Genetics, TREX1 Mutations


Article Author:
Seyed Alireza Hosseini


Article Editor:
Anatalia Labilloy


Editors In Chief:
Sisira Reddy
Joseph Nahas
Chokkalingam Siva


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
6/17/2019 11:15:39 PM

Introduction

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] In this activity, we will outline features of these various diseases and describe the role of TREX1 genes in the pathophysiology of these diseases.

Development

TREX1, which stands for three prime repair exonuclease 1,  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]

Cellular

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]

Biochemical

TREX1 is a member of the DEDDh family of 3′ to 5′ exonucleases, also named 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.[14][8][15][16][13]

Molecular

The TREX1 gene consists of a single exon, and its location on chromosome 3.[17] TREX1 encodes a protein with 314 amino acid 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 with providing open access for DNA. The amino-terminus region of TREX1 contains exonuclease domain, and the carboxyl-terminus region contains a hydrophobic leucine-rich sequence which is necessary for endoplasmic reticulum localization. Although TREX1 catalytic effects are similar to Escherichia coli exonuclease X, TREX1 is only present in mammals.[14][13][19][17]

Function

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 one 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 host innate immune tolerance to cytosolic self-DNA by degrading a range of substrates to prevent initiation of autoimmunity.[4][10][22]

Pathophysiology

Studies have shown a clear mechanism by which TREX1 maintains host innate immune tolerance to cytosolic self-DNA. TREX1 mutations lead to accumulation of self-DNA in the cytosol of TREX1-deficient cells. 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 an autoinflammatory response. Increased interferon alpha (IFN-α) level in AGS and SLE is similar to antiviral immune responses.[10]

Additionally, research has shown that the TREX1 associates 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, translocate 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]

Distinct activities of TREX1, variety of its nucleic acid substrates, its role in DNA degradation in dying cells[23], and 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 level 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 two clinical presentations:

  1. Aan early-onset neonatal form that most frequently associated with recessive missense mutations in the TREX1 gene and presents in infancy as progressive microcephaly, dystonia, spasticity, and psychomotor retardation.
  2. Aa later-onset presentation particularly due to mutations in RNASEH2B subunit of 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 interferon alpha (IFN-α)  activation signature. Researchers have identified that TREX1 is involved in SLE pathogenesis and 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 autosomal dominant inheritance pattern. RVCL is characterized by microvascular endotheliopathy that involves cerebrum, retina, kidney, and other systemic microvessels. Research has recognized that carboxyl-terminus frameshift mutations in the TREX1 gene as contributing 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]


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Genetics, TREX1 Mutations - Questions

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Which of the following is not associated with TREX1 gene mutation?



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A 2-year-old boy undergoes evaluation for progressive encephalopathy and been diagnosed with Aicardi-Goutieres syndrome. What is the normal post-translational modification of the disrupted protein in this disease?



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A patient with retinal vasculopathy with cerebral leukodystrophy (RVCL) has been identified with muted TREX1 protein. What is the most expected consequence of muted TREX1 in this condition?



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Twin brothers born to consanguineous parents were initially diagnosed with infantile systemic lupus erythematosus. The diagnosis was based on autoantibody profile, an early encephalopathic disease, CNS calcification, and some evidence of multisystemic involvement. Also, both infants had a rash on the extremities from a few months of age. The patients were referred to a tertiary hospital, and it was observed that the features of the two brothers match well with those of the Aicardi-Goutieres syndrome (AGS). Further evaluations identified a certain genetic immunological deficit, and the underlying mutation responsible for the phenotype was discovered. Which of the following is the most common laboratory finding among autoimmune disease caused by mutations of this gene?



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A 6-year-old girl presents with painful inflammatory skin lesions on her fingers and cheeks. skin lesions worsen by cold or wet exposure. Her antinuclear antibody is positive. Her fother is healthy, Her mother has a history of familial chilblain lupus (FCL) and she does not have siblings. After precise evaluation, she is diagnosed with FCL as well. What is the inheritance pattern of this disorder and what chromosome is the responsible gene located on?



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A recent experiment investigated the effect of knockdown in a specific gene on type 1 human immunodeficiency retrovirus transmission in humanized mice. The target gene, which is known to be the major 3'-5' exonuclease in human cells, was knocked down in the genital tract of female humanized mice and the effect on HIV transmission was evaluated in infected cells. It was demonstrated that the gene knockdown inhibits HIV transmission in humanized mice for several weeks. What is the mechanism by which the target gene plays a role in modulating the innate immune response to type 1 human immunodeficiency retrovirus?



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A group of investigators is conducting a study to assess the genes and specific mutations associated with a rare neurological disorder which is characterized by early onset encephalopathy, cerebral calcification, leukodystrophy, chronic CSF lymphocytosis, and increased expression of interferon-stimulated genes. Next-generation sequencing (NGS) analysis is performed on 28 patients from 8 tertiary hospitals in different states, and NGS identified mutations in 26 of 28 subjects with 14 patients demonstrating a mutation in the gene that encodes the most abundant human 3'-5' exonuclease. Which of the following is the most accurate statement about this gene and its product?



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Genetics, TREX1 Mutations - References

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