Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.
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.
Crow
Yanick J
YJ
Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK. yanickcrow@mac.com
Hayward
Bruce E
BE
Parmar
Rekha
R
Robins
Peter
P
Leitch
Andrea
A
Ali
Manir
M
Black
Deborah N
DN
van Bokhoven
Hans
H
Brunner
Han G
HG
Hamel
Ben C
BC
Corry
Peter C
PC
Cowan
Frances M
FM
Frints
Suzanne G
SG
Klepper
Joerg
J
Livingston
John H
JH
Lynch
Sally Ann
SA
Massey
Roger F
RF
Meritet
Jean François
JF
Michaud
Jacques L
JL
Ponsot
Gerard
G
Voit
Thomas
T
Lebon
Pierre
P
Bonthron
David T
DT
Jackson
Andrew P
AP
Barnes
Deborah E
DE
Lindahl
Tomas
T
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
D010750:Phosphoproteins; D011506:Proteins; D004247:DNA; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1