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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 infection1,2. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype3. Here, we show that TREX1, encoding the major mammalian 3′ → 5′ DNA exonuclease4, 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 phenotype5. 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.

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Figure 1: Schematic of the AGS1 critical interval and TREX1 gene depicting the location of identified mutations.
Figure 2: DNA 3′ → 5′ exonuclease activity in AGS cells.

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We sincerely thank the participating Aicardi-Goutières syndrome families for the use of genetic samples and clinical information. We thank A. Markham for helpful discussions and J. Stephenson for images and information about skin biopsy findings. We thank all clinicians for contributing samples not included in this manuscript. We thank the MRC Human Genetics Unit core sequencing service in Edinburgh, Cell Services at Clare Hall, London and the Genethon Cell Bank in Evry, France. Thanks to B. Smith for assistance with the figures, D. Webb for secretarial support and A. Sharpe for help with sample handling. This work was supported by the Leeds Teaching Hospitals Charitable Foundation and the West Riding Medical Research Trust. A.P.J. is an MRC Clinician Scientist and is funded by the MRC. P.R., D.E.B. and T.L. are funded by Cancer Research UK.

Author information




Y.J.C. was responsible for the development of the project and wrote the paper with D.T.B., A.P.J., D.E.B. and T.L. B.E.H., R.P., M.A., A.L. and A.P.J. performed mutation screening of patients and controls. P.R. performed the TREX1 enzyme assays. All other authors provided clinical samples and data.

Note: Supplementary information is available on the Nature Genetics website.

Corresponding author

Correspondence to Yanick J Crow.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Primer sequences. (PDF 104 kb)

Supplementary Table 1

Chilblain-type lesions seen in individuals with AGS. (PDF 39 kb)

Supplementary Note (PDF 47 kb)

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Crow, Y., Hayward, B., Parmar, R. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet 38, 917–920 (2006).

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