597281	15743538	15743612
ENSE00003619733	15757791	15757855
ENSE00003671211	15748375	15748465

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 99.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 53.8010 / max 530.7366, expressed in 1455 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87506	50.6655	1446
87505	2.4261	1117
87504	0.7094	198

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	99.05	gold quality
cortical plate	UBERON:0005343	98.74	gold quality
stromal cell of endometrium	CL:0002255	98.71	gold quality
adrenal tissue	UBERON:0018303	98.70	gold quality
islet of Langerhans	UBERON:0000006	98.43	gold quality
bronchial epithelial cell	CL:0002328	98.30	gold quality
right adrenal gland cortex	UBERON:0035827	97.83	gold quality
right adrenal gland	UBERON:0001233	97.75	gold quality
adenohypophysis	UBERON:0002196	97.67	gold quality
pituitary gland	UBERON:0000007	97.66	gold quality
epithelium of bronchus	UBERON:0002031	97.63	gold quality
left adrenal gland	UBERON:0001234	97.58	gold quality
ventricular zone	UBERON:0003053	97.46	gold quality
left adrenal gland cortex	UBERON:0035825	97.41	gold quality
adrenal cortex	UBERON:0001235	97.36	gold quality
bronchus	UBERON:0002185	97.32	gold quality
adrenal gland	UBERON:0002369	97.23	gold quality
ganglionic eminence	UBERON:0004023	97.09	gold quality
corpus epididymis	UBERON:0004359	97.04	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.04	gold quality
embryo	UBERON:0000922	96.63	gold quality
right uterine tube	UBERON:0001302	96.15	gold quality
smooth muscle tissue	UBERON:0001135	95.88	gold quality
placenta	UBERON:0001987	95.60	gold quality
left ovary	UBERON:0002119	95.51	gold quality
periodontal ligament	UBERON:0008266	95.41	gold quality
prefrontal cortex	UBERON:0000451	94.81	gold quality
heart right ventricle	UBERON:0002080	94.59	gold quality
nucleus accumbens	UBERON:0001882	94.48	gold quality
ovary	UBERON:0000992	94.46	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	127.68
E-MTAB-3929	yes	83.98
E-HCAD-31	yes	30.06
E-HCAD-13	yes	24.42
E-ANND-3	yes	10.62
E-GEOD-125970	yes	8.50
E-CURD-112	yes	3.88
E-MTAB-5061	no	989.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

110 targeting TUSC3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4503	99.85	71.45	1869

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 33)

