Alternative titles; symbols
HGNC Approved Gene Symbol: TREX1
SNOMEDCT: 783787000;
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:48,465,830-48,467,645 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | {Systemic lupus erythematosus, susceptibility to} | 152700 | Autosomal dominant | 3 |
| Aicardi-Goutieres syndrome 1, dominant and recessive | 225750 | Autosomal dominant; Autosomal recessive | 3 | |
| Chilblain lupus | 610448 | Autosomal dominant | 3 | |
| Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations | 192315 | Autosomal dominant | 3 |
The multistep processes of DNA replication, repair, and recombination require the excision of nucleotides from DNA 3-prime termini. Enzymes containing 3-prime-to-5-prime exonuclease activity remove mismatched, modified, fragmented, and normal nucleotides to generate the appropriate 3-prime termini for subsequent steps in the DNA metabolic pathways (Mazur and Perrino, 1999).
By micropeptide sequence analysis of the 30-kD bovine Trex1 protein, PCR with degenerate primers, and EST database searching, Mazur and Perrino (1999) obtained cDNAs encoding mouse and human TREX1 and TREX2 (300370). Sequence analysis predicted that the 304-amino acid TREX1 protein is 44% identical to TREX2 (Mazur and Perrino (2001) corrected the TREX1 sequence to 314 amino acids). TREX1 contains 3 conserved exonuclease motifs, with an HxAxxD sequence in the third motif. Functional analysis confirmed that the 3-prime-to-5-prime exonuclease activity of the recombinant protein is comparable to that of the native protein and prefers mismatched 3-prime termini. Mazur and Perrino (1999) concluded that the TREX proteins are small, independent 3-prime excision enzymes, whereas the multifunctional p53 (191170) and WRN (RECQL2; 604611) proteins, which also have 3-prime-to-5-prime exonuclease activity, are much larger.
Using rabbit Trex1 to search an EST database, Hoss et al. (1999) also isolated human TREX1, which they termed DNase III. Northern blot analysis revealed expression of a 1.15-kb TREX1 transcript in all tissues tested.
Mazur and Perrino (2001) used 5-prime RACE to identify the flanking region of TREX1. Genomic sequence analysis suggested that TREX1 open reading frames are produced by a variety of mechanisms, including alternate promoter usage, alternative splicing, and varied sites for 3-prime cleavage. RT-PCR analysis detected ubiquitous expression of TREX1.
The TREX1 gene contains a single exon (Hoss et al., 1999; Mazur and Perrino, 2001).
Hoss et al. (1999) and Mazur and Perrino (2001) identified clones containing the TREX1 gene that map to chromosome 3p21.3-p21.2.
SET (600960) and NM23H1 (NME1; 156490) reside in an endoplasmic reticulum-associated complex, the SET complex, that translocates to the nucleus in response to superoxide generation by granzyme A (GZMA; 140050). Chowdhury et al. (2006) identified TREX1 as a component of the SET complex. TREX1 bound SET and colocalized and translocated with the SET complex. On its own, TREX1 did not damage intact DNA, but it acted in concert with NM23H1 to destroy DNA during granzyme A-mediated cell death. After NM23H1 nicked 1 strand, TREX1 removed bases from the free 3-prime end to enhance the damage and prevent DNA end reannealing and repair.
Using mass spectrometry and Western blot analysis, Stetson et al. (2008) identified mouse Trex1 as a protein involved in recognition of interferon stimulatory DNA (ISD) BrdU-labeled intracellular oligonucleotides. Microarray analysis showed that Trex1 was upregulated in response to ISD stimulation. However, Trex1 -/- cells retained an intact ISD response, ruling out Trex1 as the ISD sensor. In contrast with Trex1 -/- mice, which succumb to lethal autoimmunity (see ANIMAL MODEL), Trex1 -/- mice lacking Irf3 (603734), Ifnar1 (107450), or Rag2 (179616) survived and regained normal body weight through amelioration of disease at discrete phases, indicating that TREX1 substrates are ligands of the ISD pathway. Single-stranded DNA derived from endogenous retroelements accumulated in Trex1 -/- cells, and Trex1 metabolized reverse-transcribed DNA. Stetson et al. (2008) concluded that TREX1 is an essential negative regulator of the ISD response and represents a mechanism to prevent autoimmunity caused by endogenous retroelements.
Yan et al. (2010) observed enhanced Ifnb (147640) and Il6 (147620) expression in Trex1 -/- mouse embryonic fibroblasts (MEFs) infected with pseudotyped human immunodeficiency virus (HIV)-1 (see 609423) compared with uninfected Trex1 -/- MEFs or infected wildtype MEFs. Ifnb induction was mediated by reverse transcribed HIV in an Irf3 (603734)-dependent manner. HIV reverse transcripts accumulated in Trex -/- MEFs. HIV-stimulated Ifnb from Trex1 -/- MEFs inhibited HIV. Yan et al. (2010) observed an increase in cytosolic HIV DNA and reduced viral spreading, accompanied by increased IFNA (147660) and IFNB expression, in human monocyte-derived macrophages treated with small interfering RNA (siRNA) against TREX1 and subsequently infected with HIV-1. Treatment of Trex1 -/- MEFs with siRNA against genes related to innate immunity showed that HIV DNA was detected by a pathway that signaled through Sting (TMEM173; 612374), Tbk1 (604834), and Irf3 but not nucleic acid sensors. Yan et al. (2010) proposed that HIV-1 uses TREX1 to avoid triggering antiviral innate immunity.
Using mutation analysis with recombinant human TREX1, Fye et al. (2011) found that arg174 and lys175 within the flexible loop and arg128 in the catalytic core contributed to single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) degradation. TREX1 degraded endonuclease-treated hamster liver nuclei, suggesting that TREX1 contributes to apoptosis-associated DNA degradation.
Mutations in the TREX1 gene cause the type I IFN-associated autoimmune disease Aicardi-Goutieres syndrome (AGS1; 225750). Ablasser et al. (2014) found that knockout of the DNA sensor Cgas (MB21D1; 613973) in Trex1-deficient mouse cells abrogated spontaneous induction of IFN-stimulated genes. They concluded that CGAS is a nonredundant sensor for endogenous DNA species and proposed that it may have value for the development of novel therapeutic approaches in sterile inflammatory conditions.
By differentiating neural stem cells into astrocytes and treating them with short hairpin RNA (shRNAs) to AGS genes, Cuadrado et al. (2015) observed increased apoptosis in cells treated with shRNA to TREX1. Similarly, TREX1 silencing led to reduced proliferation of endothelial cells, but not of cells involved in angiogenesis. Silencing of TREX1 or SAMHD1 (606754), but not RNASEH2A (606034) or ADAR1 (146920), resulted in enhanced expression of IFN-stimulated genes (ISGs), such as IFIT1 (147690). TREX1 shRNA treatment led to increased production of proinflammatory and chemotactic cytokines. Cuadrado et al. (2015) proposed that activation of antiviral status in astrocytes and endothelial cells may lead to cerebral pathology and ultimately severe disease in AGS.
Maciejowski et al. (2020) examined the mechanism underlying chromothripsis and kataegis using an in vitro telomere crisis model in human cells and showed that the cytoplasmic exonuclease TREX1, which promotes resolution of dicentric chromosomes, played a prominent role in chromothriptic fragmentation. In the absence of TREX1, genome alterations induced by telomere crisis primarily involved breakage-fusion-bridge cycles and simple genome rearrangements rather than chromothripsis. Kataegis observed at chromothriptic breakpoints was due to cytosine deamination by APOBEC3B (607110). Maciejowski et al. (2020) concluded that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.
Aicardi-Goutieres Syndrome 1
In affected members of 10 families with Aicardi-Goutieres syndrome (AGS1; 225750), Crow et al. (2006) identified 5 different mutations in the TREX1 gene in homozygous or compound heterozygous state (see, e.g., 606609.0001-606609.0004). One of the mutations, R114H (606609.0001), was identified in 7 European pedigrees. Crow et al. (2006) identified a homozygous mutation in the TREX1 gene (606609.0002) in a patient originally diagnosed with Cree encephalitis, indicating that Cree encephalitis is the same disorder as AGS1.
Rice et al. (2007) described a de novo heterozygous TREX1 mutation, affecting a critical catalytic residue in TREX1 (D200N; 606609.0006), that resulted in typical Aicardi-Goutieres syndrome, thus defining a dominant form of the disorder.
Haaxma et al. (2010) reported a second patient with Aicardi-Goutieres syndrome and a de novo heterozygous TREX1 mutation (D18N; 606609.0007). The D18N mutation had previously been identified in heterozygosity by Lee-Kirsch et al. (2007) in a family with chilblain lupus.
