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TREX1

three prime repair exonuclease 1

Chromosome 3p21.31 Various HGNC:12269 Tier C
TREX1 3p21.31 p arm q arm 3

TREX1 is located on the short (p) arm of chromosome 3, at band 3p21.31. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 3 in the library →

Available at Jeen Health

Clinical tests that include this

Carrier Screening panel
TREX1 is 1 of 1,008 genes on this panel
Expanded carrier screening for recessive and X-linked conditions

Overview

TREX1 (three prime repair exonuclease 1) encodes a DNA-processing enzyme that plays a critical role in maintaining genomic stability and preventing aberrant immune activation. The protein functions as an exonuclease, removing nucleotides from the ends of DNA molecules to create clean, stable structures. This activity is particularly important for clearing DNA fragments that arise during routine cellular events such as DNA repair, cell division, and programmed cell death. Without effective TREX1 function, these DNA remnants can accumulate within cells and trigger inappropriate immune responses, as the immune system may recognise them as signs of viral infection. Pathogenic variants in TREX1 are associated with several inflammatory and neurological disorders, most notably Aicardi-Goutières syndrome.

What the gene does

The three prime repair exonuclease 1 enzyme removes DNA building blocks from the 3' ends of DNA molecules, a process essential for maintaining clean DNA termini throughout the cell. During normal cellular metabolism, various processes generate short DNA fragments and damaged nucleotides that require removal. TREX1 acts as a cellular quality-control mechanism, trimming these excess or incorrect nucleotides to prevent their accumulation. This editing function ensures that DNA ends remain stable and prevents fragmented DNA from persisting in the cytoplasm, where it could be detected by innate immune sensors. The enzyme localises to both the endoplasmic reticulum and the cytoplasm, depending on which regions of the protein are present. By removing DNA debris that might otherwise resemble viral genetic material, TREX1 helps prevent the immune system from mounting inflammatory responses against the body's own cellular components. When TREX1 function is compromised, unprocessed DNA accumulates and activates interferon signalling pathways, leading to chronic inflammation particularly affecting the brain and skin.

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Chromosome location

TREX1 is located on chromosome 3 at position 3p21.31. This chromosomal region contains numerous genes involved in immune regulation and cellular metabolism. The precise genomic context influences how variants in TREX1 may interact with other nearby genetic factors affecting inflammatory responses.

Protein structure

The TREX1 protein comprises 314 amino acids with distinct functional regions that determine its cellular localisation and activity. The C-terminal region is necessary for endoplasmic reticulum localisation (amino acids 236-314), anchoring the protein to this organelle membrane. A disordered region spans amino acids 240-278, which may provide structural flexibility. The protein contains an interaction region with UBQLN1 (amino acids 243-314), facilitating quality-control processes. The extreme C-terminus is necessary for cytoplasmic retention (amino acids 281-314), allowing the protein to process DNA in different cellular compartments depending on which portions are expressed.

Domain map · 314 amino acids
Necessary for endoplasmic reticulum localization (236-314)Interaction with UBQLN1 (243-314)Necessary for cytoplasmic retention (281-314)Necessary for endoplas236-314Interaction with UBQLN243-314Necessary for cytoplas281-3141~157314
Region - functional region
🧬 Explore 3D structure on AlphaFold
UniProt:Q9NSU2Length:314 aaStructure:AlphaFold

Key variants

Pathogenic variants in TREX1 typically result in loss of enzyme function, either by preventing protein production entirely or by disrupting the catalytic activity of the exonuclease domain. Most disease-causing changes are believed to eliminate the protein's ability to trim DNA fragments effectively. The variant spectrum includes missense changes that impair enzymatic activity, frameshift variants leading to premature termination, and deletions affecting critical functional regions.

No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.

Associated conditions

Variants in TREX1 are primarily associated with Aicardi-Goutières syndrome, a severe neuroinflammatory disorder characterised by brain calcification, white matter abnormalities, and skin lesions. The syndrome typically presents in early infancy with progressive brain dysfunction. TREX1 variants also cause Aicardi-Goutières syndrome type 1, the specific subtype linked to this gene. Additionally, some TREX1 changes have been identified in individuals with chilblain lupus, a rare form of systemic lupus erythematosus affecting primarily the skin, and in autosomal dominant retinal vasculopathy with cerebral leukodystrophy, which affects brain white matter and retinal blood vessels.