• Down regulated in ovarian cancer or absent in ovarian cancer and impact survival. (PMID:16270321)
• N33, STK11 (19p13) and TP53 might play a role in the development of metastasis in larynx and pharynx squamous cell carcinomas. (PMID:17641416)
• TUSC3 is only the fifth gene implicated in NS-ARMR and the first for which mutations have been reported in more than one family. (PMID:18452889)
• study shows that mutations in two OTase-subunit genes, N33/TUSC3 and IAP result in autosomal-recessive nonsyndromic mental retardation (PMID:18455129)
• Knockdown of either MagT1 or TUSC3 protein significantly lowers the total and free intracellular Mg(2+) concentrations in cell lines. (PMID:19717468)
• These findings suggest that inactivation through methylation of the putative tumor suppressor genes N-33 may not be associated with colorectal carcinogenesis in UC. (PMID:20505342)
• analysis of a novel deletion mutation in the TUSC3 gene in a consanguineous Pakistani family that may have a role in autosomal recessive nonsyndromic intellectual (PMID:21513506)
• Genotyping and linkage analysis excluded linkage of the GRIK2 gene and TUSC3 gene with mental retardation. (PMID:21557188)
• A novel nonsense mutation in TUSC3 is responsible for non-syndromic autosomal recessive mental retardation (PMID:21739581)
• TUSC3 is a tumor suppressor gene in ovarian cancer. (PMID:23404293)
• Homozygous deletion in TUSC3 causes syndromic intellectual disability. (PMID:23825019)
• TUSC3 loss alters the ER stress response and accelerates prostate cancer growth in vivo (PMID:24435307)
• TUSC3 increases glycosylation efficiency for a subset of human glycoproteins by slowing glycoprotein folding. (PMID:24685145)
• IGFII and N33 methylation status may be related to gastric carcinogenesis. (PMID:25086101)
• Loss of TUSC3 alters the molecular response to endoplasmic reticulum stress. (PMID:25735931)
• The TUSC3 gene is associated with mental retardation in the Qinba mountain area in China; the sixth exon of the TUSC3 gene may contribute to the risk of developing the disease. (PMID:25966277)
• Report frequencies of short tandem repeat markers linked to TUSC3 (MRT7) or NSUN2 (MRT5) genes used for homozygosity mapping of recessive intellectual disability. (PMID:26427135)
• decreased immunological TUSC3 staining is a factor prognostic of poor survival in pancreatic cancer patients. (PMID:26871953)
• This paper supports the previous clinical descriptions of the condition caused by TUSC3 mutations and describes the seventh family with mutations in this gene, thus contributing to the genetic spectrum of mutations. This is the first report of a family from the Arabian peninsula with this form of Intellectual disability . (PMID:27148795)
• TUSC3 regulates proliferation and invasion of glioblastoma cells by inhibiting the activity of the Akt signaling pathway. (PMID:27177902)
• Decreased Tumor Suppressor Candidate 3 Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma (PMID:27994502)
• SOX2 regulates the proliferation, migration and invasiveness of breast cancer cells through miR-181a-5p and miR-30e-5p which modulate TUSC3 protein levels (PMID:28288641)
• miR-UL112-3p exerts its oncogene function by directly targeting TUSC3 in Glioblastoma. (PMID:28303930)
• study demonstrated an oncogenic role of TUSC3 in Non-small cell lung cancer and showed that dis-regulation of TUSC3 may affect tumour cell invasion and migration through possible involvement in the Hedgehog (Hh) signalling pathway. (PMID:28487226)
• TUSC3 can function both as an oncogene and as a tumor suppressor. (Review) (PMID:28929175)
• TUSC3 accelerates cancer growth and induces the epithelial-mesenchymal transition in non-small-cell lung cancer cells by upregulating claudin-1. (PMID:30098333)
• TUSC3 may act as an oncogene in the progression of colorectal cancer. (PMID:30115537)
• UHRF1-KAT7-mediated regulation of TUSC3 expression via histone methylation/acetylation is critical for the proliferation of colon cancer cells. (PMID:31582837)
• Tumour suppressor candidate 3 inhibits biological function and increases endoplasmic reticulum stress of melanoma cells WM451 by regulating AKT/GSK3-beta/beta-catenin pathway. (PMID:32090352)
• TUSC3 induces drug resistance and cellular stemness via Hedgehog signaling pathway in colorectal cancer. (PMID:32338281)
• Concentrations of persistent organic pollutants in maternal plasma and epigenome-wide placental DNA methylation. (PMID:32653021)
• TUSC3 inhibits cell proliferation and invasion in cervical squamous cell carcinoma via suppression of the AKT signalling pathway. (PMID:35137520)
• Downregulation of TUSC3 promotes EMT and hepatocellular carcinoma progression through LIPC/AKT axis. (PMID:36274132)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tusc3	ENSDARG00000078854
mus_musculus	Tusc3	ENSMUSG00000118664
rattus_norvegicus	Tusc3	ENSRNOG00000013061
drosophila_melanogaster	Ostgamma	FBGN0032015
caenorhabditis_elegans		WBGENE00022793

Paralogs (1): MAGT1 (ENSG00000102158)

Protein

Protein identifiers

Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit TUSC3 — Q13454 (reviewed: Q13454)

Alternative names: Magnesium uptake/transporter TUSC3, Protein N33, Tumor suppressor candidate 3

All UniProt accessions (5): A0A0A0MTC2, D6RA37, D6RDV0, D6RIY7, Q13454

UniProt curated annotations — full annotation on UniProt →

Function. Acts as accessory component of the N-oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains. Involved in N-glycosylation of STT3B-dependent substrates. Specifically required for the glycosylation of a subset of acceptor sites that are near cysteine residues; in this function seems to act redundantly with MAGT1. In its oxidized form proposed to form transient mixed disulfides with a glycoprotein substrate to facilitate access of STT3B to the unmodified acceptor site. Also has oxidoreductase-independent functions in the STT3B-containing OST complex possibly involving substrate recognition. Could indirectly play a role in Mg(2+) transport.

