Mi-Ae Jang^{1, 16}, Eun Kyoung Kim^{2, 16}, Hesung Now³, Nhung T.H. Nguyen³, Woo-Jong Kim³, Joo-Yeon Yoo³, Jinhyuk Lee^{4, 5}, Yun-Mi Jeong⁶, Cheol-Hee Kim⁶, Ok-Hwa Kim⁷, Seongsoo Sohn⁸, Seong-Hyeuk Nam⁹, Yoojin Hong⁹, Yong Seok Lee⁹, Sung-A Chang², Shin Yi Jang², Jong-Won Kim¹, Myung-Shik Lee¹⁰, So Young Lim¹¹, Ki-Sun Sung¹², Ki-Tae Park¹³, Byoung Joon Kim¹⁴, Joo-Heung Lee¹⁵, Duk-Kyung Kim^{2, 17}, Changwon Kee^{8, 17}, Chang-Seok Ki^{1, 17}

¹Departments of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea;
²Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea;
³Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea;
⁴Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea;
⁵Department of Bioinformatics, University of Sciences and Technology, Daejeon 305-350, Korea;
⁶Department of Biology, Chungnam National University, Daejeon 305-764, Korea;
⁷Department of Radiology, Woorisoa Children’s Hospital, Seoul 152-862, Korea;
⁸Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea;
⁹Samsung SDS, Seoul 138-240, Korea;
¹⁰Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea;
¹¹Department of Plastic Surgery, SamsungMedical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea;
¹²Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine,
Seoul 135-710, Korea;
¹³Department of Pediatric Dentistry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea;
¹⁴Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea;
¹⁵Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
¹⁶ These authors contributed equally to this work
¹⁷ These authors contributed equally to this work

Corresponding author : Changwon Kee, Chang-Seok Ki

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.Glu373Ala) 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.