UK clinical status

TREX1 appears on multiple NHS Genomic Medicine Service gene panels, reflecting its clinical importance across several diagnostic pathways. The gene has green (diagnostic-grade) classification on panels including inherited white matter disorders, intracerebral calcification disorders, and intellectual disability. It is also included in panels for early onset or syndromic epilepsy, childhood onset dystonia or movement disorders, and adult onset leukodystrophy. TREX1's presence on the primary immunodeficiency panel reflects the immune dysregulation caused by variants in this gene. These panel memberships indicate that TREX1 sequencing may be offered through the NHS when patients present with relevant clinical features such as unexplained white matter changes, brain calcification, or early-onset neurological decline.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Dystonia, chorea or related movement disorder, childhood onset · R57 NHS GMS → Fetal anomalies · R21 NHS GMS → Leukodystrophy, adult onset · R62 NHS GMS → Likely inborn error of metabolism · R98 NHS GMS → Primary immunodeficiency or monogenic inflammatory bowel disease · R15 NHS GMS → Rare genetic inflammatory skin disorders · R332 NHS GMS → Retinal disorders · R32 NHS GMS → DDG2P NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Frequently asked questions

What does the TREX1 enzyme do in cells?

TREX1 functions as a DNA exonuclease that removes unwanted DNA fragments from cells. By trimming these DNA pieces, it prevents the immune system from mistaking normal cellular debris for viral genetic material, thereby avoiding inappropriate inflammatory responses.

How do TREX1 variants cause disease?

Pathogenic variants typically eliminate or severely reduce TREX1 enzyme activity, allowing DNA fragments to accumulate within cells. This accumulated DNA triggers immune sensors, leading to chronic interferon production and inflammation that particularly affects the developing brain, causing the features seen in Aicardi-Goutières syndrome.

Is TREX1 testing available through the NHS?

Yes, TREX1 is included on multiple NHS gene panels for conditions such as inherited white matter disorders, brain calcification, intellectual disability, and early-onset epilepsy. Testing may be offered when a patient's clinical features align with these diagnostic pathways, as determined by a specialist.

References

  1. Livingston JH, Crow YJ. Neurologic Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutières Syndrome and Beyond. Neuropediatrics. 2016. PMID: 27643693
  2. Crow YJ, Chase DS, Lowenstein Schmidt J. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. American journal of medical genetics. Part A. 2015. PMID: 25604658
  3. Cuadrado E, Michailidou I, van Bodegraven EJ. Phenotypic variation in Aicardi-Goutières syndrome explained by cell-specific IFN-stimulated gene response and cytokine release. Journal of immunology (Baltimore, Md. : 1950). 2015. PMID: 25769924
  4. Crow YJ. Aicardi-Goutières syndrome. Handbook of clinical neurology. 2013. PMID: 23622384
  5. Rice GI, Forte GM, Szynkiewicz M. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. The Lancet. Neurology. 2013. PMID: 24183309
  6. Lindahl T, Barnes DE, Yang YG. Biochemical properties of mammalian TREX1 and its association with DNA replication and inherited inflammatory disease. Biochemical Society transactions. 2009. PMID: 19442247
  7. Crow YJ, Rehwinkel J. Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Human molecular genetics. 2009. PMID: 19808788
  8. Kavanagh D, Spitzer D, Kothari PH. New roles for the major human 3'-5' exonuclease TREX1 in human disease. Cell cycle (Georgetown, Tex.). 2008. PMID: 18583934
  9. Lehtinen DA, Harvey S, Mulcahy MJ. The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease. The Journal of biological chemistry. 2008. PMID: 18805785
  10. Rice G, Newman WG, Dean J. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. American journal of human genetics. 2007. PMID: 17357087
  11. Rice G, Patrick T, Parmar R. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. American journal of human genetics. 2007. PMID: 17846997
  12. Adam MP, Bick S, Mirzaa GM. Aicardi-Goutières Syndrome. 1993. PMID: 20301648
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 17 April 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .