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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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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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