Richards A, van den Maagdenberg AM, Jen JC et al.C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 39:1068-1070

Leiden University, Leyden, South Holland, Netherlands
Nature Genetics (Impact Factor: 29.35). 10/2007; 39(9):1068-70. DOI: 10.1038/ng2082
Source: PubMed


Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.

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    • "TREX1 mutations that disrupt its DNase activity were mostly found in AGS, and many disease-associated mutations of TREX1 do not affect its DNase activity, especially the ones associated with SLE and RVCL (Lee-Kirsch et al., 2007; Richards et al., 2007). TREX1 is a single exon gene that encodes an exonuclease domain at its amino terminus, and an ER localization domain at its carboxyl terminus. "
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    ABSTRACT: Innate immune recognition is crucial for host responses against viral infections, including infection by human immunodeficiency virus 1 (HIV-1). Human cells detect such invading pathogens with a collection of pattern recognition receptors that activate the production of antiviral proteins, such as the cytokine interferon-type I, to initiate antiviral responses immediately as well as the adaptive immune response for long-term protection. To establish infection in the host, many viruses have thus evolved strategies for subversion of these mechanisms of innate immunity. For example, acute infection by HIV-1 and other retroviruses have long been thought to be non-immunogenic, signifying suppression of host defenses by these pathogens. Studies in the past few years have begun to uncover a multifaceted scheme of how HIV-1 evades innate immune detection, especially of its DNA, by exploiting host proteins. This review will discuss the host mechanisms of HIV-1 DNA sensing and viral immune evasion, with a particular focus on TREX1, three prime repair exonuclease 1, a host 3' exonuclease (also known as DNase III).
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    • "These variations were not found in 1712 controls [4]. Heterozygous mutations of TREX1 have also been described in familial chilblain lupus (FCL), a rare autosomaldominant form of cutaneous lupus erythematosus manifesting in early childhood [6]; in retinal vasculopathy with cerebral leukodystrophy (RVCL), an adult-onset disease characterized by central nervous system degeneration, retinal vasculopathy , and nephropathy [7]; and in a Taiwanese family with a hereditary small vessel disease of the brain clinically distinct from RVCL (CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ) [8]. Furthermore, TREX1 mutations cause "
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    ABSTRACT: TREX1 (DNase III) is an exonuclease involved in response to oxidative stress and apoptosis. Heterozygous mutations in TREX1 were previously observed in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). We performed a mutational analysis of the TREX1 gene on three autoimmune diseases: SLE (210 patients) and SS (58 patients), to confirm a TREX1 involvement in the Italian population, and systemic sclerosis (SSc, 150 patients) because it shares similarities with SLE (presence of antinuclear antibodies and connective tissue damage). We observed 7 variations; two of these are novel nonsynonymous variants (p.Glu198Lys and p.Met232Val). They were detected in one SS and in one SSc patient, respectively, and in none of the 200 healthy controls typed in this study and of the 1712 published controls. In silico analysis predicts a possibly damaging role on protein function for both variants. The other 5 variations are synonymous and only one of them is novel (p.Pro48Pro). This study contributes to the demonstration that TREX1 is involved in autoimmune diseases and proposes that the spectrum of involved autoimmune diseases can be broader and includes SSc. We do not confirm a role of TREX1 variants in SLE.
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    • "DNase I and DNase III knockout mice showed systemic lupus erythematosus (SLE)-like symptoms and inflammatory myocarditis, respectively (Napirei et al., 2000; Yasutomo et al., 2001; Morita et al., 2004). The functional mutations of DNase I and DNase III in humans have also been associated with several autoimmune disorders, such as SLE (Yasutomo et al., 2001; Lee-Kirsch et al., 2007b), Aicardi–Goutieres syndrome (Crow et al., 2006), familial chilblain lupus (Lee-Kirsch et al., 2007a), and retinal vasculopathy with cerebral leukodystrophy (Richards et al., 2007). Thus, DNA-induced immune responses are involved in the prevention of both microbial infection and autoimmune responses. "
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