TREX1

Summary

TREX1 (three prime repair exonuclease 1, HGNC:12269) is a protein-coding gene on chromosome 3p21.31, encoding Three-prime repair exonuclease 1 (Q9NSU2). Major cellular 3’-to-5’ DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3’ termini.

This gene encodes a nuclear protein with 3’ exonuclease activity. The encoded protein may play a role in DNA repair and serve as a proofreading function for DNA polymerase. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, Cree encephalitis, and other diseases of the immune system. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 11277 — RefSeq curated summary.

At a glance

• Gene–disease (curated): retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 58 total — 6 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 215
• MANE Select transcript: NM_033629

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12269
Approved symbol	TREX1
Name	three prime repair exonuclease 1
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	DRN3
Ensembl gene	ENSG00000213689
Ensembl biotype	protein_coding
OMIM	606609
Entrez	11277

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000433541, ENST00000444177, ENST00000456089, ENST00000492235, ENST00000625293, ENST00000635452

RefSeq mRNA: 2 — MANE Select: NM_033629 NM_007248, NM_033629

CCDS: CCDS2769, CCDS59451

Canonical transcript exons

ENST00000625293 — 2 exons

Exon	Start	End
ENSE00003768438	48466630	48467645
ENSE00003823332	48466230	48466309

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 93.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.6764 / max 336.8999, expressed in 1676 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36580	21.0699	1655
36579	0.6066	337

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	93.86	gold quality
granulocyte	CL:0000094	93.41	gold quality
leukocyte	CL:0000738	92.34	gold quality
monocyte	CL:0000576	92.33	gold quality
spleen	UBERON:0002106	91.25	gold quality
skin of abdomen	UBERON:0001416	91.23	gold quality
skin of leg	UBERON:0001511	91.18	gold quality
zone of skin	UBERON:0000014	91.10	gold quality
adenohypophysis	UBERON:0002196	91.02	gold quality
pituitary gland	UBERON:0000007	90.61	gold quality
blood	UBERON:0000178	90.40	gold quality
saliva-secreting gland	UBERON:0001044	90.26	gold quality
minor salivary gland	UBERON:0001830	90.02	gold quality
mucosa of transverse colon	UBERON:0004991	89.60	gold quality
lymph node	UBERON:0000029	88.99	gold quality
right uterine tube	UBERON:0001302	88.64	gold quality
right adrenal gland	UBERON:0001233	88.55	gold quality
right adrenal gland cortex	UBERON:0035827	88.55	gold quality
lower esophagus mucosa	UBERON:0035834	88.30	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.20	gold quality
left adrenal gland	UBERON:0001234	87.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.79	gold quality
esophagus mucosa	UBERON:0002469	87.77	gold quality
left adrenal gland cortex	UBERON:0035825	87.68	gold quality
amygdala	UBERON:0001876	87.30	gold quality
temporal lobe	UBERON:0001871	87.29	gold quality
prostate gland	UBERON:0002367	87.26	gold quality
right coronary artery	UBERON:0001625	87.16	gold quality
hypothalamus	UBERON:0001898	86.87	gold quality
substantia nigra	UBERON:0002038	86.57	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, JUN

Literature-anchored findings (GeneRIF, showing 40)

