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

Yanick J Crow; Bruce E Hayward; Rekha Parmar; Peter Robins; Andrea Robertson (nee Leitch); Manir Ali; Deborah N Black; Hans van Bokhoven; Han G Brunner; Ben C Hamel; Peter C Corry; Frances M Cowan; Suzanne G Frints; Joerg Klepper; John H Livingston; Sally Ann Lynch; Roger F Massey; Jean François Meritet; Jacques L Michaud; Gerard Ponsot; Thomas Voit; Pierre Lebon; David T Bonthron; Andrew P Jackson; Deborah E Barnes; Tomas Lindahl

doi:10.1038/ng1845

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

Yanick J Crow, Bruce E Hayward, Rekha Parmar, Peter Robins, Andrea Robertson (nee Leitch), Manir Ali, Deborah N Black, Hans van Bokhoven, Han G Brunner, Ben C Hamel, Peter C Corry, Frances M Cowan, Suzanne G Frints, Joerg Klepper, John H Livingston, Sally Ann Lynch, Roger F Massey, Jean François Meritet, Jacques L Michaud, Gerard PonsotThomas Voit, Pierre Lebon, David T Bonthron, Andrew P Jackson, Deborah E Barnes, Tomas Lindahl

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Abstract / Description of output

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.

Original language	English
Pages (from-to)	917-20
Number of pages	4
Journal	Nature Genetics
Volume	38
Issue number	8
DOIs	https://doi.org/10.1038/ng1845
Publication status	Published - 2006

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Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Robertson (nee Leitch), A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C., Corry, P. C., Cowan, F. M., Frints, S. G., Klepper, J., Livingston, J. H., Lynch, S. A., Massey, R. F., Meritet, J. F., Michaud, J. L., ... Lindahl, T. (2006). Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nature Genetics, 38(8), 917-20. https://doi.org/10.1038/ng1845

@article{963b4e6eeb83416aa79ee9870a11dc58,

title = "Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Gouti{\`e}res syndrome at the AGS1 locus",

abstract = "Aicardi-Gouti{\`e}res 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.",

author = "Crow, {Yanick J} and Hayward, {Bruce E} and Rekha Parmar and Peter Robins and {Robertson (nee Leitch)}, Andrea and Manir Ali and Black, {Deborah N} and {van Bokhoven}, Hans and Brunner, {Han G} and Hamel, {Ben C} and Corry, {Peter C} and Cowan, {Frances M} and Frints, {Suzanne G} and Joerg Klepper and Livingston, {John H} and Lynch, {Sally Ann} and Massey, {Roger F} and Meritet, {Jean Fran{\c c}ois} and Michaud, {Jacques L} and Gerard Ponsot and Thomas Voit and Pierre Lebon and Bonthron, {David T} and Jackson, {Andrew P} and Barnes, {Deborah E} and Tomas Lindahl",

year = "2006",

doi = "10.1038/ng1845",

language = "English",

volume = "38",

pages = "917--20",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "8",

}

Crow, YJ, Hayward, BE, Parmar, R, Robins, P, Robertson (nee Leitch), A, Ali, M, Black, DN, van Bokhoven, H, Brunner, HG, Hamel, BC, Corry, PC, Cowan, FM, Frints, SG, Klepper, J, Livingston, JH, Lynch, SA, Massey, RF, Meritet, JF, Michaud, JL, Ponsot, G, Voit, T, Lebon, P, Bonthron, DT, Jackson, AP, Barnes, DE & Lindahl, T 2006, 'Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus', Nature Genetics, vol. 38, no. 8, pp. 917-20. https://doi.org/10.1038/ng1845

TY - JOUR

T1 - Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus

AU - Crow, Yanick J

AU - Hayward, Bruce E

AU - Parmar, Rekha

AU - Robins, Peter

AU - Robertson (nee Leitch), Andrea

AU - Ali, Manir

AU - Black, Deborah N

AU - van Bokhoven, Hans

AU - Brunner, Han G

AU - Hamel, Ben C

AU - Corry, Peter C

AU - Cowan, Frances M

AU - Frints, Suzanne G

AU - Klepper, Joerg

AU - Livingston, John H

AU - Lynch, Sally Ann

AU - Massey, Roger F

AU - Meritet, Jean François

AU - Michaud, Jacques L

AU - Ponsot, Gerard

AU - Voit, Thomas

AU - Lebon, Pierre

AU - Bonthron, David T

AU - Jackson, Andrew P

AU - Barnes, Deborah E

AU - Lindahl, Tomas

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1038/ng1845

DO - 10.1038/ng1845

M3 - Article

C2 - 16845398

SN - 1061-4036

VL - 38

SP - 917

EP - 920

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

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