An Aicardi-Goutieres Syndrome-Causative Point Mutation in Adar1 Gene Invokes Multiorgan Inflammation and Late-Onset Encephalopathy in Mice
An Aicardi-Goutieres Syndrome-Causative Point Mutation in Adar1 Gene Invokes Multiorgan Inflammation and Late-Onset Encephalopathy in Mice
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DOI：
10.4049/jimmunol.2100526
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发表时间：
2021-12-15
影响因子：
4.4
通讯作者：
Kawahara, Yukio
中科院分区：
文献类型：
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作者：
Inoue, Maal;Nakahama, Taisuke;Kawahara, Yukio
Aicardi-Goutieres综合征（AGS）是一种先天性炎症性疾病，伴有I型IFN信号过度激活和脑病，伴有脑白质营养不良和颅内钙化。到目前为止，没有一个携带AGS致病突变的小鼠模型模拟了这种大脑病理学。在这里，我们建立了一个突变小鼠模型携带K948 N点突变，对应于一个AGS致病K999 N突变，位于一个编码RNA编辑酶的Adar 1基因的脱氨酶结构域。Adar 1（K948 N/K948 N）小鼠表现出出生后生长迟缓。从2月龄开始观察到脾脏白色髓增生，伴有生殖中心和肝脏局灶性炎症。肺部和心脏出现炎症，淋巴细胞浸润呈年龄依赖性。此外，白色物质异常与星形细胞增多症和小胶质细胞增生在1岁时检测。从出生开始，在包括大脑在内的多个器官中检测到IFN刺激基因的表达增加。此外，单核RNA测序显示，这种IFN刺激基因的表达升高通常在所有神经元亚型中观察到，包括神经元、少突胶质细胞和星形胶质细胞。我们进一步表明，K948 N点突变降低了体内ADAR 1的RNA编辑活性。在Adar 1（K948 N/K948 N）小鼠中发现的病理异常通过同时缺失MDA 5（未编辑转录物的胞质传感器）或单独表达活性ADAR 1 p150（ADAR 1的同种型）得到改善。总的来说，这些数据表明，虽然程度是轻微的，但Adar 1（K948 N/K948 N）小鼠模拟多种AGS表型，包括脑病，这是由ADAR 1 p150亚型的RNA编辑活性降低引起的。
Aicardi-Goutieres syndrome (AGS) is a congenital inflammatory disorder accompanied by overactivated type I IFN signaling and encephalopathy with leukodystrophy and intracranial calcification. To date, none of the mouse models carrying an AGS-causative mutation has mimicked such brain pathology. Here, we established a mutant mouse model carrying a K948N point mutation, corresponding to an AGS-causative K999N mutation, located in a deaminase domain of the Adar1 gene that encodes an RNA editing enzyme. Adar1(K948N/K948N) mice displayed postnatal growth retardation. Hyperplasia of splenic white pulps with germinal centers and hepatic focal inflammation were observed from 2 mo of age. Inflammation developed in the lungs and heart with lymphocyte infiltration in an age-dependent manner. Furthermore, white matter abnormalities with astrocytosis and microgliosis were detected at 1 y of age. The increased expression of IFN-stimulated genes was detected in multiple organs, including the brain, from birth. In addition, single-nucleus RNA sequencing revealed that this elevated expression of IFN-stimulated genes was commonly observed in all neuronal subtypes, including neurons, oligodendrocytes, and astrocytes. We further showed that a K948N point mutation reduced the RNA editing activity of ADAR1 in vivo. The pathological abnormalities found in Adar1(K948N/K948N) mice were ameliorated by either the concurrent deletion of MDA5, a cytosolic sensor of unedited transcripts, or the sole expression of active ADAR1 p150, an isoform of ADAR1. Collectively, such data suggest that although the degree is mild, Adar1(K948N/K948N) mice mimic multiple AGS phenotypes, including encephalopathy, which is caused by reduced RNA editing activity of the ADAR1 p150 isoform.