• TREX1, encoding the major mammalian 3’ –> 5’ DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. (PMID:16845398)
• Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. (PMID:17357087)
• identification of a heterozygous missense mutation (D18N) in TREX1 in affected individuals of the family with chilblain lupus; lymphoblastoid cells with the D18N mutation are less sensitive to granzyme A-mediated cell death (PMID:17440703)
• Findings implicate TREX1 in the pathogenesis of systemic lupus erythematosus. (PMID:17660818)
• Truncated proteins retain exonuclease activity but lose normal perinuclear localization. (PMID:17660820)
• Trex1 acts on a single-stranded DNA polynucleotide species generated from processing of aberrant replication intermediates to attenuate DNA damage checkpoint signaling and prevent pathological immune activation. (PMID:18045533)
• The objective of this study was to confirm whether polymorphisms of TREX1 and TREX2 are associated with genetic susceptibility to systemic lupus erythematosus (SLE), and examine associations with autoantibodies (auto-Abs) in SLE. (PMID:18092167)
• TREX1-deficiency resulted in the intracellular accumulation of single stranded DNA resulting in chronic activation of the DNA damage response network, even in cells from Trex1-mutated Aicardi-Goutieres syndrome patients (PMID:18406216)
• A review of the putative functions of TREX1 in relationship to the clinical, genetic and functional characteristics of several diseases caused by mutations in TREX1. (PMID:18583934)
• dysfunctional dsDNA degradation activities of these disease-related TREX1 mutants could account for persistent dsDNA from dying cells leading to an aberrant immune response in these clinically related disorders (PMID:18805785)
• genetic deficiency causes the spontaneous inflammatory myocarditis (PMID:19120481)
• gene mutations cause Aicardi-Goutieres syndrome and chilblain lupus, autoimmune diseases known to involve elevated type I IFN production (PMID:19362700)
• Study demonstrated TREX1 enzyme deficiency in Aicardi-Goutieres syndrome. (PMID:19442247)
• TREX1 may act in degrading DNA in all cell types undergoing a dying process before phagocytosis occurs. (PMID:19617005)
• TREX1 mutations do not play a role in the pathogenesis of Sporadic inclusion body myositis. (PMID:20192983)
• The deficiency of Trex-1 in rheumatoid arthritis synovial fibroblasts allows a longer half-life of gene products encoded by active endogenous L1 retrotransposons. (PMID:20496420)
• A single case of a heterozygous TREX1 mutation has been associated with Aicardi-Goutieres syndrome, an encephalopathy often resembling congenital infection. (PMID:20799324)
• TREX1 bound to cytosolic HIV DNA and digested excess HIV DNA that would otherwise activate interferon expression via a pathway dependent on the kinase TBK1, the adaptor STING and the transcription factor IRF3 (PMID:20871604)
• data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis (PMID:21270825)
• failure to degrade genomic dsDNA is a principal pathway of immune activation in TREX1-mediated autoimmune disease. (PMID:21808053)
• TREX1 residues in one protomer contributing to DNA degradation catalyzed in the opposing protomer and help to explain the dimeric TREX1 structure required for full catalytic competency. (PMID:21937424)
• The structures of the mutant TREX1 proteins provide insight into the dysfunction relating to human disease. (PMID:22071149)
• Despite its central role in the HIV-1 infection process, genetic diversity at TREX1 is not a major determinant of susceptibility to infection in humans. (PMID:22526516)
• Aicardi-Goutieres syndrome and familial chilblain lupus can be caused by a heterozygous TREX1 p.Asp18Asn mutation. (PMID:22829693)
• TREX is the major complex used to recruit Nxf1 to mRNA in human cells. (PMID:22893130)
• TREX1 knockdown resulted in enhanced cell death following nimustine. (PMID:23578789)
• TREX1 mutation is not a common cause of hereditary small vessel diseases of the brain (PMID:23602593)
• Studies indicate that the biosensing strategy is based on the protection of DNA duplex from exonuclease III (Exo III)-mediated digestion by specific binding of estrogen receptor (ER) to its DNA response element. (PMID:23681011)
• Data indicate that the single nucleotide polymorphism rs3135945 was significantly associated with HIV infection, emphasizing the involvement of TREX-1 in the anti-HIV response. (PMID:23773365)
• Screening of our patient cohort yielded heterozygous TREX1 mutations in two patients with early-onset cerebrovascular disease (PMID:23881107)
• TREX1 post-translational modification indicates an additional mechanism by which mutations disrupt TREX1 biology, leading to human autoimmune disease. (PMID:23979357)
• TREX1 gene variants confer an increased risk for the development of systemic lupus erythematosus. (PMID:24034389)
• This study contributes to the demonstration that TREX1 is involved in autoimmune diseases and proposes that the spectrum of involved autoimmune diseases can be broader and includes systemic sclerosis . (PMID:24224166)
• Spontaneous type I INF dependent cutaneous pathology in TREX1 deficiency illustrates common pathogenetic pathway in chilblain lupus. (PMID:24270665)
• A nationwide survey of Aicardi-Goutieres syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions in Japan. (PMID:24300241)
• These data provide compelling evidence for the required TREX1 dimeric structure for full catalytic function. (PMID:24616097)
• knocking out the DNA sensor cyclic GMP-AMP synthase completely abrogates spontaneous induction of IFN-stimulated genes in TREX1-deficient cells. (PMID:24813208)
• The authors observed that the minor allele of SNP rs3135941 in Trex1 is associated with faster HIV-1 disease progression. (PMID:25162766)
• Functional analysis of retinal vasculopathy with cerebral leukodystrophy-associated TREX1 T270 frameshift-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region (PMID:25213617)
• Data suggest that the 3’-5’ DNA exonuclease TREX1 may contribute to stabilization of poly(ADP-ribose) polymerase-1 (PARP1) levels in the DNA damage response and its activity. (PMID:25278026)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	plex9.1	ENSDARG00000092584
danio_rerio	plex9.2	ENSDARG00000093773
mus_musculus	Trex1	ENSMUSG00000049734
rattus_norvegicus	Trex1	ENSRNOG00000022540
drosophila_melanogaster	CG3165	FBGN0031484
caenorhabditis_elegans		WBGENE00020949

