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Genetics, TREX1 Mutations

Editor: Anatalia Labilloy Updated: 9/19/2022 11:56:43 AM


Three prime repair exonuclease 1 (TREX1) is a widely expressed protein that acts as part of the SET complex in granzyme A-mediated apoptosis to degrade single-stranded DNA. TREX1 encodes a 3'-exonuclease 1 protein that removes nucleotides from the 3' ends of DNA molecules to remove unneeded fragments that may form during DNA replication. The TREX1 gene has also been found to play a role in immune regulation and viral infection. Research has found that mutations in this gene correlate with many diseases, including Aicardi-Goutieres syndrome (AGS), systemic lupus erythematosus (SLE), familial chilblain lupus (FCL), Cree encephalitis, cryofibrinogenemia, and retinal vasculopathy with cerebral leukodystrophy (RVCL).[1] This topic outlines the features of these various diseases and describes the role of TREX1 genes in the pathophysiology of these diseases.


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TREX1 was initially described in 1969 as DNase III and further characterized in 1999 in biochemical assays from rabbit liver and calf thymus and is considered the most abundant mammalian DNA-specific  3′ to 5′ exonuclease.[2][3] TREX1 plays an important role in genomic DNA degradation, cell death processes, and gap-filling during DNA repair or proofreading during lagging-strand DNA synthesis.[4][5][6][7] A connection between immune activation and TREX1 was first observed where TREX1 null mice developed inflammatory myocarditis due to an interferon-dependent autoimmune response leading to dilated cardiomyopathy and a significantly reduced survival.[7]

In a subsequent development, mutations in TREX1 were described in patients with Aicardi-Goutieres syndrome (AGS)[8], and more recently, malfunctioning of TREX1 has shown correlations with systemic lupus erythematosus (SLE), familial chilblain lupus (FCL), cryofibrinogenemia, and retinal vasculopathy with cerebral leukodystrophy (RVCL).[1]


TREX1 protein is typically in the cytosol and has a transmembrane domain that anchors the protein to the endoplasmic reticulum, allowing the protein to degrade extranuclear DNA in the cytosol and prevent abnormal accumulation.[9] TREX1 at least partly mobilizes to the cell nucleus in normal S-phase upon activation of caspase-independent cell death pathway and also in response to treatments with DNA-damaging agents.[10]


TREX1 is a member of the DEDDh family of 3′ to 5′ exonucleases, also named the DnaQ-like exonuclease family.[11][12] TREX1 degrades both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with a preference for ssDNA.[13] Single nucleotide G to A mutation at position 341 is one of the most common TREX1 mutations leading to the R114H substitution, which is found to be associated with AGS.[8][13][14][8][15][16]

Molecular Level

The TREX1 gene consists of a single exon and its location on chromosome 3.[17] TREX1 encodes a protein with 314 amino acids in length, and the only known post-translational modification of TREX1 is monoubiquitination by ubiqulin1 which regulates its endoplasmic reticulum localization.[14][18]

The TREX1 enzyme exists as a homodimer like many other 3' exonucleases and anchors to the endoplasmic reticulum through the carboxyl-terminus domain. It has a unique dimeric structure with a flexible region located adjacent to the active site. The symmetric and flexible dimer is responsible for the positioning of the active sites on opposite edges and facilitates DNA interactions by providing open access for DNA. The amino-terminus region of TREX1 contains the exonuclease domain, and the carboxyl-terminus region contains a hydrophobic leucine-rich sequence which is necessary for the endoplasmic reticulum localization. Although TREX1 catalytic effects are similar to Escherichia coli exonuclease X, TREX1 is only present in mammals.[13][14][13][19][17]


