Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
NCBI Reference Sequence
Crow, Y.J. & Livingston, J.H. Aicardi-Goutieres syndrome: an important Mendelian mimic of congenital infection. Dev. Med. Child Neurol. 50, 410–416 (2008).
Dussaix, E., Lebon, P., Ponsot, G., Huault, G. & Tardieu, M. Intrathecal synthesis of different alpha-interferons in patients with various neurological diseases. Acta Neurol. Scand. 71, 504–509 (1985).
Crow, M.K. Type I interferon in systemic lupus erythematosus. Curr. Top. Microbiol. Immunol. 316, 359–386 (2007).
Dale, R.C., Tang, S.P., Heckmatt, J.Z. & Tatnall, F.M. Familial systemic lupus erythematosus and congenital infection-like syndrome. Neuropediatrics 31, 155–158 (2000).
Aicardi, J. & Goutieres, F. Systemic lupus erythematosus or Aicardi-Goutieres syndrome? Neuropediatrics 31, 113 (2000).
De Laet, C. et al. Phenotypic overlap between infantile systemic lupus erythematosus and Aicardi-Goutieres syndrome. Neuropediatrics 36, 399–402 (2005).
Rasmussen, M., Skullerud, K., Bakke, S.J., Lebon, P. & Jahnsen, F.L. Cerebral thrombotic microangiopathy and antiphospholipid antibodies in Aicardi-Goutieres syndrome–report of two sisters. Neuropediatrics 36, 40–44 (2005).
Crow, Y.J. et al. Cree encephalitis is allelic with Aicardi-Goutieres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism. J. Med. Genet. 40, 183–187 (2003).
Crow, Y.J. et al. Mutations in the gene encoding the 3′–5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat. Genet. 38, 917–920 (2006).
Crow, Y.J. et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat. Genet. 38, 910–916 (2006).
Rice, G. et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am. J. Hum. Genet. 80, 811–815 (2007).
Lee-Kirsch, M.A. et al. Mutations in the gene encoding the 3′–5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet. 39, 1065–1067 (2007).
Yang, Y.G., Lindahl, T. & Barnes, D.E. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131, 873–886 (2007).
Stetson, D.B., Ko, J.S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).
Rice, G. et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am. J. Hum. Genet. 81, 713–725 (2007).
Farrugia, R. et al. Molecular genetics of tetrahydrobiopterin (BH4) deficiency in the Maltese population. Mol. Genet. Metab. 90, 277–283 (2007).
Li, N., Zhang, W. & Cao, X. Identification of human homologue of mouse IFN-gamma induced protein from human dendritic cells. Immunol. Lett. 74, 221–224 (2000).
Hartman, Z.C. et al. Adenovirus infection triggers a rapid, MyD88-regulated transcriptome response critical to acute-phase and adaptive immune responses in vivo. J. Virol. 81, 1796–1812 (2007).
Prehaud, C., Megret, F., Lafage, M. & Lafon, M. Virus infection switches TLR-3-positive human neurons to become strong producers of beta interferon. J. Virol. 79, 12893–12904 (2005).
Zhao, D., Peng, D., Li, L., Zhang, Q. & Zhang, C. Inhibition of G1P3 expression found in the differential display study on respiratory syncytial virus infection. Virol. J. 5, 114 (2008).
Liao, W., Bao, Z., Cheng, C., Mok, Y.K. & Wong, W.S. Dendritic cell-derived interferon-gamma-induced protein mediates tumor necrosis factor-alpha stimulation of human lung fibroblasts. Proteomics 8, 2640–2650 (2008).
Crow, M.K., Kirou, K.A. & Wohlgemuth, J. Microarray analysis of interferon-regulated genes in SLE. Autoimmunity 36, 481–490 (2003).
Qiao, F. & Bowie, J.U. The many faces of SAM. Sci. STKE 2005, re7 (2005).
Oberstrass, F.C. et al. Shape-specific recognition in the structure of the Vts1p SAM domain with RNA. Nat. Struct. Mol. Biol. 13, 160–167 (2006).
Aravind, L. & Koonin, E.V. The HD domain defines a new superfamily of metal-dependent phosphohydrolases. Trends Biochem. Sci. 23, 469–472 (1998).
Zimmerman, M.D., Proudfoot, M., Yakunin, A. & Minor, W. Structural insight into the mechanism of substrate specificity and catalytic activity of an HD-domain phosphohydrolase: the 5′-deoxyribonucleotidase YfbR from Escherichia coli. J. Mol. Biol. 378, 215–226 (2008).
Oussenko, I.A., Sanchez, R. & Bechhofer, D.H. Bacillus subtilis YhaM, a member of a new family of 3′-to-5′ exonucleases in gram-positive bacteria. J. Bacteriol. 184, 6250–6259 (2002).
Alarcón-Riquelme, M.E. Nucleic acid by-products and chronic inflammation. Nat. Genet. 38, 866–867 (2006).
Coscoy, L. & Raulet, D.H. DNA mismanagement leads to immune system oversight. Cell 131, 836–838 (2007).
Bhoj, V.G. & Chen, Z.J. Linking retroelements to autoimmunity. Cell 134, 569–571 (2008).
We thank the participating families with Aicardi-Goutières syndrome for the use of genetic samples and clinical information. We thank all clinicians for contributing samples not included in the current manuscript. We thank C. Ponting and E. Morrison for helpful discussions and R. Smith for technical support in preparing images. This work was supported by BDF Newlife, the Royal Society, a Wellcome Trust VIP award to G.I.R., the National Institutes for Health Research Manchester Biomedical Research Centre, and the International Aicardi-Goutières syndrome Association (IAGSA).
About this article
Cite this article
Rice, G., Bond, J., Asipu, A. et al. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet 41, 829–832 (2009). https://doi.org/10.1038/ng.373
The Role of Nucleases and Nucleic Acid Editing Enzymes in the Regulation of Self-Nucleic Acid Sensing
Frontiers in Immunology (2021)
Pediatric Infectious Disease Journal (2021)
Dirty Fish Versus Squeaky Clean Mice: Dissecting Interspecies Differences Between Animal Models of Interferonopathy
Frontiers in Immunology (2021)
Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification
Nature Communications (2021)