Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 95, Issue 1, Pages 121-125Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2014.06.007
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Japanese Ministry of Health, Labor and Welfare
- Japanese Ministry of Education, Culture, Sports, Science, Technology (MEXT)
- Grants-in-Aid for Scientific Research [25280109, 25670474, 24390263] Funding Source: KAKEN
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Aicardi-Goutieres 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.
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