Subunit / interactions. Accessory component of the STT3B-containing form of the oligosaccharyltransferase (OST) complex. OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits. OST can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes. The association of TUSC3 or MAGT1 with the STT3B-containing complex seems to be mutually exclusvice.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in most non-lymphoid cells and tissues examined, including prostate, lung, liver, colon, heart, kidney and pancreas.

Disease relevance. Intellectual developmental disorder, autosomal recessive 7 (MRT7) [MIM:611093] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the OST3/OST6 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13454-1	1	yes
Q13454-2	2

RefSeq proteins (27): NP_001343358, NP_001400512, NP_001400598, NP_001400599, NP_001400600, NP_001400601, NP_001400602, NP_001400603, NP_001400604, NP_001400605, NP_001400606, NP_001400607, NP_001400608, NP_001400609, NP_001400610, NP_001400611, NP_001400612, NP_001400613, NP_001400614, NP_001400615, NP_001400616, NP_001400617, NP_001400618, NP_001400619, NP_001400620, NP_006756, NP_839952 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021149	MAGT1/OST3/OST6	Family
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF04756

UniProt features (32 total): helix 8, topological domain 5, strand 5, transmembrane region 4, sequence variant 2, mutagenesis site 2, signal peptide 1, chain 1, domain 1, disulfide bond 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4M91	X-RAY DIFFRACTION	1.1
4M90	X-RAY DIFFRACTION	1.6
4M92	X-RAY DIFFRACTION	1.6
4M8G	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13454-F1	84.78	0.56

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (1): 99–102

Mutagenesis-validated functional residues (2):

Position	Phenotype
99	reduces n-glycosylation of cysteine-proximal acceptor sites; when associated with s-102.
102	reduces n-glycosylation of cysteine-proximal acceptor sites; when associated with s-99.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5223345	Miscellaneous transport and binding events
R-HSA-9694548	Maturation of spike protein
R-HSA-9918432	Maturation of DENV proteins
R-HSA-9931295	PD-L1(CD274) glycosylation and translocation to plasma membrane

MSigDB gene sets: 184 (showing top): RNGTGGGC_UNKNOWN, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_COGNITION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, BECKER_TAMOXIFEN_RESISTANCE_UP, KEGG_N_GLYCAN_BIOSYNTHESIS, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, MODULE_453, GOBP_MAGNESIUM_ION_TRANSPORT, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, MODULE_66

GO Biological Process (7): protein N-linked glycosylation (GO:0006487), magnesium ion transport (GO:0015693), obsolete protein N-linked glycosylation via asparagine (GO:0018279), cognition (GO:0050890), transmembrane transport (GO:0055085), magnesium ion transmembrane transport (GO:1903830), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (1): magnesium ion transmembrane transporter activity (GO:0015095)

GO Cellular Component (6): mitochondrion (GO:0005739), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), oligosaccharyltransferase complex (GO:0008250), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Post-translational protein modification	1
Transport of small molecules	1
Translation of Structural Proteins	1
Dengue Virus Genome Translation and Replication	1
Regulation of PD-L1(CD274) Post-translational modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
intracellular membrane-bounded organelle	2
glycoprotein biosynthetic process	1
metal ion transport	1
nervous system process	1
transport	1
cellular process	1
magnesium ion transport	1
monoatomic cation transmembrane transport	1
metal ion transmembrane transporter activity	1
magnesium ion transmembrane transport	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
transferase complex	1
endomembrane system	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1198 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TUSC3	PDGFRL	Q15198	962
TUSC3	DAD1	P46966	916
TUSC3	DDOST	P39656	880
TUSC3	TMEM258	P61165	876
TUSC3	OST4	P0C6T2	858
TUSC3	STT3B	Q8TCJ2	827
TUSC3	RPN2	P04844	802
TUSC3	RPN1	P04843	797
TUSC3	STT3A	P46977	749
TUSC3	KRTCAP2	Q8N6L1	737
TUSC3	OSTC	Q9NRP0	701
TUSC3	SEC61A1	P38378	483
TUSC3	ALG12	Q9BV10	482
TUSC3	ALG6	Q9Y672	461
TUSC3	ZDHHC2	Q9UIJ5	458

IntAct

48 interactions, top by confidence:

