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Mutations involved in Aicardi-Goutieres 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.

SUBMITTER: Rice GI

PROVIDER: S-EPMC4154505 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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

Rice Gillian I GI Bond Jacquelyn J Asipu Aruna A Brunette Rebecca L RL Manfield Iain W IW Carr Ian M IM Fuller Jonathan C JC Jackson Richard M RM Lamb Teresa T Briggs Tracy A TA Ali Manir M Gornall Hannah H Couthard Lydia R LR Aeby Alec A Attard-Montalto Simon P SP Bertini Enrico E Bodemer Christine C Brockmann Knut K Brueton Louise A LA Corry Peter C PC Desguerre Isabelle I Fazzi Elisa E Cazorla Angels Garcia AG Gener Blanca B Hamel Ben C J BC Heiberg Arvid A Hunter Matthew M Hunter Matthew M van der Knaap Marjo S MS Kumar Ram R Lagae Lieven L Landrieu Pierre G PG Lourenco Charles M CM Marom Daphna D McDermott Michael F MF van der Merwe William W Orcesi Simona S Prendiville Julie S JS Rasmussen Magnhild M Shalev Stavit A SA Soler Doriette M DM Shinawi Marwan M Spiegel Ronen R Tan Tiong Y TY Vanderver Adeline A Wakeling Emma L EL Wassmer Evangeline E Whittaker Elizabeth E Lebon Pierre P Stetson Daniel B DB Bonthron David T DT Crow Yanick J YJ

Nature genetics 20090614 7

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 ...[more]

PMID: 19525956

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Project description:BackgroundAicardi-Goutières syndrome (AGS) is a severe infant or juvenile-onset autoimmune disease characterized by inflammatory encephalopathy with an elevated type 1 interferon-stimulated gene (ISG) expression signature in the brain. Mutations in seven different protein-coding genes, all linked to DNA/RNA metabolism or sensing, have been identified in AGS patients, but none of them has been demonstrated to activate the IFN pathway in the brain of an animal. The molecular mechanism of inflammatory encephalopathy in AGS has not been well defined. Adenosine Deaminase Acting on RNA 1 (ADAR1) is one of the AGS-associated genes. It carries out A-to-I RNA editing that converts adenosine to inosine at double-stranded RNA regions. Whether an AGS-associated mutation in ADAR1 activates the IFN pathway and causes autoimmune pathogenesis in the brain is yet to be determined.MethodsMutations in the ADAR1 gene found in AGS patients were introduced into the mouse genome via CRISPR/Cas9 technology. Molecular activities of the specific p.K999N mutation were investigated by measuring the RNA editing levels in brain mRNA substrates of ADAR1 through RNA sequencing analysis. IFN pathway activation in the brain was assessed by measuring ISG expression at the mRNA and protein level through real-time RT-PCR and Luminex assays, respectively. The locations in the brain and neural cell types that express ISGs were determined by RNA in situ hybridization (ISH). Potential AGS-related brain morphologic changes were assessed with immunohistological analysis. Von Kossa and Luxol Fast Blue staining was performed on brain tissue to assess calcification and myelin, respectively.ResultsMice bearing the ADAR1 p.K999N were viable though smaller than wild type sibs. RNA sequencing analysis of neuron-specific RNA substrates revealed altered RNA editing activities of the mutant ADAR1 protein. Mutant mice exhibited dramatically elevated levels of multiple ISGs within the brain. RNA ISH of brain sections showed selective activation of ISG expression in neurons and microglia in a patchy pattern. ISG-15 mRNA was upregulated in ADAR1 mutant brain neurons whereas CXCL10 mRNA was elevated in adjacent astroglia. No calcification or gliosis was detected in the mutant brain.ConclusionsWe demonstrated that an AGS-associated mutation in ADAR1, specifically the p.K999N mutation, activates the IFN pathway in the mouse brain. The ADAR1 p.K999N mutant mouse replicates aspects of the brain interferonopathy of AGS. Neurons and microglia express different ISGs. Basal ganglia calcification and leukodystrophy seen in AGS patients were not observed in K999N mutant mice, indicating that development of the full clinical phenotype may need an additional stimulus besides AGS mutations. This mutant mouse presents a robust tool for the investigation of AGS and neuroinflammatory diseases including the modeling of potential "second hits" that enable severe phenotypes of clinically variable diseases.

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

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

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