Abstract：
Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-β-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-β on TM cells. Our study is the first to demonstrate that IFN-β significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-β remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-β-induced autophagy in TM cells, we performed microarray analysis in IFN-β-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-β-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-β. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-β, which elevates IOP by modulating autophagy through RSAD2 in TM cells.
摘要：
Singleton-Merten综合征（SMS）是一种罕见的免疫遗传障碍，影响多个系统，以牙齿发育不良为特征，主动脉钙化,青光眼,骨骼异常,牛皮癣。青光眼,古典和非典型短信的一个关键特征，在其由DDX58突变引起的分子机制方面仍然知之甚少。这项研究提出了一种新的DDX58变体（c.1649A>C[p。Asp550Ala]）在一个患有儿童青光眼的家庭中。功能分析显示DDX58变体引起IFN刺激的基因表达和高IFN-β-I型IFN的增加。由于小梁网（TM）负责控制眼内压（IOP），我们检测IFN-β对TM细胞的影响。我们的研究首次证明IFN-β通过激活自噬显着降低TM细胞的活力和功能。此外,前房注射IFN-β显著增加小鼠眼压水平,可以通过自噬抑制剂氯喹治疗来减毒。揭示IFN-β诱导TM细胞自噬的具体机制,我们在IFN-β处理和DDX58p.Asp550AlaTM细胞中进行了微阵列分析。表明RSAD2是IFN-β诱导的自噬所必需的。通过siRNA敲除RSAD2显著降低IFN-β诱导的自噬通量。我们的研究结果表明，DDX58突变导致IFN-β的过度产生，通过调节TM细胞中的RSAD2自噬来提高IOP。