Paralogs (1): TREX2 (ENSG00000183479)

Protein

Protein identifiers

Three-prime repair exonuclease 1 — Q9NSU2 (reviewed: Q9NSU2)

Alternative names: 3’-5’ exonuclease TREX1, Deoxyribonuclease III

All UniProt accessions (3): C9J052, Q9NSU2, Q5TZT0

UniProt curated annotations — full annotation on UniProt →

Function. Major cellular 3’-to-5’ DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3’ termini. Prevents cell-intrinsic initiation of autoimmunity. Acts by metabolizing DNA fragments from endogenous retroelements, including L1, LTR and SINE elements. Plays a key role in degradation of DNA fragments at cytosolic micronuclei arising from genome instability: its association with the endoplasmic reticulum membrane directs TREX1 to ruptured micronuclei, leading to micronuclear DNA degradation. Micronuclear DNA degradation is required to limit CGAS activation and subsequent inflammation. Unless degraded, these DNA fragments accumulate in the cytosol and activate the cGAS-STING innate immune signaling, leading to the production of type I interferon. Prevents chronic ATM-dependent checkpoint activation, by processing ssDNA polynucleotide species arising from the processing of aberrant DNA replication intermediates. Inefficiently degrades oxidized DNA, such as that generated upon antimicrobial reactive oxygen production or upon absorption of UV light. During GZMA-mediated cell death, contributes to DNA damage in concert with NME1. NME1 nicks one strand of DNA and TREX1 removes bases from the free 3’ end to enhance DNA damage and prevent DNA end reannealing and rapid repair.

Subunit / interactions. Homodimer. Interacts (via proline-rich region) with TCERG1/CA150 (via the second WW domain). Component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1. Within this complex, directly interacts with SET; this interaction does not result in TREX1 inhibition. Also interacts with NME1, but only following translocation to the nucleus. Directly interacts with UBQLN1 (via ubiquitin-like domain); the interaction may control TREX1 subcellular location.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Endoplasmic reticulum membrane.

Tissue specificity. Detected in thymus, spleen, liver, brain, heart, small intestine and colon.

Post-translational modifications. Ubiquitinated, but not targeted to proteasomal degradation. Ubiquitination may be important for interaction with UBQLN1.

