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Am J Hum Genet. 2014 Jul 3;95(1):121-5. doi: 10.1016/j.ajhg.2014.06.007.

Aicardi-Goutières syndrome is caused by IFIH1 mutations.

Author information

1
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.
2
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan.
3
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.
4
Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 6068507, Japan.
5
Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 5260829, Japan.
6
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan. Electronic address: rnishiko@kuhp.kyoto-u.ac.jp.
7
Department of Pediatrics, Tokyo Women's Medical University, Tokyo 1628666, Japan.
8
Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, Fukui 9108507, Japan.
9
Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 1138510, Japan.
10
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.
11
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.

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.

PMID:
24995871
PMCID:
PMC4085581
DOI:
10.1016/j.ajhg.2014.06.007
[Indexed for MEDLINE]
Free PMC Article

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