Susceptibility to Systemic Lupus Erythematosus
Aicardi-Goutieres syndrome shows overlap with systemic erythematosus (SLE; 152700) at both clinical and pathologic levels. Lee-Kirsch et al. (2007) analyzed the TREX1 gene in 417 patients with SLE and 1,712 controls and identified heterozygosity for a 3-prime UTR variant and 11 nonsynonymous changes in 12 patients (see, e.g., 606609.0001). They found only 2 nonsynonymous changes in 2 controls (p = 1.7 X 10(-7), relative risk = 25.3). In vitro studies of 2 frameshift mutations revealed that both caused altered subcellular distribution.
Chilblain Lupus
Rice et al. (2007) reported a heterozygous TREX1 mutation (606609.0005) causing familial chilblain lupus (CHBL; 610448), a rare cutaneous form of SLE.
In affected members of the large 5-generation German family with chilblain lupus in which the disease was mapped to chromosome 3p21-p14 by Lee-Kirsch et al. (2006), Lee-Kirsch et al. (2007) identified heterozygosity for a missense mutation (D18N; 606609.0007) in the TREX1 gene.
Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
In 9 families with autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS; 192315), Richards et al. (2007) identified 5 different heterozygous frameshift mutations at the C terminus of the TREX1 gene (see, e.g., 606609.0008 and 606609.0009). In expression studies, the truncated proteins retained exonuclease activity but lost normal perinuclear localization.
The TREX1 D200N and D18N dominant heterozygous mutations are associated with AGS1 and CHBL, respectively. Using exonuclease enzyme analysis, Lehtinen et al. (2008) showed that TREX1 heterodimers containing wildtype TREX1 and either D200N or D18N mutant proteins were completely deficient in degrading dsDNA and degraded ssDNA at an approximately 2-fold lower rate than wildtype TREX1. In addition, D200N- and D18N-containing homo- and heterodimers inhibited the dsDNA degradation activity of wildtype TREX1, providing an explanation for the dominant phenotype of the mutant alleles. In contrast, the R114H mutation, which causes AGS1 when present as a homozygous mutation and SLE when present as a heterozygous mutation, had dysfunctional dsDNA and ssDNA degradation activities as a homodimer, but it was functional as a heterodimer. The R114H homodimer lacked inhibitory activity against wildtype TREX1, supporting the recessive genetics of the R114H mutation in AGS1. Lehtinen et al. (2008) concluded that the dysfunctional dsDNA activities of the disease-related TREX1 mutants could account for persistent dsDNA from dying cells leading to an aberrant autoimmune response in these disorders.
Morita et al. (2004) found that Trex1 -/- mice developed inflammatory myocarditis, suggesting a role for this enzyme in immune regulation.
Peschke et al. (2016) found that mice with conditional loss of Trex1 in dendritic cells had increased Ifn-inducible gene expression (e.g., IFI44; 610468) and autoimmunity, as assessed by histologic analysis. Loss of Trex1 in keratinocytes or microglia resulted in Ifn production but did not induce inflammation. Inactivation of Trex1 in B cells, cardiomyocytes, neurons, or astrocytes did not produce detectable responses. Peschke et al. (2016) concluded that TREX1 expression in dendritic cells is essential to prevent loss of self-tolerance resulting from aberrant detection of endogenous DNA.
Simpson et al. (2020) found that mice expressing the catalytically inactive D18N Trex1 mutation developed lupus-like autoimmunity associated with self-DNA sensing and abnormal expression of IFN-alpha and -beta in T cells. Trex1 inactivation resulted in activated T cells that constitutively expressed all molecular components of the DNA sensing and signaling pathways required for cytosolic DNA detection and IFN-alpha/beta production, leading to abnormal production of type I IFN in T cells and, consequently, autoimmunity.
Aicardi-Goutieres Syndrome 1
In affected members of 7 families of European origin with Aicardi-Goutieres syndrome-1 (AGS1; 225750), Crow et al. (2006) identified a 341G-A transition in the TREX1 gene, resulting in an arg114-to-his (R114H) substitution at a residue predicted to be involved in protein dimerization. Five of the families were homozygous for the mutation and 2 were compound heterozygous with another TREX1 mutation (606609.0003). Patient-derived fibroblasts showed no detectable TREX1 3-prime exonuclease activity.
