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Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

Abstract

Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

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Figure 1: Schematic of the human ADAR1 gene.
Figure 2: Structural context of ADAR1 protein substitutions.
Figure 3: Protein blot of lymphoblastoid cell lines (LCLs).
Figure 4: Site-specific and competition editing assays.
Figure 5: Quantitative RT-PCR of a panel of six ISGs in whole blood measured in individuals with AGS, their parents and individuals with DSH.

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NCBI Reference Sequence

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Acknowledgements

We sincerely thank the participating families for the use of genetic samples and clinical information. We thank B. Hamel, H. Brunner and other clinical collaborators for contributing samples not included in the current manuscript, A.P. Jackson for highlighting the presence of intracranial calcification in individuals with DSH with a p.Gly1007Arg alteration in ADAR1 and D.B. Stetson and D.T. Bonthron for critical reading of the manuscript. D.B. Stetson (University of Washington) provided the ADAR1 constructs used in the editing assays. We thank the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). Y.J.C. acknowledges the Manchester National Institute for Health Research (NIHR) Biomedical Research Centre. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement 241779 and from the Great Ormond Street Hospital Children's Charity.

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Contributions

G.I.R. performed quantitative PCR analysis. P.R.K. performed protein blot analysis. G.M.A.F. performed cell culture and interferon stimulation experiments with assistance from G.I.R. and T.A.B. M.S. performed Sanger sequencing with assistance from M.Z., G.M.A.F. and E.M.J. G.I.R. analyzed sequence data. M.S. and G.M.A.F. undertook microsatellite genotyping. J.E.D. and S.S.B. undertook analysis of the exome sequence data. J.H.L. was responsible for neuroradiological phenotyping. P.L. and F.R. measured interferon activity in affected individuals. M.A.O., L.P.K., S.M.G. and N.M.M. carried out ADAR1 editing assays. T.S. and M.K. provided the DSH RNA samples. S.C.L. and P.J.M. carried out ADAR1 structural analysis. Y.J.C. designed and supervised the project and wrote the manuscript with support from G.I.R. C.A.B., R.B., E.B., P.A.B., L.A.B., M.C., C.D.L., P.d.L., M.d.T., I.D., E.F., A.G.-C., A.H., R.K., J.-P.S.-M.L., C.M.L., A.M.M., W.M., C.M., I.O., S.O., P.P., M.R., R.A.R., J.L.S., K.S., T.Y.T., W.G.v.d.M., A.V., G.V., E.L.W., E. Wassmer and E. Whittaker identified subjects with AGS or assisted with related clinical and laboratory studies.

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Correspondence to Yanick J Crow.

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Rice, G., Kasher, P., Forte, G. et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet 44, 1243–1248 (2012). https://doi.org/10.1038/ng.2414

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