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Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response

Abstract

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.

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Figure 1: SAMHD1 is the AGS5 gene.
Figure 2: Localization of SAMHD1.
Figure 3: Fold induction of IFN-β, Samhd1 and Trex1 following transfection with interferon-stimulatory DNA.

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References

  1. 1

    Crow, Y.J. & Livingston, J.H. Aicardi-Goutieres syndrome: an important Mendelian mimic of congenital infection. Dev. Med. Child Neurol. 50, 410–416 (2008).

    Article  Google Scholar 

  2. 2

    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).

    CAS  Article  Google Scholar 

  3. 3

    Crow, M.K. Type I interferon in systemic lupus erythematosus. Curr. Top. Microbiol. Immunol. 316, 359–386 (2007).

    CAS  PubMed  Google Scholar 

  4. 4

    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).

    CAS  Article  Google Scholar 

  5. 5

    Aicardi, J. & Goutieres, F. Systemic lupus erythematosus or Aicardi-Goutieres syndrome? Neuropediatrics 31, 113 (2000).

    CAS  Article  Google Scholar 

  6. 6

    De Laet, C. et al. Phenotypic overlap between infantile systemic lupus erythematosus and Aicardi-Goutieres syndrome. Neuropediatrics 36, 399–402 (2005).

    CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    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).

    CAS  Article  Google Scholar 

  9. 9

    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).

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  Google Scholar 

  11. 11

    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).

    CAS  Article  Google Scholar 

  12. 12

    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).

    CAS  Article  Google Scholar 

  13. 13

    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).

    CAS  Article  Google Scholar 

  14. 14

    Stetson, D.B., Ko, J.S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).

    CAS  Article  Google Scholar 

  15. 15

    Rice, G. et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am. J. Hum. Genet. 81, 713–725 (2007).

    CAS  Article  Google Scholar 

  16. 16

    Farrugia, R. et al. Molecular genetics of tetrahydrobiopterin (BH4) deficiency in the Maltese population. Mol. Genet. Metab. 90, 277–283 (2007).

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    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).

    CAS  Article  Google Scholar 

  19. 19

    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).

    CAS  Article  Google Scholar 

  20. 20

    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).

    Article  Google Scholar 

  21. 21

    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).

    CAS  Article  Google Scholar 

  22. 22

    Crow, M.K., Kirou, K.A. & Wohlgemuth, J. Microarray analysis of interferon-regulated genes in SLE. Autoimmunity 36, 481–490 (2003).

    CAS  Article  Google Scholar 

  23. 23

    Qiao, F. & Bowie, J.U. The many faces of SAM. Sci. STKE 2005, re7 (2005).

    PubMed  Google Scholar 

  24. 24

    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).

    CAS  Article  Google Scholar 

  25. 25

    Aravind, L. & Koonin, E.V. The HD domain defines a new superfamily of metal-dependent phosphohydrolases. Trends Biochem. Sci. 23, 469–472 (1998).

    CAS  Article  Google Scholar 

  26. 26

    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).

    CAS  Article  Google Scholar 

  27. 27

    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).

    CAS  Article  Google Scholar 

  28. 28

    Alarcón-Riquelme, M.E. Nucleic acid by-products and chronic inflammation. Nat. Genet. 38, 866–867 (2006).

    Article  Google Scholar 

  29. 29

    Coscoy, L. & Raulet, D.H. DNA mismanagement leads to immune system oversight. Cell 131, 836–838 (2007).

    CAS  Article  Google Scholar 

  30. 30

    Bhoj, V.G. & Chen, Z.J. Linking retroelements to autoimmunity. Cell 134, 569–571 (2008).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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).

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G.I.R. performed genotyping and sequencing with contributions from T.A.B., T.L., H.G. and M.A. G.I.R. and J.B. undertook localization studies. A.A. and I.W.M. performed SPR experiments. I.M.C. carried out the SNP analysis. D.B.S. and R.L.B. performed the ISD studies. R.M.J. and J.C.F. undertook protein modeling. All other co-authors identified subjects with AGS and performed related clinical and laboratory studies. D.T.B. provided critical input into project direction and manuscript preparation. Y.J.C. designed and supervised the project and wrote the manuscript.

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Correspondence to Yanick J Crow.

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Supplementary Figures 1–7 and Supplementary Tables 1–4 (PDF 2291 kb)

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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

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