In an extensive study of the clinical and molecular phenotypes of Aicardi-Goutieres syndrome, Rice et al. (2007) found biallelic mutations in TREX1 in 31 of 127 families with the clinical diagnosis of the disorder. Eighteen families, 14 of which were of northern European origin, were homozygous (15) or compound heterozygous (3) for the 341G-A transition (R114H). Notably, all R114H homozygotes were also homozygous for the T allele of a SNP at position 531. This allele exhibited highly significant (P less than 0.001) overrepresentation in patients compared with controls (with a T allele population frequency of 0.4), suggesting that R114H might be an ancient founder mutation.
Systemic Lupus Erythematosus, Susceptibility to
Lee-Kirsch et al. (2007) analyzed the TREX1 gene in 417 patients with systemic lupus erythematosus (152700) and identified heterozygosity for the R114H mutation in a European female patient who had nephritis, arthritis, and antinuclear and anti-dsDNA antibodies.
In a patient with Cree encephalitis, also known as Aicardi-Goutieres syndrome-1 (AGS1; 225750), who was born of consanguineous parents, Crow et al. (2006) identified a homozygous 490C-T transition in the TREX1 gene, resulting in an arg164-to-ter (R164X) substitution. A lymphoblastoid cell line derived from the patient showed no detectable 3-prime exonuclease activity. The findings confirmed that Cree encephalitis and AGS1 are the same disorder.
In affected members of 2 unrelated families with Aicardi-Goutieres syndrome (AGS1; 225750), Crow et al. (2006) identified compound heterozygosity for 2 mutations in the TREX1 gene: a 3-bp insertion (600_601insGAT), resulting in duplication of an aspartate residue involved in divalent cation binding within the catalytic site, and R114H (606609.0001).
In a patient with Aicardi-Goutieres syndrome (AGS1; 225750), who was born of consanguineous Turkish parents, Crow et al. (2006) identified a homozygous 602T-A transversion in the TREX1 gene, resulting in a val201-to-asp (V201D) substitution in the catalytic site of the protein. Patient-derived fibroblasts showed no detectable TREX1 3-prime exonuclease activity.
In a nonconsanguineous Bangladeshi family, Rice et al. (2007) found association between chilblain lupus (CHBL1; 610448) and a heterozygous mutation in the TREX1 gene, the duplication of a single base (375dupT) that resulted in a truncated protein missing the last 188 amino acids. The mutation was present in 3 affected sibs; it was found also in a fourth sib with a subclinical phenotype.
In a child with a classic history of Aicardi-Goutieres syndrome (AGS1; 225750), who was born to nonconsanguineous Scottish parents, Rice et al. (2007) found heterozygosity for a missense mutation in the TREX1 gene: a 598G-A transition that resulted in a substitution of asparagine for aspartic acid at codon 200 (D200N). Both parents had a homozygous wildtype genotype at this position, suggesting a de novo occurrence. Differentiation of the maternal and paternal alleles was possible because of a frequently observed C-to-T SNP at position 531, which allowed the authors to demonstrate that the mutation has arisen on the maternal allele. A standard exonuclease assay indicated close-to-normal TREX1 enzymatic activity. Rice et al. (2007) hypothesized that the aspartic acid at position 200 of TREX1 represents one of 4 residues essential for coordinating 2 magnesium ions involved in DNA binding and catalysis, and that the D200N mutation represents a gain-of-function mutation conferring altered substrate specificity, DNA binding, or protein-protein interaction which would not be detected in a standard TREX1 exonuclease assay.
Fye et al. (2011) stated that asp18 and asp200 are the 2 aspartates that coordinate the divalent metal ion Mg(2+) at the TREX1 active site and contribute to DNA binding and catalysis. They found that homodimers of recombinant human TREX1 containing D200N or D18N (606609.0007) mutations had negligible nuclease activity against ssDNA and dsDNA compared with wildtype. Heterodimers of wildtype TREX1 with D18N or D200N TREX1 mutants had more modestly reduced ssDNA nuclease activity, but profoundly reduced dsDNA nuclease activity, compared with wildtype homodimers. Fye et al. (2011) concluded that the dominant phenotypes of asp18 and asp200 mutations relate predominantly to impaired dsDNA degradation and indicate that TREX1 dsDNA degradation activity is fundamental to the prevention of autoimmunity.
