Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus

• Published in: Nature genetics Vol. 38; no. 8; pp. 917 - 920
• Main Authors: Bonthron, David T, Lindahl, Tomas, Ali, Manir, Ponsot, Gerard, Robins, Peter, Voit, Thomas, van Bokhoven, Hans, Barnes, Deborah E, Livingston, John H, Massey, Roger F, Crow, Yanick J, Parmar, Rekha, Lebon, Pierre, Jackson, Andrew P, Hayward, Bruce E, Hamel, Ben C, Leitch, Andrea, Klepper, Joerg, Cowan, Frances M, Frints, Suzanne G, Black, Deborah N, Lynch, Sally Ann, Meritet, Jean François, Brunner, Han G, Corry, Peter C, Michaud, Jacques L
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2006; Nature Publishing Group
• Subjects: Agriculture; Aicardi syndrome; Animal Genetics and Genomics; Animals; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Complications and side effects; Deoxyribonucleic acid; DNA; DNA - genetics; Enzymatic activity; Exodeoxyribonucleases - deficiency; Exodeoxyribonucleases - genetics; Exonucleases; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic aspects; Genetic disorders; Genetics of eukaryotes. Biological and molecular evolution; Heredodegenerative Disorders, Nervous System - enzymology; Heredodegenerative Disorders, Nervous System - genetics; Heredodegenerative Disorders, Nervous System - immunology; Human Genetics; Humans; Immune response; Immunity, Innate; Immunology; letter; Malformations of the nervous system; Mammals; Medical sciences; Mice; Mice, Knockout; Molecular Sequence Data; Mutation; Neurological disorders; Neurology; Phosphoproteins - deficiency; Phosphoproteins - genetics; Physiological aspects; Proteins - genetics; Risk factors; Rodents; Syndrome; United Kingdom; Eye disease; Nervous system diseases; Gene; Malformation; DNA; Aicardi syndrome; Central nervous system disease; Mutation; Locus; Congenital disease; Cerebral disorder
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1845

Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3′ → 5′ DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1−/− mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.