Disease relevance. Aicardi-Goutieres syndrome 1 (AGS1) [MIM:225750] A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. The disease is caused by variants affecting the gene represented in this entry. Systemic lupus erythematosus (SLE) [MIM:152700] A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Disease susceptibility is associated with variants affecting the gene represented in this entry. Enhanced immune sensing of oxidized DNA may be involved in the phototoxicity experienced by SLE patients. Exposure to UV-light produces DNA oxidative damage. Oxidized DNA being a poor TREX1 substrate, it accumulates in skin, leading to enhanced auto-immune reactivity and eventually skin lesions. Chilblain lupus 1 (CHBL1) [MIM:610448] A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure. The disease is caused by variants affecting the gene represented in this entry. Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations (RVCLS) [MIM:192315] An adult-onset, autosomal dominant endotheliopathy affecting the microvessels of the brain. It results in central nervous system degeneration and retinopathy, with progressive loss of vision, stroke, motor impairment, and cognitive decline. The ocular manifestations are characterized by telangiectasias, microaneurysms and retinal capillary obliteration starting in the macula. Diseased cerebral white matter has prominent small infarcts that often coalesce to pseudotumors. A subset of patients have systemic vascular involvement that can manifest as Raynaud phenomenon, micronodular cirrhosis, and glomerular dysfunction. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 Mg(2+) per subunit. The second magnesium ion interacts with only one residue. Substitution with Mn(2+) results in partial activity.

Similarity. Belongs to the exonuclease superfamily. TREX family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NSU2-3	3	yes
Q9NSU2-1	1
Q9NSU2-2	2

RefSeq proteins (2): NP_009179, NP_338599* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR013520	Ribonucl_H	Domain
IPR036397	RNaseH_sf	Homologous_superfamily
IPR040393	TREX1/2	Family

Enzyme classification (BRENDA):

• EC 3.1.11.2 — exodeoxyribonuclease III (BRENDA: 8 organisms, 121 substrates, 13 inhibitors, 13 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N1 DUPLEX DNA	—	8
PUC18 DNA PSTI	0.05–0.75	2
APURINIC DNA	3.5	1
UREA-CONTAINING DNA	9.5	1

UniProt features (65 total): sequence variant 17, helix 11, mutagenesis site 8, binding site 7, strand 6, region of interest 4, modified residue 3, turn 3, splice variant 2, chain 1, sequence conflict 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
7TQO	X-RAY DIFFRACTION	1.25
9O0W	X-RAY DIFFRACTION	1.43
9O0Y	X-RAY DIFFRACTION	1.5
9O0X	X-RAY DIFFRACTION	1.68
7TQN	X-RAY DIFFRACTION	1.8
8VL7	X-RAY DIFFRACTION	1.88
7TQP	X-RAY DIFFRACTION	1.95
7TQQ	X-RAY DIFFRACTION	2.2
9AVA	X-RAY DIFFRACTION	2.3
9L89	X-RAY DIFFRACTION	2.38
9L8C	X-RAY DIFFRACTION	2.52
9L88	X-RAY DIFFRACTION	2.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NSU2-F1	81.03	0.67

Functional residue map

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

Catalytic / active sites (1): 195 (proton donor/acceptor)

Ligand- & substrate-binding residues (7): 20; 129; 200; 200; 18; 18; 20–21

Post-translational modifications (3): 78, 167, 261

Mutagenesis-validated functional residues (8):

Position	Phenotype
30	reduces ubiquitination.
66	no effect on ubiquitination.
75	reduces ubiquitination.
160	reduces ubiquitination.
175	reduces ubiquitination.
242	reduces ubiquitination.
271	reduces ubiquitination. strongly reduces ubiquitination; when associated with r-277.
277	reduces ubiquitination. strongly reduces ubiquitination; when associated with r-271.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3248023	Regulation by TREX1
R-HSA-3270619	IRF3-mediated induction of type I IFN

MSigDB gene sets: 822 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_VACUOLE_ORGANIZATION, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, FISCHER_G1_S_CELL_CYCLE, GOMF_NUCLEASE_ACTIVITY

