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| Symbol | TREX1 |
| Full Name |
Three Prime Repair Exonuclease 1 |
| Chromosome |
3p21.31 |
| NCBI Gene |
9349 |
| Ensembl |
ENSG00000213465 |
| OMIM |
607400 |
| UniProt |
Q9NSW9 |
| Diseases |
[Aicardi-Goutières Syndrome](/diseases/aicardi-goutieres-syndrome), [Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS)](/diseases/chronic-lymphocytic-inflammation), [Alzheimer's Disease](/diseases/alzheimers) |
| Expression |
Ubiquitously expressed; high expression in brain, liver, spleen |
TREX1 (Three Prime Repair Exonuclease 1) is a gene located on chromosome 3p21.31 that encodes a 3' to 5' exonuclease involved in DNA repair and immune regulation. TREX1 is a critical component of the innate immune system and plays important roles in preventing autoimmune responses and potentially in neurodegenerative disease pathogenesis. Mutations in TREX1 cause Aicardi-Goutières syndrome (AGS), a severe neurodevelopmental disorder, and have been implicated in Alzheimer's disease, systemic lupus erythematosus, and other autoimmune conditions [1][2].
The TREX1 gene spans approximately 3.5 kb and consists of 3 exons. The gene encodes a 314-amino acid protein that localizes primarily to the endoplasmic reticulum (ER). TREX1 is one of the most abundant proteins in the ER and is highly conserved across mammals [3].
- Chromosome: 3p21.31
- Location: 3p21.31 (chr3: 48428750-48432113)
- Strand: Minus strand
- Exons: 3
¶ Protein Structure and Function
¶ Domain Architecture
TREX1 is a member of the DEDDh family of exonucleases, characterized by a conserved exonuclease domain with the motif DEDDy. The protein:
- N-terminal ER targeting sequence: Directs localization to the endoplasmic reticulum
- Exonuclease domain: Contains the catalytic DEDDy motif
- C-terminal tail: Involved in protein-protein interactions
TREX1 functions as a 3' to 5' exonuclease that degrades single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with 3' overhangs. The enzyme:
- Prefers substrates with 3' recessed ends
- Can degrade nucleic acids in a non-sequence-specific manner
- Requires divalent metal ions (Mg²⁺ or Mn²⁺) for catalytic activity
TREX1 participates in multiple DNA repair pathways:
- Base excision repair (BER): Removes damaged nucleotides at DNA termini
- Mismatch repair: Excises mispaired nucleotides
- Nucleotide excision repair: Processes repair intermediates
- Immune evasion: Degrades foreign DNA in the cytosol
TREX1 plays a critical role in preventing autoimmune responses:
- Degrades cytosolic DNA that may originate from retroelements or pathogens
- Prevents activation of the cGAS-STING pathway
- Limits type I interferon (IFN) production
- Mutations lead to constitutive IFN activation (AGS)
TREX1 mutations are a major cause of Aicardi-Goutières syndrome, a severe early-onset neurodevelopmental disorder characterized by:
- Progressive encephalopathy
- Microcephaly
- Intracranial calcifications
- Leukodystrophy
- Elevated interferon signature
Over 80 pathogenic mutations have been identified in TREX1, including:
- Missense mutations (e.g., D200N, G198V, R169T)
- Nonsense mutations causing truncated proteins
- Frameshift mutations
Recent research has implicated TREX1 in Alzheimer's disease pathogenesis:
- DNA damage accumulation: TREX1 deficiency leads to increased DNA damage in neurons
- cGAS-STING activation: TREX1 loss triggers chronic type I interferon responses
- Neuroinflammation: TREX1 mutations may exacerbate neuroinflammation
- Amyloid relationship: Aβ can induce TREX1 expression, potentially as a protective response
TREX1 polymorphisms are associated with increased susceptibility to SLE:
- Common variants (e.g., D178N) increase SLE risk
- TREX1 autoantibodies have been detected in some SLE patients
- Role in clearing apoptotic DNA debris
- CLIPPERS: TREX1 mutations cause chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids
- Retinal vasculopathy with cerebral leukoencephalopathy (RVCL): TREX1 mutations cause a distinct syndrome with vascular involvement
- Heterozygous TREX1 variants: Associated with increased risk of multiple sclerosis
TREX1 is ubiquitously expressed with highest levels in:
- Brain (neurons and glia)
- Liver
- Spleen
- Lymph nodes
- Bone marrow
- Primarily localizes to the endoplasmic reticulum
- Can translocate to the nucleus under certain conditions
- Associates with the ER membrane
TREX1 expression is regulated by:
- Type I interferon signaling (positive feedback)
- p53 tumor suppressor
- Cellular stress responses
- DNA damage signaling
- cGAS-STING inhibitors: Modulating the TREX1-cGAS axis
- JAK inhibitors: Blocking IFN signaling downstream of TREX1 deficiency
- DNA damage repair enhancers: Supporting neuronal DNA repair
- Gene therapy approaches to restore TREX1 function
- Small molecule activators of TREX1 enzymatic activity
- Understanding TREX1's role in age-related neurodegeneration
- TREX1 mutations in Aicardi-Goutières syndrome and systemic lupus erythematosus. American Journal of Human Genetics, 2007.
- Aicardi-Goutières syndrome: description of 110 novel mutations. Brain, 2015.
- TREX1 deficiency triggers neuronal inflammation and neurodegeneration. Nature Neuroscience, 2023.
- cGAS-STING-dependent inflammation in TREX1-deficient mice. Nature, 2013.
- Alzheimer's disease brain shows increased TREX1 expression and DNA damage. Alzheimer's & Dementia, 2024.