A	B	Type	Score
TUSC3	RPN2	psi-mi:“MI:0914”(association)	0.730
TUSC3		psi-mi:“MI:0915”(physical association)	0.550
MCOLN3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
PEX19	FAM20B	psi-mi:“MI:0914”(association)	0.530
GABRA3	HLA-C	psi-mi:“MI:0914”(association)	0.530
GABRD	ATF6	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
LDLRAD4	WWP2	psi-mi:“MI:0914”(association)	0.530
EVI2B	TUSC3	psi-mi:“MI:0915”(physical association)	0.400
TUSC3	PPP1CA	psi-mi:“MI:0915”(physical association)	0.370
	TMEM223	psi-mi:“MI:0914”(association)	0.350
DDOST	ATL3	psi-mi:“MI:0914”(association)	0.350
CCDC47	ESYT2	psi-mi:“MI:0914”(association)	0.350
OST4	ATL3	psi-mi:“MI:0914”(association)	0.350
RANBP1	RGPD3	psi-mi:“MI:0914”(association)	0.350
RPN2	APBB1	psi-mi:“MI:0914”(association)	0.350
STT3B	APBB1	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CHRNB2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SIDT2	KLRG2	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
NKAIN1	GPR89A	psi-mi:“MI:0914”(association)	0.350
CHRNB4	GPR89A	psi-mi:“MI:0914”(association)	0.350
HTR3C	GET1	psi-mi:“MI:0914”(association)	0.350
SYNE4	GOLIM4	psi-mi:“MI:0914”(association)	0.350

BioGRID (100): TUSC3 (Affinity Capture-MS), TUSC3 (Affinity Capture-MS), TUSC3 (Affinity Capture-MS), TUSC3 (Affinity Capture-MS), RPN2 (Affinity Capture-MS), FAM122B (Affinity Capture-MS), TUSC3 (Affinity Capture-MS), TUSC3 (Affinity Capture-MS), STXBP2 (Affinity Capture-MS), LIN54 (Affinity Capture-MS), TUSC3 (Affinity Capture-MS), TUSC3 (Affinity Capture-MS), TUSC3 (Affinity Capture-MS), STXBP1 (Affinity Capture-MS), NDRG3 (Affinity Capture-MS)

ESM2 similar proteins: A2XSY1, A6QP01, A8WG88, F1QR43, O18756, O35777, O65085, O94923, P51398, P62341, P62342, Q07984, Q0IHY5, Q0JDK9, Q13454, Q1H5H1, Q2M146, Q2TBU2, Q2UF96, Q32L57, Q39080, Q4R5B4, Q58E26, Q5R419, Q5RE31, Q5RF53, Q5XIK2, Q5ZJ06, Q5ZJN8, Q62186, Q63ZR0, Q6DFS0, Q6IQC7, Q6PBD1, Q7TNK0, Q7ZV50, Q802F2, Q8BTV1, Q9CQY5, Q9D710

Diamond homologs: O35777, P34669, Q13454, Q32L57, Q5RE31, Q5ZJ06, Q63ZR0, Q7ZV50, Q8BTV1, Q9CQY5, Q9H0U3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
PD-L1(CD274) glycosylation and translocation to plasma membrane	5	53.0×	2e-06
Maturation of spike protein	5	27.1×	3e-05
Maturation of DENV proteins	6	25.9×	4e-06
Neurotransmitter receptors and postsynaptic signal transmission	7	14.3×	2e-05
Transmission across Chemical Synapses	7	10.9×	9e-05
Asparagine N-linked glycosylation	6	7.4×	3e-03
Neuronal System	7	6.3×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
acetylcholine receptor signaling pathway	5	48.0×	1e-05
membrane depolarization	6	47.1×	7e-07
monoatomic ion transmembrane transport	8	25.6×	4e-07
protein N-linked glycosylation	5	20.2×	3e-04
ERAD pathway	6	16.7×	2e-04
chemical synaptic transmission	6	7.1×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

337 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	9
Uncertain significance	172
Likely benign	64
Benign	42