GO Biological Process (62): blood vessel development (GO:0001568), kidney development (GO:0001822), activation of immune response (GO:0002253), macrophage activation involved in immune response (GO:0002281), lymphoid progenitor cell differentiation (GO:0002320), immune response in brain or nervous system (GO:0002383), inflammatory response to antigenic stimulus (GO:0002437), T cell antigen processing and presentation (GO:0002457), regulation of immunoglobulin production (GO:0002637), heart morphogenesis (GO:0003007), heart process (GO:0003015), atrial cardiac muscle tissue development (GO:0003228), generation of precursor metabolites and energy (GO:0006091), regulation of glycolytic process (GO:0006110), DNA metabolic process (GO:0006259), DNA replication (GO:0006260), DNA repair (GO:0006281), mismatch repair (GO:0006298), DNA modification (GO:0006304), DNA catabolic process (GO:0006308), DNA recombination (GO:0006310), determination of adult lifespan (GO:0008340), glycoprotein biosynthetic process (GO:0009101), regulation of fatty acid metabolic process (GO:0019217), mitotic G1 DNA damage checkpoint signaling (GO:0031571), retrotransposition (GO:0032197), regulation of type I interferon production (GO:0032479), regulation of tumor necrosis factor production (GO:0032680), cellular response to reactive oxygen species (GO:0034614), cellular response to interferon-beta (GO:0035458), apoptotic cell clearance (GO:0043277), regulation of cellular respiration (GO:0043457), establishment of protein localization (GO:0045184), negative regulation of innate immune response (GO:0045824), regulation of lipid biosynthetic process (GO:0046890), regulation of inflammatory response (GO:0050727), protein stabilization (GO:0050821), regulation of T cell activation (GO:0050863), defense response to virus (GO:0051607), type I interferon-mediated signaling pathway (GO:0060337)

GO Molecular Function (21): magnesium ion binding (GO:0000287), double-stranded DNA binding (GO:0003690), single-stranded DNA binding (GO:0003697), 3’-5’-DNA exonuclease activity (GO:0008296), DNA binding, bending (GO:0008301), double-stranded DNA 3’-5’ DNA exonuclease activity (GO:0008311), 3’-5’ exonuclease activity (GO:0008408), MutLalpha complex binding (GO:0032405), MutSalpha complex binding (GO:0032407), adenyl deoxyribonucleotide binding (GO:0032558), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), WW domain binding (GO:0050699), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), nuclease activity (GO:0004518), exonuclease activity (GO:0004527), DNA exonuclease activity (GO:0004529), protein binding (GO:0005515), hydrolase activity (GO:0016787), identical protein binding (GO:0042802)

GO Cellular Component (10): nuclear envelope (GO:0005635), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), oligosaccharyltransferase complex (GO:0008250), protein-DNA complex (GO:0032993), nuclear replication fork (GO:0043596), nucleus (GO:0005634), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Regulation of innate immune responses to cytosolic DNA	1
STING mediated induction of host immune responses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	4
DNA binding	3
cellular anatomical structure	3
immune response	2
DNA nuclease activity	2
exonuclease activity	2
mismatch repair complex binding	2
binding	2
nucleus	2
endomembrane system	2
cytoplasm	2
intracellular membrane-bounded organelle	2
vasculature development	1
anatomical structure development	1
animal organ development	1
renal system development	1
immune system process	1
positive regulation of immune response	1
myeloid cell activation involved in immune response	1
leukocyte activation involved in immune response	1
macrophage activation	1
hematopoietic progenitor cell differentiation	1
organ or tissue specific immune response	1
inflammatory response	1
T cell mediated immunity	1
antigen processing and presentation	1
immunoglobulin production	1
regulation of production of molecular mediator of immune response	1
heart development	1
animal organ morphogenesis	1
circulatory system process	1
cardiac muscle tissue development	1
metabolic process	1
glycolytic process	1
regulation of purine nucleotide catabolic process	1
regulation of generation of precursor metabolites and energy	1
regulation of carbohydrate catabolic process	1
regulation of ATP metabolic process	1
nucleic acid metabolic process	1
DNA biosynthetic process	1