The excision of 3′ nucleotides to produce DNA 3′ termini suitable for downstream events is a critical step in DNA replication, repair, and recombination pathways. The 3′ to 5′ exonucleases play an important role in DNA repair pathways to excise mismatched, fragmented, modified, or even normal nucleotides from DNA 3′ termini.[20] Moreover, the 3′ to 5′ proofreading of DNA synthesis is 1 of the major factors that determine genome stability and mutagenesis. Cells with impaired 3′ exonuclease activities display genome instability, cell cycle defects, sensitivity to ionizing radiation, and a high incidence of cancers.[19][21]

The most important role of TREX1 is to maintain the host's innate immune tolerance to cytosolic self-DNA by degrading a range of substrates to prevent the initiation of autoimmunity.[4][10][22]


Studies have shown a clear mechanism by which TREX1 maintains the host's innate immune tolerance to cytosolic self-DNA. TREX1 mutations lead to the accumulation of self-DNA in the cytosol of TREX1-deficient cells. The persistence of the ssDNA species substrate of TREX1 triggers systemic inflammation and uncontrolled autoimmunity by chronic activation of checkpoint signaling and cGAS-STING-mediated type I interferon response.[4] TREX1 has a significant preference for special DNA sequences. Endogenous ssDNA species of 60 to 65 nucleotides, DNA viruses, and retroviruses are the sources of ssDNA species that could accumulate in TREX1-deficient cells.[10]

Previous studies have shown that TREX1 gene deletion in mice leads to inflammatory myocarditis and shortened lifespan due to an interferon-dependent autoimmune response.[7] Recessive missense mutations in TREX1 are mostly associated with AGS, whereas dominant frame-shift mutations are predominantly associated with RVCL.[4] The encephalopathy in AGS and the cardiomyopathy of TREX1 null mice are both autoinflammatory responses. Increased interferon-alpha (IFN-α) levels in AGS and SLE are similar to antiviral immune responses.[10]

Additionally, research has shown that the TREX1 is associated with the SET complex.[23] The SET complex is a DNA repair complex that is targeted by Granzyme A during caspase-independent T cell-mediated death.[24] TREX1 binds to the SET complex, translocates to the nucleus, and rapidly degrades 3′ ends of DNA during granzyme A-mediated cell death. Thus, TREX-1-deficient cells are relatively resistant to apoptosis.[10][23][25] Moreover, there are suggestions that there is a connection between chromothripsis in human cancer and TREX1-mediated chromosomal fragmentation in telomere crisis.[26]

The distinct activities of TREX1, the variety of its nucleic acid substrates, its role in DNA degradation in dying cells[23], and the linkage of TREX1 to human cancer by chromosomal fragmentation in telomere crisis have made it recognizable as an important factor in the treatment of cancers.[26][27][28]

Clinical Significance

Malfunctioning of TREX1 is associated with a broad spectrum of inflammatory and autoimmune diseases which are apparently independent such as Aicardi-Goutieres syndrome (AGS),[8][15] systemic lupus erythematosus (SLE),[29] familial chilblain lupus (FCL),[30][31] cryofibrinogenemia,[32] and retinal vasculopathy with cerebral leukodystrophy (RVCL).[17] Clinical overlap and elevated levels of type-I interferon among these autoimmune disorders are likely related to the accumulation of self-DNA and a subsequent aberrant immune response.[15][33][34]

Aicardi-Goutieres syndrome (AGS) is a genetically heterogeneous progressive encephalopathy that presents as a severe encephalopathy with demyelination, calcification of white matter and basal ganglia, and chronic CSF lymphocytosis. Disruption of innate immunity is a primary pathogenic event in AGS, and disrupted TREX1 enzyme fails to maintain host innate immune tolerance to cytosolic self-DNA and results in an abnormal innate immune response.[8][15]There are currently seven different genes associated with AGS, which include ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and TREX1[35]

AGS is an autosomal recessive disease and has 2 clinical presentations:

  1. An early-onset neonatal form: Most frequently associated with recessive missense mutations in the TREX1 gene; presents in infancy as progressive microcephaly, dystonia, spasticity, and psychomotor retardation
  2. A later-onset presentation: Particularly due to mutations in the RNASEH2B subunit of the RNASEH2 endonuclease complex.[4][15][36]