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
2428857	NM_006765.4(TUSC3):c.244C>T (p.Arg82Ter)	Pathogenic
2603687	NM_006765.4(TUSC3):c.529C>T (p.Gln177Ter)	Pathogenic
3245514	NC_000008.10:g.(?15397940)(15615318_?)del	Pathogenic
3603041	NM_006765.4(TUSC3):c.199C>T (p.Arg67Ter)	Pathogenic
3778770	NM_006765.4(TUSC3):c.567+1G>C	Pathogenic
449114	NM_006765.4(TUSC3):c.1028G>C (p.Ser343Thr)	Pathogenic
4687305	NC_000008.10:g.(15531346_15588174)_(15615365_15621711)del	Pathogenic
495148	NM_006765.4(TUSC3):c.225del (p.Lys75fs)	Pathogenic
560138	Single allele	Pathogenic
686462	GRCh37/hg19 8p22(chr8:15282408-15423270)x1	Pathogenic
686619	GRCh37/hg19 8p22(chr8:15241652-15413345)x1	Pathogenic
8183	NM_006765.4(TUSC3):c.786dup (p.Asn263fs)	Pathogenic
973756	NM_006765.4(TUSC3):c.420dup (p.Gln141fs)	Pathogenic
1325320	NM_006765.4(TUSC3):c.220C>T (p.Arg74Ter)	Likely pathogenic
1333604	NM_006765.4(TUSC3):c.568-2A>G	Likely pathogenic
1710460	NM_006765.4(TUSC3):c.55_69delinsGC (p.Tyr19fs)	Likely pathogenic
1766755	NM_006765.4(TUSC3):c.938-8_939del	Likely pathogenic
2503415	NM_006765.4(TUSC3):c.119dup (p.Gly41fs)	Likely pathogenic
30177	NM_006765.4(TUSC3):c.163C>T (p.Gln55Ter)	Likely pathogenic
3381904	NM_006765.4(TUSC3):c.327T>A (p.Tyr109Ter)	Likely pathogenic
4813718	NM_006765.4(TUSC3):c.286C>T (p.Gln96Ter)	Likely pathogenic
996631	NM_006765.4(TUSC3):c.714A>G (p.Ile238Met)	Likely pathogenic

SpliceAI

3477 predictions. Top by Δscore:

Variant	Effect	Δscore
8:15540566:G:T	donor_gain	1.0000
8:15612947:T:G	donor_gain	1.0000
8:15623072:A:AG	acceptor_gain	1.0000
8:15623073:A:G	acceptor_gain	1.0000
8:15623078:A:AG	acceptor_gain	1.0000
8:15623079:G:A	acceptor_loss	1.0000
8:15623079:G:GA	acceptor_gain	1.0000
8:15623079:GA:G	acceptor_gain	1.0000
8:15623079:GAA:G	acceptor_gain	1.0000
8:15623079:GAAT:G	acceptor_gain	1.0000
8:15623079:GAATC:G	acceptor_gain	1.0000
8:15623245:TGCAG:T	donor_loss	1.0000
8:15623246:GCAGG:G	donor_loss	1.0000
8:15623248:AGG:A	donor_loss	1.0000
8:15623249:GGT:G	donor_loss	1.0000
8:15623250:GTA:G	donor_loss	1.0000
8:15649817:T:G	donor_gain	1.0000
8:15650696:GGCAA:G	acceptor_gain	1.0000
8:15650810:AGCAG:A	donor_loss	1.0000
8:15650811:GCAG:G	donor_gain	1.0000
8:15650812:CAG:C	donor_loss	1.0000
8:15650813:AGGT:A	donor_loss	1.0000
8:15650814:G:GC	donor_loss	1.0000
8:15650815:G:GA	donor_loss	1.0000
8:15650816:T:C	donor_loss	1.0000
8:15659501:TTACA:T	acceptor_loss	1.0000
8:15659502:TACAG:T	acceptor_loss	1.0000
8:15659505:A:AC	acceptor_loss	1.0000
8:15659505:A:AG	acceptor_gain	1.0000
8:15659506:G:A	acceptor_loss	1.0000

AlphaMissense

2279 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:15623245:T:C	C102R	1.000
8:15623246:G:A	C102Y	1.000
8:15623247:C:G	C102W	1.000
8:15650806:T:C	F140L	1.000
8:15650808:T:A	F140L	1.000
8:15650808:T:G	F140L	1.000
8:15659523:C:A	A148D	1.000
8:15659525:C:T	P149S	1.000
8:15659526:C:A	P149H	1.000
8:15673772:G:A	G245D	1.000
8:15673772:G:T	G245V	1.000
8:15673780:T:A	W248R	1.000
8:15673780:T:C	W248R	1.000
8:15673782:G:C	W248C	1.000
8:15673782:G:T	W248C	1.000
8:15743555:G:A	G294R	1.000
8:15743555:G:C	G294R	1.000
8:15748389:G:A	G318R	1.000
8:15748389:G:C	G318R	1.000
8:15748390:G:A	G318E	1.000
8:15623194:T:C	S85P	0.999
8:15623204:T:A	V88D	0.999
8:15623210:T:C	F90S	0.999
8:15623213:C:T	T91I	0.999
8:15623216:C:A	A92D	0.999
8:15623236:T:A	C99S	0.999
8:15623236:T:C	C99R	0.999
8:15623237:G:A	C99Y	0.999
8:15623237:G:C	C99S	0.999
8:15623238:T:G	C99W	0.999