Protein interactions and networks

STRING

1148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TREX1	SAMHD1	Q9Y3Z3	918
TREX1	RNASEH2A	O75792	883
TREX1	RNASEH2C	Q8TDP1	882
TREX1	RNASEH2B	Q5TBB1	873
TREX1	EXO1	Q9UQ84	727
TREX1	CGAS	Q8N884	718
TREX1	IRF3	Q14653	701
TREX1	IFNAR1	P17181	668
TREX1	NME1	P15531	659
TREX1	GZMA	P12544	622
TREX1	ADAR	P55265	605
TREX1	IFNA13	P01562	596
TREX1	WRN	Q14191	541
TREX1	TBK1	Q9UHD2	506
TREX1	STING1	Q86WV6	502

IntAct

8 interactions, top by confidence:

A	B	Type	Score
	SHTN1	psi-mi:“MI:0914”(association)	0.350
TREX1	ITGB8	psi-mi:“MI:0914”(association)	0.350
ATF2	PLOD2	psi-mi:“MI:0914”(association)	0.350
ATF3	ILVBL	psi-mi:“MI:0914”(association)	0.350
CEBPA	MYO1C	psi-mi:“MI:0914”(association)	0.350
GATA2	ILVBL	psi-mi:“MI:0914”(association)	0.350
ERBB2	AGPS	psi-mi:“MI:0914”(association)	0.350

BioGRID (58): KRTAP10-7 (Two-hybrid), TREX1 (Affinity Capture-RNA), TREX1 (Affinity Capture-RNA), UBQLN1 (Affinity Capture-Western), UBQLN1 (Reconstituted Complex), RIBC2 (Two-hybrid), IFT20 (Two-hybrid), CHCHD2 (Two-hybrid), KRTAP10-7 (Two-hybrid), RAB23 (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), TREX1 (Affinity Capture-MS), TREX1 (Two-hybrid), TREX1 (Two-hybrid), TREX1 (Two-hybrid)

ESM2 similar proteins: A7E3N7, A8VU90, B1WBU5, D3KCC4, O95382, P08923, P0C263, P0C264, P0C5K0, P0C5K1, P54265, Q06418, Q09013, Q13470, Q14296, Q16671, Q28616, Q4FZD7, Q53GL7, Q58EX7, Q60806, Q62070, Q62893, Q643R3, Q6DT37, Q6F5E8, Q6NVG1, Q6P5Z2, Q6VY05, Q76MJ5, Q80UW5, Q8CIE4, Q8CJ00, Q8IYX4, Q8K045, Q8K592, Q8NAG6, Q8NCV1, Q95JV3, Q96LW2

Diamond homologs: Q91XB0, Q9BG99, Q9BQ50, Q9NSU2, Q9R1A9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 11 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of gene expression	5	19.4×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	4
Uncertain significance	24
Likely benign	18
Benign	1

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1457024	NM_033629.6(TREX1):c.399dup (p.Leu134fs)	Pathogenic
209199	NM_033629.6(TREX1):c.212_213del (p.Val71fs)	Pathogenic
2921624	NM_033629.6(TREX1):c.130del (p.Leu44fs)	Pathogenic
2945022	NM_033629.6(TREX1):c.55dup (p.Met19fs)	Pathogenic
915280	NM_033629.6(TREX1):c.243_246del (p.Ser82fs)	Pathogenic
930977	NM_033629.6(TREX1):c.856_865dup (p.Ala289fs)	Pathogenic
126387	NM_033629.6(TREX1):c.393_408dup (p.Glu137fs)	Likely pathogenic
2627816	NM_033629.6(TREX1):c.82del (p.Gln28fs)	Likely pathogenic
692082	NM_007248.3(TREX1):c.1033_1050del	Likely pathogenic
809481	NM_033629.6(TREX1):c.806del (p.Gly269fs)	Likely pathogenic

SpliceAI

307 predictions. Top by Δscore:

Variant	Effect	Δscore
3:48466090:G:GT	donor_gain	0.9700
3:48465913:A:T	donor_gain	0.9400
3:48466627:CAG:C	acceptor_loss	0.9200
3:48466628:A:C	acceptor_loss	0.9200
3:48466119:G:T	donor_gain	0.8900
3:48466706:C:CA	acceptor_gain	0.8900
3:48466710:AT:A	acceptor_gain	0.8900
3:48465912:G:GT	donor_gain	0.8800
3:48466628:AGGCT:A	acceptor_gain	0.8600
3:48466709:CATGG:C	acceptor_gain	0.8600
3:48466710:ATGGA:A	acceptor_gain	0.8600
3:48466091:A:T	donor_gain	0.8500
3:48466628:A:AG	acceptor_gain	0.8400
3:48466629:G:GG	acceptor_gain	0.8400
3:48466626:CCAGG:C	acceptor_gain	0.8300
3:48466627:CAGGC:C	acceptor_gain	0.8300
3:48466711:T:G	acceptor_gain	0.8300
3:48466307:ACGG:A	donor_loss	0.8200
3:48466308:CGGTG:C	donor_loss	0.8200
3:48466309:GGTG:G	donor_loss	0.8200
3:48466310:G:T	donor_loss	0.8200
3:48466311:T:G	donor_loss	0.8200
3:48466310:G:GG	donor_gain	0.8000
3:48466312:GA:G	donor_loss	0.8000
3:48466111:G:GT	donor_gain	0.7900
3:48466629:GGCT:G	acceptor_gain	0.7800
3:48466711:TGG:T	acceptor_gain	0.7700
3:48466313:A:AC	donor_loss	0.7600
3:48466710:ATG:A	acceptor_gain	0.7600
3:48466711:T:TA	acceptor_gain	0.7300

AlphaMissense

1992 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:48467118:A:C	S155R	0.996
3:48467120:C:A	S155R	0.996
3:48467120:C:G	S155R	0.996
3:48467032:G:T	G126V	0.982
3:48467245:C:A	A197D	0.982
3:48466715:G:C	E20D	0.981
3:48466715:G:T	E20D	0.981
3:48466753:A:T	E33V	0.980
3:48467254:A:T	D200V	0.980
3:48466708:A:T	D18V	0.979
3:48466760:C:G	C35W	0.979
3:48467047:T:G	F131C	0.978
3:48467115:G:C	D154H	0.978
3:48466849:A:T	D65V	0.977
3:48467044:A:T	D130V	0.977
3:48466986:T:C	F111L	0.975
3:48466988:C:A	F111L	0.975
3:48466988:C:G	F111L	0.975
3:48467046:T:C	F131L	0.975
3:48467047:T:C	F131S	0.975
3:48467048:C:A	F131L	0.975
3:48467048:C:G	F131L	0.975
3:48467116:A:T	D154V	0.975
3:48467254:A:C	D200A	0.975
3:48466709:C:A	D18E	0.974
3:48466709:C:G	D18E	0.974
3:48467032:G:A	G126D	0.974
3:48466714:A:T	E20V	0.973
3:48466768:C:A	A38D	0.973
3:48467025:C:G	H124D	0.973

dbSNP variants (sampled 300 via entrez): RS1001416785 (3:48467882 C>T), RS1001904036 (3:48464175 T>C), RS1002379489 (3:48464519 G>A,C), RS1003727618 (3:48465950 A>G), RS1003855092 (3:48466327 A>G), RS1004005638 (3:48465199 A>C), RS1004374077 (3:48466531 G>A,T), RS1005635836 (3:48467632 C>A,G,T), RS1005935582 (3:48467377 C>T), RS1006076959 (3:48468120 A>C,G), RS1007795947 (3:48467134 A>T), RS1008168580 (3:48465022 C>A,T), RS1008387400 (3:48466155 G>A), RS1008389650 (3:48465965 G>C), RS1010558113 (3:48464775 G>A)

Disease associations

OMIM: gene MIM:606609 | disease phenotypes: MIM:192315, MIM:225750, MIM:610448, MIM:152700, MIM:601744

