HTRA1 Overexpression Induces the Exudative Form of Age-related Macular Degeneration.
HTRA1 Overexpression Induces the Exudative Form of Age-related Macular Degeneration.
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发表时间：
2015
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通讯作者：
D. Iejima;Mao Nakayama;T. Iwata
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作者：
D. Iejima;Mao Nakayama;T. Iwata
视网膜相关性黄斑变性（AMD）是老年人视力丧失和失明的主要原因。干型更为常见，约占美国AMD患者的85-90%，而日本AMD患者主要进展为湿型或息肉状脉络膜血管病变（PCV）。最近的研究已经显示HTRA 1（一种丝氨酸蛋白酶基因）是湿性AMD的主要危险因素（De Wan et al.，Science 2006）。此外，我们报道了日本典型湿性AMD患者显示与ARMS 2/HTRA 1显著相关（后藤，Akahori等人，JOBDI 2009）。本研究旨在探讨ARMS 2/HTRA 1基因启动子在湿性AMD患者中的功能。启动子序列测定结果表明，在AMD患者中，HTRA 1基因上游3.8kb处存在特异性indel突变。2-3-与对照序列相比，在插入缺失HTRA 1启动子中观察到启动子活性的倍数增加（Iejima等，JBC 2015）。此外，我们使用鸡act in启动子创建了普遍过表达小鼠HtrA 1的转基因小鼠，体内HtrA 1的连续诱导显示导致CNV，类似于湿性AMD患者（Nakayama，Iejima et al.，IOVS 2014）。提示AMD患者HTRA 1基因启动子区的indel突变可增强HTRA 1的表达，这种增强的HTRA 1表达可能与AMD诱导视网膜新生血管形成有关。
Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness in the elderly. The dry form is more common and accounts for about 85-90% of AMD patients in US, while Japanese AMD patients predominantly progress to wet-form or polypoidal choroidal vasculopathy (PCV). Recent studies have shown HTRA1, a serine protease gene, as major risk factor for wet form AMD (De Wan et al., Science 2006). Furthermore, we reported that the Japanese typical wet form AMD patients showed significant association with ARMS2/HTRA1 (Goto, Akahori et al., JOBDI 2009). The purpose of this study is to elucidate the function of ARMS2/HTRA1 gene promoter in wet-form AMD patients. The promoter sequence experiment showed that a great number of AMD patients had specific indel mutation in 3.8 kb upstream of HTRA1 gene. 2-3-fold increase of promoter activity was observed in indel HTRA1 promoter compared to control sequence (Iejima et al., JBC 2015). Furthermore, we created transgenic mice ubiquitously overexpressing mouse HtrA1 using the chicken act in promoter, continuous induction of HtrA1 in vivo was shown to lead to CNV, similar to wet AMD patients (Nakayama, Iejima et al., IOVS 2014). These results suggest that human HTRA1 expression is enhanced by AMD specific indel mutation in the promoter region of HTRA1 gene, and this enhanced HTRA1 may be concerned with induce retinal neovasucularization.