dbSNP variants (sampled 300 via entrez): RS1000000934 (8:15599688 T>C,G), RS1000012322 (8:15743776 T>C), RS1000013129 (8:15592860 A>G), RS1000016254 (8:15703786 C>G,T), RS1000031127 (8:15625860 G>T), RS1000036720 (8:15618957 C>A,G,T), RS1000041264 (8:15634619 A>G), RS1000041431 (8:15652074 C>T), RS1000045264 (8:15744002 C>T), RS1000050786 (8:15714464 T>C), RS1000054752 (8:15563283 C>G), RS1000076568 (8:15647380 T>C), RS1000085187 (8:15619110 T>C), RS1000089087 (8:15690656 C>T), RS1000116582 (8:15599419 G>A)

Disease associations

OMIM: gene MIM:601385 | disease phenotypes: MIM:611093, MIM:614345

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability	Definitive	Autosomal recessive
intellectual disability, autosomal recessive 7	Definitive	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
intellectual disability	Definitive	AR

Mondo (7): intellectual disability, autosomal recessive 7 (MONDO:0012615), congenital disorder of glycosylation (MONDO:0015286), congenital nervous system disorder (MONDO:0002320), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), intellectual disability, autosomal recessive 24 (MONDO:0013707), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (3): Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Congenital disorder of glycosylation (Orphanet:137), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0010864	Severe intellectual disability
HP:0011463	Childhood onset

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001428_13	Intelligence	2.000000e-06
GCST001444_26	Pulmonary function decline	5.000000e-08
GCST001972_1	Methamphetamine dependence	4.000000e-06
GCST002345_21	Response to cytadine analogues (cytosine arabinoside)	2.000000e-06
GCST004639_24	Prudent dietary pattern	5.000000e-06
GCST005834_3	Response to SSRI in MDD or openness	6.000000e-07
GCST009391_823	Metabolite levels	5.000000e-06
GCST010396_48	Gut microbiota (bacterial taxa, hurdle binary method)	7.000000e-06
GCST010397_7	Gut microbiota (bacterial taxa, rank normal transformation method)	9.000000e-07
GCST010988_288	Adult body size	5.000000e-08
GCST010989_135	Body size at age 10	4.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004713	FEV/FVC ratio
EFO:0008111	diet measurement
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0007914	openness measurement
EFO:0010398	sphingomyelin 24:1 measurement
EFO:0007874	gut microbiome measurement
EFO:0009819	comparative body size at age 10, self-reported

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D018981	Congenital Disorders of Glycosylation	C16.320.565.202.125; C18.452.648.202.125
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C567016	Mental Retardation, Autosomal Recessive 7 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC58 MagT-like magnesium transporter family

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases expression	3
Valproic Acid	increases expression	3
Cyclosporine	decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
incobotulinumtoxinA	increases expression	1
perfluoroundecanoic acid	affects expression, affects methylation	1
Temozolomide	increases expression	1
Decitabine	decreases expression, decreases reaction	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Azathioprine	increases expression	1
Ivermectin	decreases expression	1
Lead	increases expression	1
Methapyrilene	increases methylation	1
Quercetin	increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression, decreases reaction	1
Theophylline	increases expression	1
Urethane	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Aflatoxin B1	decreases expression	1
Sodium Selenite	increases expression	1
Copper Sulfate	increases expression	1
tert-Butylhydroperoxide	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D4FM	1321N1-TUSC3-KO-c10	Cancer cell line	Male
CVCL_D4FN	1321N1-TUSC3-KO-c4	Cancer cell line	Male
CVCL_TV23	HAP1 TUSC3 (-) 1	Cancer cell line	Male
CVCL_TV24	HAP1 TUSC3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

399 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT07572825	PHASE1	NOT_YET_RECRUITING	Assessing the Safety and Tolerability of NMN in DHDDS-CDG
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood