Aicardi-Goutieres Syndrome Is Caused by IFIH1 Mutations

作者：Oda Hirotsugu; Nakagawa Kenji; Abe Junya; Awaya Tomonari; Funabiki Masahide; Hijikata Atsushi; Nishikomori Ryuta^*; Funatsuka Makoto; Ohshima Yusei; Sugawara Yuji; Yasumi Takahiro; Kato Hiroki; Shirai Tsuyoshi; Ohara Osamu; Fujita Takashi; Heike Toshio

来源：American Journal of Human Genetics, 2014, 95(1): 121-125.

DOI：10.1016/j.ajhg.2014.06.007

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.

• 出版日期2014-7-13