title: Aicardi-Goutières syndrome is caused by IFIH1 mutations.
abstract: Aicardi-Goutières syndrome (AGS) is a rare, genetically determined early-onset progressive encephalopathy. To date, mutations in six genes have been identified as etiologic for AGS. Our Japanese nationwide AGS survey identified six AGS-affected individuals without a molecular diagnosis; we performed whole-exome sequencing on three of these individuals. After removal of the common polymorphisms found in SNP databases, we were able to identify IFIH1 heterozygous missense mutations in all three. In vitro functional analysis revealed that IFIH1 mutations increased type I interferon production, and the transcription of interferon-stimulated genes were elevated. IFIH1 encodes MDA5, and mutant MDA5 lacked ligand-specific responsiveness, similarly to the dominant Ifih1 mutation responsible for the SLE mouse model that results in type I interferon overproduction. This study suggests that the IFIH1 mutations are responsible for the AGS phenotype due to an excessive production of type I interferon.
authors.affiliation: Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan; Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 2300045, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Oda
authors.affiliation: Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan; Department of Pediatrics, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka 5308480, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Abe
authors.affiliation: Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Awaya
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 6068507, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Funabiki
authors.affiliation: Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 5260829, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hijikata
authors.affiliation: Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan. Electronic address: rnishiko@kuhp.kyoto-u.ac.jp.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Nishikomori
authors.affiliation: Department of Pediatrics, Tokyo Women's Medical University, Tokyo 1628666, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Funatsuka
authors.affiliation: Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, Fukui 9108507, Japan.
authors.forename: Yusei
authors.initials: Y
authors.lastname: Ohshima
authors.affiliation: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 1138510, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sugawara
authors.affiliation: Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yasumi
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 6068507, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Science and Technology Agency (JST), Kawaguchi 3320012, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 5260829, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shirai
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 2300045, Japan; Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu 2920818, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 6068507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics*; D005260:Female; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009421:Nervous System Malformations / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1