Cree encephalitis and intracranial calcification syndrome (MICS), which were first described as separate disorders, have been found to have increased levels of interferon-alpha (IFN-alpha) and considerable overlap with AGS.[8][37]

Systemic lupus erythematosus (SLE) is a chronic, autoimmune, multisystem, and clinically heterogeneous disorder with a multifactorial etiology in which genetic, hormonal, immunologic, and environmental factors play a role. As with AGS, SLE is notable for its interferon-alpha (IFN-α)  activation signature. Researchers have identified that TREX1 is involved in SLE pathogenesis although rarely TREX1 mutations have been reported in sporadic SLE cases.[29][31][38]

Familial chilblain lupus (FCL) is a rare form of cutaneous lupus erythematosus presenting in early childhood with painful inflammatory skin lesions on fingers, ears, nose, toes, and cheeks which are aggravated by cold. Other manifestations include arthralgias and positive antinuclear antibodies. This disorder demonstrates an autosomal dominant inheritance and is mostly due to TREX1 mutations.[30][31][39]

Cryofibrinogenemia is a rare disorder due to the formation of cryoprecipitate in plasma and manifests with cold-induced acrocyanosis and skin lesions due to cutaneous ischemia. Cutaneous lesions typically involve hands, feet, ears, nose, and buttocks. Recent observations suggest that heterozygous mutations in TREX1 are associated with Cryofibrinogenemia.[32][40]

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare genetic disorder with an autosomal dominant inheritance pattern. RVCL is characterized by microvascular endotheliopathy that involves the cerebrum, retina, kidney, and other systemic microvessels. Research has recognized that carboxyl-terminus frameshift mutations in the TREX1 gene contribute to RVCL. Muted TREX1 protein maintains DNase activity, but aberrant localization of muted protein due to impaired translocation into the nucleus in response to oxidative DNA damage may be associated with systemic microvascular endotheliopathy in patients with RVCL.[17][41]

TREX1 also plays an important role in modulating the innate immune response to type 1 human immunodeficiency retrovirus (HIV-1). Partial length DNA species produced by abortive HIV-1 reverse transcriptase get cleared by TREX1 enzyme leading to escape from type I interferon antiviral response.[4][42] In the absence of TREX1, accumulated cytosolic HIV DNA species are detected by the nucleic acid sensors, leading to induce type 1 interferon response, thereby delaying HIV infection and suppressing viral replication.[43]



Huang KW, Liu TC, Liang RY, Chu LY, Cheng HL, Chu JW, Hsiao YY. Structural basis for overhang excision and terminal unwinding of DNA duplexes by TREX1. PLoS biology. 2018 May:16(5):e2005653. doi: 10.1371/journal.pbio.2005653. Epub 2018 May 7     [PubMed PMID: 29734329]


Lindahl T, Gally JA, Edelman GM. Properties of deoxyribonuclease 3 from mammalian tissues. The Journal of biological chemistry. 1969 Sep 25:244(18):5014-9     [PubMed PMID: 5824576]

Level 3 (low-level) evidence


Perrino FW, Mazur DJ, Ward H, Harvey S. Exonucleases and the incorporation of aranucleotides into DNA. Cell biochemistry and biophysics. 1999:30(3):331-52     [PubMed PMID: 10403055]

Level 3 (low-level) evidence


Yan N. Immune Diseases Associated with TREX1 and STING Dysfunction. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2017 May:37(5):198-206. doi: 10.1089/jir.2016.0086. Epub     [PubMed PMID: 28475463]


Mazur DJ, Perrino FW. Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3'--}5' exonucleases. The Journal of biological chemistry. 1999 Jul 9:274(28):19655-60     [PubMed PMID: 10391904]

Level 3 (low-level) evidence


Höss M, Robins P, Naven TJ, Pappin DJ, Sgouros J, Lindahl T. A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein. The EMBO journal. 1999 Jul 1:18(13):3868-75     [PubMed PMID: 10393201]