GenCC curated gene-disease

Disease	Classification	Inheritance
Aicardi-Goutieres syndrome 1	Definitive	Autosomal recessive
retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Strong	Autosomal dominant
chilblain lupus 1	Strong	Autosomal dominant
systemic lupus erythematosus	Strong	Autosomal dominant
familial chilblain lupus	Supportive	Autosomal dominant
Aicardi-Goutieres syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Definitive	AD
TREX1-related type 1 interferonopathy	Definitive	AD
TREX1-related type 1 interferonopathy	Definitive	AR

Mondo (7): retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (MONDO:0008641), Aicardi-Goutieres syndrome 1 (MONDO:0009165), chilblain lupus 1 (MONDO:0012500), systemic lupus erythematosus (MONDO:0007915), Aicardi-Goutieres syndrome (MONDO:0018866), neurodevelopmental disorder (MONDO:0700092), familial chilblain lupus (MONDO:0018827)

Orphanet (6): Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (Orphanet:247691), Cerebroretinal vasculopathy (Orphanet:3421), Aicardi-Goutières syndrome (Orphanet:51), HERNS syndrome (Orphanet:63261), Hereditary vascular retinopathy (Orphanet:71291), Systemic lupus erythematosus (Orphanet:536)

HPO phenotypes

215 total (30 of 215 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000112	Nephropathy
HP:0000123	Nephritis
HP:0000155	Oral ulcer
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000369	Low-set ears
HP:0000444	Convex nasal ridge
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000496	Abnormality of eye movement
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000529	Progressive visual loss
HP:0000573	Retinal hemorrhage
HP:0000625	Eyelid coloboma
HP:0000639	Nystagmus
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000726	Dementia
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000742	Self-mutilation

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001762_130	Obesity-related traits	6.000000e-06
GCST004131_23	Inflammatory bowel disease	1.000000e-33
GCST004132_17	Crohn’s disease	3.000000e-23
GCST004133_11	Ulcerative colitis	8.000000e-20
GCST009067_4	Mosaic loss of chromosome Y (Y chromosome dosage)	5.000000e-08
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004626	IGFBP-3 measurement
EFO:0007783	mosaic loss of chromosome Y measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590
D065886	Neurodevelopmental Disorders	F03.625
C535607	Aicardi-Goutieres syndrome (supp.)
C566007	Vasculopathy, Retinal, With Cerebral Leukodystrophy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	2
Valproic Acid	increases methylation, affects expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
FR900359	decreases phosphorylation	1
myristicin	decreases expression	1
4-biphenylamine	decreases expression	1
bromoacetate	decreases expression	1
cobaltous chloride	decreases expression	1
vanadyl sulfate	increases expression	1
fotemustine	increases expression, affects binding, increases reaction, affects response to substance, decreases reaction	1
benzo(a)pyrene diolepoxide I	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
brevetoxin 2	increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Amiodarone	increases expression	1
Calcitriol	affects cotreatment, decreases expression	1
Cannabidiol	decreases expression	1
Carmustine	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Estradiol	decreases expression	1
Selenium	increases expression	1
Selenomethionine	affects expression	1
Smoke	decreases expression	1
Testosterone	affects cotreatment, decreases expression	1
Vincristine	decreases expression	1

Cellosaurus cell lines

14 cell lines: 7 cancer cell line, 7 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A8AJ	THP1-Dual KO-TREX1	Cancer cell line	Male
CVCL_B1I9	Abcam A-549 TREX1 KO	Cancer cell line	Male
CVCL_B2JK	Abcam HeLa TREX1 KO	Cancer cell line	Female
CVCL_C1P2	CRTDi006-A	Induced pluripotent stem cell	Male
CVCL_C1P3	CRTDi007-A	Induced pluripotent stem cell	Male
CVCL_C1YD	CRTDi006-B	Induced pluripotent stem cell	Male
CVCL_C1YE	CRTDi007-B	Induced pluripotent stem cell	Male
CVCL_F1PY	HyCyte HeLa KO-hTREX1	Cancer cell line	Female
CVCL_TT71	HAP1 TREX1 (-) 1	Cancer cell line	Male
CVCL_TT72	HAP1 TREX1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients