title: Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.
abstract: 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.
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK. yanickcrow@mac.com
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Hayward
authors.forename: Rekha
authors.initials: R
authors.lastname: Parmar
authors.forename: Peter
authors.initials: P
authors.lastname: Robins
authors.forename: Andrea
authors.initials: A
authors.lastname: Leitch
authors.forename: Manir
authors.initials: M
authors.lastname: Ali
authors.forename: Deborah N
authors.initials: DN
authors.lastname: Black
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Ben C
authors.initials: BC
authors.lastname: Hamel
authors.forename: Peter C
authors.initials: PC
authors.lastname: Corry
authors.forename: Frances M
authors.initials: FM
authors.lastname: Cowan
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Frints
authors.forename: Joerg
authors.initials: J
authors.lastname: Klepper
authors.forename: John H
authors.initials: JH
authors.lastname: Livingston
authors.forename: Sally Ann
authors.initials: SA
authors.lastname: Lynch
authors.forename: Roger F
authors.initials: RF
authors.lastname: Massey
authors.forename: Jean François
authors.initials: JF
authors.lastname: Meritet
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Gerard
authors.initials: G
authors.lastname: Ponsot
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebon
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Barnes
authors.forename: Tomas
authors.initials: T
authors.lastname: Lindahl
mesh_terms: D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D005090:Exodeoxyribonucleases / Q000172:deficiency / Q000235:genetics*; D020271:Heredodegenerative Disorders, Nervous System / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
chemical_list: D010750:Phosphoproteins; D011506:Proteins; D004247:DNA; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1