Chilblain Lupus
In affected members of the large 5-generation German family with chilblain lupus (CHBL1; 610448) described by Lee-Kirsch et al. (2006), Lee-Kirsch et al. (2007) identified heterozygosity for a 52G-A transition in exon 1 of the TREX1 gene, resulting in an asp18-to-asn (D18N) substitution at a highly conserved residue critical for catalytic activity. The mutation was not found in unaffected family members or in 400 control chromosomes. Recombinant mutant TREX1 homodimers were enzymatically inactive, whereas mutant/wildtype heterodimers had approximately 40% of the activity of wildtype dimers, indicating that D18N is a loss-of-function allele that does not exhibit a dominant-negative effect. Compared to control cells, patient-derived lymphoblastoid cells were substantially less sensitive to cell death after treatment with granzyme A (GZMA; 140050) but not granzyme B (GZMB; 123910), indicating that D18N specifically interferes with GZMA-mediated cell death in the caspase-independent form of apoptosis.
Aicardi-Goutieres Syndrome 1
In a 16-year-old girl with relatively mild Aicardi-Goutieres syndrome (AGS1; 225750), who was negative for mutation in other known AGS genes, Haaxma et al. (2010) identified a de novo heterozygous D18N missense mutation in the TREX1 gene. The mutation was not found in either parent or in 200 control chromosomes. The patient also displayed features of mitochondrial disease, with cytochrome oxidase-negative and ragged-red fibers seen on histologic examination of the quadriceps muscle; biochemical measurements showed decreased overall energy production (ATP and CrP) in the presence of normal activities of individual respiratory chain complexes, again compatible with mitochondrial dysfunction. However, heteroduplex analysis of the entire mitochondrial DNA did not show any mutations. This patient also had peripheral neuropathy with prominent axonal loss and disturbances of myelination without strict demyelination.
Fye et al. (2011) stated that asp18 and asp200 are the 2 aspartates that coordinate the divalent metal ion Mg(2+) at the TREX1 active site and contribute to DNA binding and catalysis. They found that homodimers of recombinant human TREX1 containing D200N (606609.0006) or D18N mutations had negligible nuclease activity against ssDNA and dsDNA compared with wildtype. Heterodimers of wildtype TREX1 with D18N or D200N TREX1 mutants had more modestly reduced ssDNA nuclease activity, but profoundly reduced dsDNA nuclease activity, compared with wildtype homodimers. Fye et al. (2011) concluded that the dominant phenotypes of asp18 and asp200 mutations relates predominantly to impaired dsDNA degradation and indicates that TREX1 dsDNA degradation activity is fundamental to the prevention of autoimmunity.
In 5 families with autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS; 192315), including 2 North American families previously reported by Grand et al. (1988) and 1 Dutch pedigree originally described by Storimans et al. (1991), Richards et al. (2007) identified heterozygosity for a 1-bp insertion (3688G) at the C terminus of the TREX1 gene, resulting in a frameshift at val235 (V235fs). Haplotype analysis suggested that these families were not related. The mutation was not found in 192 Caucasian, 192 Chinese, or 300 Dutch control alleles. In expression studies, the truncated protein retained exonuclease activity but lost normal perinuclear localization.
In a North American family of Chinese ancestry with autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS; 192315), previously reported by Jen et al. (1997), Richards et al. (2007) identified heterozygosity for a 4-bp duplication (3727dupGTCA) at the C terminus of the TREX1 gene, resulting in a frameshift at thr249 (T249fs). The mutation was not found in 192 Caucasian, 192 Chinese, or 300 Dutch control alleles. In expression studies, the truncated protein retained exonuclease activity but lost normal perinuclear localization.
In a 2-month-old boy (patient 4) with Aicardi-Goutieres syndrome (AGS1; 225750), Adang et al. (2018) identified compound heterozygous mutations in the TREX1 gene: a c.506G-A transition, resulting in an arg169-to-his (R169H) substitution, and a 1-bp deletion (c.581delC), resulting in frameshift (Arg194fs). The patient presented with pulmonary hypertension that ultimately caused his death at 12 weeks of age. He also had CNS perivascular calcifications and gastrointestinal symptoms, but no dermatologic manifestations.
For discussion of the 1-bp deletion (c.581delC) in the TREX1 gene that was found in compound heterozygous state in a patient with Aicardi-Goutieres syndrome (AGS1; 225750) by Adang et al. (2018), see 606609.0010.
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Chowdhury, D., Beresford, P. J., Zhu, P., Zhang, D., Sung, J.-S., Demple, B., Perrino, F. W., Lieberman, J. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Molec. Cell 23: 133-142, 2006. [PubMed: 16818237] [Full Text: https://doi.org/10.1016/j.molcel.2006.06.005]
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