Journal Article

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

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

2009

Overview

Aicardi-Goutieres syndrome is a genetically determined encephalopathy that is associated with an increased production of interferon alpha, which in turn is central to the pathogenesis of systemic lupus erythematosus. Yanick Crow and colleagues now identify homozygous mutations in an interferon-inducible nuclear gene encoding SAMHD1 in AGS-affected individuals across several pedigrees and characterize its function in modulating an innate immune response. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Agriculture / Aicardi syndrome / Amino Acid Substitution / Animal Genetics and Genomics / Biological and medical sciences / Biomedical and Life Sciences / Biomedical research / Biomedicine / Brain Diseases, Metabolic, Inborn - genetics / Brain Diseases, Metabolic, Inborn - immunology / Cancer Research / Care and treatment / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genetic aspects / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Health aspects / Human Genetics / Humans / Immune response / Immunity, Innate / Interferon / letter / Lupus / Malformations of the nervous system / Medical research / Medical sciences / Monomeric GTP-Binding Proteins - genetics / Monomeric GTP-Binding Proteins - immunology / Mutation / Natural immunity / Neurology / Nucleic acids / Proteins / Risk factors / SAM Domain and HD Domain-Containing Protein 1 / Studies