Level 3 (low-level) evidence


Morita M, Stamp G, Robins P, Dulic A, Rosewell I, Hrivnak G, Daly G, Lindahl T, Barnes DE. Gene-targeted mice lacking the Trex1 (DNase III) 3'--}5' DNA exonuclease develop inflammatory myocarditis. Molecular and cellular biology. 2004 Aug:24(15):6719-27     [PubMed PMID: 15254239]

Level 3 (low-level) evidence


Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, van Bokhoven H, Brunner HG, Hamel BC, Corry PC, Cowan FM, Frints SG, Klepper J, Livingston JH, Lynch SA, Massey RF, Meritet JF, Michaud JL, Ponsot G, Voit T, Lebon P, Bonthron DT, Jackson AP, Barnes DE, Lindahl T. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nature genetics. 2006 Aug:38(8):917-20     [PubMed PMID: 16845398]

Level 3 (low-level) evidence


Thomas CA, Tejwani L, Trujillo CA, Negraes PD, Herai RH, Mesci P, Macia A, Crow YJ, Muotri AR. Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation. Cell stem cell. 2017 Sep 7:21(3):319-331.e8. doi: 10.1016/j.stem.2017.07.009. Epub 2017 Aug 10     [PubMed PMID: 28803918]


Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell. 2007 Nov 30:131(5):873-86     [PubMed PMID: 18045533]

Level 3 (low-level) evidence


Zuo Y, Deutscher MP. Exoribonuclease superfamilies: structural analysis and phylogenetic distribution. Nucleic acids research. 2001 Mar 1:29(5):1017-26     [PubMed PMID: 11222749]

Level 3 (low-level) evidence


Hsiao YY, Fang WH, Lee CC, Chen YP, Yuan HS. Structural insights into DNA repair by RNase T--an exonuclease processing 3' end of structured DNA in repair pathways. PLoS biology. 2014 Mar:12(3):e1001803. doi: 10.1371/journal.pbio.1001803. Epub 2014 Mar 4     [PubMed PMID: 24594808]


Lindahl T, Barnes DE, Yang YG, Robins P. Biochemical properties of mammalian TREX1 and its association with DNA replication and inherited inflammatory disease. Biochemical Society transactions. 2009 Jun:37(Pt 3):535-8. doi: 10.1042/BST0370535. Epub     [PubMed PMID: 19442247]

Level 3 (low-level) evidence


Orebaugh CD, Fye JM, Harvey S, Hollis T, Perrino FW. The TREX1 exonuclease R114H mutation in Aicardi-Goutières syndrome and lupus reveals dimeric structure requirements for DNA degradation activity. The Journal of biological chemistry. 2011 Nov 18:286(46):40246-54. doi: 10.1074/jbc.M111.297903. Epub 2011 Sep 21     [PubMed PMID: 21937424]


Rice G, Patrick T, Parmar R, Taylor CF, Aeby A, Aicardi J, Artuch R, Montalto SA, Bacino CA, Barroso B, Baxter P, Benko WS, Bergmann C, Bertini E, Biancheri R, Blair EM, Blau N, Bonthron DT, Briggs T, Brueton LA, Brunner HG, Burke CJ, Carr IM, Carvalho DR, Chandler KE, Christen HJ, Corry PC, Cowan FM, Cox H, D'Arrigo S, Dean J, De Laet C, De Praeter C, Dery C, Ferrie CD, Flintoff K, Frints SG, Garcia-Cazorla A, Gener B, Goizet C, Goutieres F, Green AJ, Guet A, Hamel BC, Hayward BE, Heiberg A, Hennekam RC, Husson M, Jackson AP, Jayatunga R, Jiang YH, Kant SG, Kao A, King MD, Kingston HM, Klepper J, van der Knaap MS, Kornberg AJ, Kotzot D, Kratzer W, Lacombe D, Lagae L, Landrieu PG, Lanzi G, Leitch A, Lim MJ, Livingston JH, Lourenco CM, Lyall EG, Lynch SA, Lyons MJ, Marom D, McClure JP, McWilliam R, Melancon SB, Mewasingh LD, Moutard ML, Nischal KK, Ostergaard JR, Prendiville J, Rasmussen M, Rogers RC, Roland D, Rosser EM, Rostasy K, Roubertie A, Sanchis A, Schiffmann R, Scholl-Burgi S, Seal S, Shalev SA, Corcoles CS, Sinha GP, Soler D, Spiegel R, Stephenson JB, Tacke U, Tan TY, Till M, Tolmie JL, Tomlin P, Vagnarelli F, Valente EM, Van Coster RN, Van der Aa N, Vanderver A, Vles JS, Voit T, Wassmer E, Weschke B, Whiteford ML, Willemsen MA, Zankl A, Zuberi SM, Orcesi S, Fazzi E, Lebon P, Crow YJ. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. American journal of human genetics. 2007 Oct:81(4):713-25     [PubMed PMID: 17846997]


Crow YJ, Rehwinkel J. Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Human molecular genetics. 2009 Oct 15:18(R2):R130-6. doi: 10.1093/hmg/ddp293. Epub     [PubMed PMID: 19808788]


Richards A, van den Maagdenberg AM, Jen JC, Kavanagh D, Bertram P, Spitzer D, Liszewski MK, Barilla-Labarca ML, Terwindt GM, Kasai Y, McLellan M, Grand MG, Vanmolkot KR, de Vries B, Wan J, Kane MJ, Mamsa H, Schäfer R, Stam AH, Haan J, de Jong PT, Storimans CW, van Schooneveld MJ, Oosterhuis JA, Gschwendter A, Dichgans M, Kotschet KE, Hodgkinson S, Hardy TA, Delatycki MB, Hajj-Ali RA, Kothari PH, Nelson SF, Frants RR, Baloh RW, Ferrari MD, Atkinson JP. C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nature genetics. 2007 Sep:39(9):1068-70     [PubMed PMID: 17660820]


Orebaugh CD, Fye JM, Harvey S, Hollis T, Wilkinson JC, Perrino FW. The TREX1 C-terminal region controls cellular localization through ubiquitination. The Journal of biological chemistry. 2013 Oct 4:288(40):28881-92. doi: 10.1074/jbc.M113.503391. Epub 2013 Aug 26     [PubMed PMID: 23979357]


de Silva U, Choudhury S, Bailey SL, Harvey S, Perrino FW, Hollis T. The crystal structure of TREX1 explains the 3' nucleotide specificity and reveals a polyproline II helix for protein partnering. The Journal of biological chemistry. 2007 Apr 6:282(14):10537-43     [PubMed PMID: 17293595]

Level 3 (low-level) evidence


Mazur DJ, Perrino FW. Excision of 3' termini by the Trex1 and TREX2 3'--}5' exonucleases. Characterization of the recombinant proteins. The Journal of biological chemistry. 2001 May 18:276(20):17022-9     [PubMed PMID: 11279105]

Level 3 (low-level) evidence


Nick McElhinny SA,Pavlov YI,Kunkel TA, Evidence for extrinsic exonucleolytic proofreading. Cell cycle (Georgetown, Tex.). 2006 May;     [PubMed PMID: 16687920]


Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008 Aug 22:134(4):587-98. doi: 10.1016/j.cell.2008.06.032. Epub     [PubMed PMID: 18724932]

Level 3 (low-level) evidence


Chowdhury D, Beresford PJ, Zhu P, Zhang D, Sung JS, Demple B, Perrino FW, 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. Molecular cell. 2006 Jul 7:23(1):133-42     [PubMed PMID: 16818237]


Beresford PJ, Zhang D, Oh DY, Fan Z, Greer EL, Russo ML, Jaju M, Lieberman J. Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks. The Journal of biological chemistry. 2001 Nov 16:276(46):43285-93     [PubMed PMID: 11555662]

Level 3 (low-level) evidence


Christmann M, Tomicic MT, Aasland D, Berdelle N, Kaina B. Three prime exonuclease I (TREX1) is Fos/AP-1 regulated by genotoxic stress and protects against ultraviolet light and benzo(a)pyrene-induced DNA damage. Nucleic acids research. 2010 Oct:38(19):6418-32. doi: 10.1093/nar/gkq455. Epub 2010 May 28     [PubMed PMID: 20511593]

Level 3 (low-level) evidence


Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T. Chromothripsis and Kataegis Induced by Telomere Crisis. Cell. 2015 Dec 17:163(7):1641-54. doi: 10.1016/j.cell.2015.11.054. Epub     [PubMed PMID: 26687355]


Wilson R, Espinosa-Diez C, Kanner N, Chatterjee N, Ruhl R, Hipfinger C, Advani SJ, Li J, Khan OF, Franovic A, Weis SM, Kumar S, Coussens LM, Anderson DG, Chen CC, Cheresh DA, Anand S. MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment. Nature communications. 2016 Nov 25:7():13597. doi: 10.1038/ncomms13597. Epub 2016 Nov 25     [PubMed PMID: 27886180]


Erdal E, Haider S, Rehwinkel J, Harris AL, McHugh PJ. A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1. Genes & development. 2017 Feb 15:31(4):353-369. doi: 10.1101/gad.289769.116. Epub 2017 Mar 9     [PubMed PMID: 28279982]


Namjou B,Kothari PH,Kelly JA,Glenn SB,Ojwang JO,Adler A,Alarcón-Riquelme ME,Gallant CJ,Boackle SA,Criswell LA,Kimberly RP,Brown E,Edberg J,Stevens AM,Jacob CO,Tsao BP,Gilkeson GS,Kamen DL,Merrill JT,Petri M,Goldman RR,Vila LM,Anaya JM,Niewold TB,Martin J,Pons-Estel BA,Sabio JM,Callejas JL,Vyse TJ,Bae SC,Perrino FW,Freedman BI,Scofield RH,Moser KL,Gaffney PM,James JA,Langefeld CD,Kaufman KM,Harley JB,Atkinson JP, Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes and immunity. 2011 Jun;     [PubMed PMID: 21270825]

Level 2 (mid-level) evidence


Lee-Kirsch MA, Chowdhury D, Harvey S, Gong M, Senenko L, Engel K, Pfeiffer C, Hollis T, Gahr M, Perrino FW, Lieberman J, Hubner N. A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. Journal of molecular medicine (Berlin, Germany). 2007 May:85(5):531-7     [PubMed PMID: 17440703]

Level 3 (low-level) evidence


Rice G, Newman WG, Dean J, Patrick T, Parmar R, Flintoff K, Robins P, Harvey S, Hollis T, O'Hara A, Herrick AL, Bowden AP, Perrino FW, Lindahl T, Barnes DE, Crow YJ. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. American journal of human genetics. 2007 Apr:80(4):811-5     [PubMed PMID: 17357087]


Paradis C, Cadieux-Dion M, Meloche C, Gravel M, Paradis J, Des Roches A, Leclerc G, Cossette P, Begin P. TREX-1-Related Disease Associated with the Presence of Cryofibrinogenemia. Journal of clinical immunology. 2019 Jan:39(1):118-125. doi: 10.1007/s10875-018-0584-x. Epub 2019 Jan 26     [PubMed PMID: 30685859]


Kavanagh D,Spitzer D,Kothari PH,Shaikh A,Liszewski MK,Richards A,Atkinson JP, New roles for the major human 3'-5' exonuclease TREX1 in human disease. Cell cycle (Georgetown, Tex.). 2008 Jun 15;     [PubMed PMID: 18583934]


