Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome

被引:165
作者
Jang, Mi-Ae [1 ,2 ]
Kim, Eun Kyoung [3 ]
Now, Hesung [4 ]
Nguyen, Nhung T. H. [4 ]
Kim, Woo-Jong [4 ]
Yoo, Joo-Yeon [4 ]
Lee, Jinhyuk [5 ,6 ]
Jeong, Yun-Mi [7 ]
Kim, Cheol-Hee [7 ]
Kim, Ok-Hwa [8 ]
Sohn, Seongsoo [9 ]
Nam, Seong-Hyeuk [10 ]
Hong, Yoojin [10 ]
Lee, Yong Seok [10 ]
Chang, Sung-A [3 ]
Jang, Shin Yi [3 ]
Kim, Jong-Won [1 ,2 ]
Lee, Myung-Shik [11 ]
Lim, So Young [12 ]
Sung, Ki-Sun [13 ]
Park, Ki-Tae [14 ]
Kim, Byoung Joon [15 ]
Lee, Joo-Heung [16 ]
Kim, Duk-Kyung [3 ]
Kee, Changwon [9 ]
Ki, Chang-Seok [1 ,2 ]
机构
[1] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Lab Med, Seoul 135710, South Korea
[2] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Genet, Seoul 135710, South Korea
[3] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Div Cardiol,Dept Med,Heart Vasc Stroke Inst, Seoul 135710, South Korea
[4] Pohang Univ Sci & Technol, Dept Life Sci, Pohang 790784, South Korea
[5] Korea Res Inst Biosci & Biotechnol, Korean Bioinformat Ctr, Taejon 305806, South Korea
[6] Univ Sci & Technol, Dept Bioinformat, Taejon 305350, South Korea
[7] Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea
[8] Woorisoa Childrens Hosp, Dept Radiol, Seoul 152862, South Korea
[9] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Ophthalmol, Seoul 135710, South Korea
[10] Samsung SDS, Seoul 138240, South Korea
[11] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Div Endocrinol & Metab,Dept Med, Seoul 135710, South Korea
[12] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Plast Surg, Seoul 135710, South Korea
[13] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Orthoped Surg, Seoul 135710, South Korea
[14] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pediat Dent, Seoul 135710, South Korea
[15] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurol, Seoul 135710, South Korea
[16] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Dermatol, Seoul 135710, South Korea
基金
新加坡国家研究基金会;
关键词
OPEN-ANGLE GLAUCOMA; CALCIFICATION; RNA; GENE; IDENTIFICATION; ACTIVATION; SPECTRUM; SENSOR; GAIN; MDA5;
D O I
10.1016/j.ajhg.2014.11.019
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:266 / 274
页数:9
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