Aicardi-Goutieres Syndrome Is Caused by IFIH1 Mutations
Aicardi-Goutieres Syndrome Is Caused by IFIH1 Mutations
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DOI：
10.1016/j.ajhg.2014.06.007
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发表时间：
2014-07-13
影响因子：
9.8
通讯作者：
Heike, Toshio
中科院分区：
文献类型：
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作者：
Oda, Hirotsugu;Nakagawa, Kenji;Heike, Toshio
Aicardi-Goutieres综合征（AGS）是一种罕见的，遗传决定的早发性进行性脑病。迄今为止，六个基因的突变已被确定为AGS的病因。我们在日本全国范围内的AGS调查确定了六个没有分子诊断的受AGS影响的个体;我们对其中三个人进行了全外显子组测序。在去除SNP数据库中常见的多态性后，我们能够在所有三个中鉴定IFIH 1杂合错义突变。体外功能分析显示，IFIH 1突变增加了I型干扰素的产生，并且干扰素刺激基因的转录升高。IFIH 1编码MDA 5，突变型MDA 5缺乏配体特异性反应，类似于导致I型干扰素过量产生的SLE小鼠模型的显性IFIH 1突变。这项研究表明，IFIH 1突变是负责AGS表型由于过度生产的I型干扰素。
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.