Ramantani G, Kohlhase J, Hertzberg C, Innes AM, Engel K, Hunger S, Borozdin W, Mah JK, Ungerath K, Walkenhorst H, Richardt HH, Buckard J, Bevot A, Siegel C, von Stülpnagel C, Ikonomidou C, Thomas K, Proud V, Niemann F, Wieczorek D, Häusler M, Niggemann P, Baltaci V, Conrad K, Lebon P, Lee-Kirsch MA. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. Arthritis and rheumatism. 2010 May:62(5):1469-77. doi: 10.1002/art.27367. Epub     [PubMed PMID: 20131292]


Crow YJ, Manel N. Aicardi-Goutières syndrome and the type I interferonopathies. Nature reviews. Immunology. 2015 Jul:15(7):429-40. doi: 10.1038/nri3850. Epub 2015 Jun 5     [PubMed PMID: 26052098]


Crow YJ, Jackson AP, Roberts E, van Beusekom E, Barth P, Corry P, Ferrie CD, Hamel BC, Jayatunga R, Karbani G, Kálmánchey R, Kelemen A, King M, Kumar R, Livingstone J, Massey R, McWilliam R, Meager A, Rittey C, Stephenson JB, Tolmie JL, Verrips A, Voit T, van Bokhoven H, Brunner HG, Woods CG. Aicardi-Goutières syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3p21. American journal of human genetics. 2000 Jul:67(1):213-21     [PubMed PMID: 10827106]


Crow YJ,Black DN,Ali M,Bond J,Jackson AP,Lefson M,Michaud J,Roberts E,Stephenson JB,Woods CG,Lebon P, Cree encephalitis is allelic with Aicardi-Goutiéres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism. Journal of medical genetics. 2003 Mar;     [PubMed PMID: 12624136]


Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, de Silva U, Bailey SL, Witte T, Vyse TJ, Kere J, Pfeiffer C, Harvey S, Wong A, Koskenmies S, Hummel O, Rohde K, Schmidt RE, Dominiczak AF, Gahr M, Hollis T, Perrino FW, Lieberman J, Hübner N. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nature genetics. 2007 Sep:39(9):1065-7     [PubMed PMID: 17660818]


Beltoise AS, Audouin-Pajot C, Lucas P, Tournier E, Rice GI, Crow YJ, Mazereeuw-Hautier J. [Familial chilblain lupus: Four cases spanning three generations]. Annales de dermatologie et de venereologie. 2018 Nov:145(11):683-689. doi: 10.1016/j.annder.2018.07.014. Epub 2018 Sep 11     [PubMed PMID: 30217686]

Level 3 (low-level) evidence


Chou HF, Wu YH, Ho CS, Kao YH. Clinical study of children with cryofibrinogenemia: a retrospective study from a single center. Pediatric rheumatology online journal. 2018 Apr 24:16(1):31. doi: 10.1186/s12969-018-0249-6. Epub 2018 Apr 24     [PubMed PMID: 29690915]

Level 2 (mid-level) evidence


Saito R,Nozaki H,Kato T,Toyoshima Y,Tanaka H,Tsubata Y,Morioka T,Horikawa Y,Oyanagi K,Morita T,Onodera O,Kakita A, Retinal Vasculopathy With Cerebral Leukodystrophy: Clinicopathologic Features of an Autopsied Patient With a Heterozygous TREX 1 Mutation. Journal of neuropathology and experimental neurology. 2019 Feb 1;     [PubMed PMID: 30561700]


Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA, Lieberman J. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nature immunology. 2010 Nov:11(11):1005-13. doi: 10.1038/ni.1941. Epub 2010 Sep 26     [PubMed PMID: 20871604]

Level 3 (low-level) evidence


Wheeler LA, Trifonova RT, Vrbanac V, Barteneva NS, Liu X, Bollman B, Onofrey L, Mulik S, Ranjbar S, Luster AD, Tager AM, Lieberman J. TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice. Cell reports. 2016 May 24:15(8):1715-27. doi: 10.1016/j.celrep.2016.04.048. Epub 2016 May 12     [PubMed PMID: 27184854]