Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome
Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome
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DOI：
10.1016/j.ajhg.2014.11.019
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发表时间：
2015-02-05
影响因子：
9.8
通讯作者：
Ki, Chang-Seok
中科院分区：
文献类型：
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作者：
Jang, Mi-Ae;Kim, Eun Kyoung;Ki, Chang-Seok
Singleton-Merten综合征（SMS）是一种常染色体显性多系统疾病，其特征为牙齿发育不良、主动脉钙化、骨骼异常、青光眼、银屑病和其他疾病。尽管有明显的常染色体显性遗传模式，SMS的遗传背景和表型异质性的信息仍然未知。最近，我们发现一个家庭受到青光眼，主动脉钙化，骨骼异常。与经典SMS受试者不同，受影响的个体显示出正常的牙列，这表明非典型SMS。为了确定该疾病的遗传原因，我们在该家族中进行了外显子组测序，并确定了DDX 58的变体（c.1118A>C [p.GLu373Ala]），其蛋白质产物也被称为RIG-I。对100例先天性青光眼患者的DDX 58进一步分析发现，在一个既无牙齿异常也无主动脉钙化但患有青光眼和骨骼异常的家族中存在另一种变异（c.803G>T [p.Cys268Phe]）。DDX 58的Cys 268和Glu 373残基分别属于ATP结合基序I和II，并且通过蛋白质结构分析预测这些残基比其他非致病性错义变体更靠近ADP和RNA分子。功能测定显示，DDX 58的改变赋予组成性激活，从而导致干扰素（IFN）活性和IFN刺激的基因表达增加。此外，当我们用c.803G>T（p.Cys268Phe）和c.1118A>C（p.Glu373A1a）突变体转导原代人小梁网细胞时，观察到细胞病变效应和细胞数量的显著减少。综上所述，我们的研究结果表明，DDX 58突变导致非典型SMS表现为青光眼，主动脉钙化和骨骼异常的可变表达，而没有牙齿异常。
Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.GLu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373A1a) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.