title: Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome.
abstract: 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.
authors.affiliation: Departments of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Mi-Ae
authors.initials: MA
authors.lastname: Jang
authors.affiliation: Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Hesung
authors.initials: H
authors.lastname: Now
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Nhung T H
authors.initials: NT
authors.lastname: Nguyen
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Woo-Jong
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea; Department of Bioinformatics, University of Sciences and Technology, Daejeon 305-350, Korea.
authors.forename: Jinhyuk
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Biology, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Yun-Mi
authors.initials: YM
authors.lastname: Jeong
authors.affiliation: Department of Biology, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Radiology, Woorisoa Children's Hospital, Seoul 152-862, Korea.
authors.forename: Ok-Hwa
authors.initials: OH
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Seongsoo
authors.initials: S
authors.lastname: Sohn
authors.affiliation: Samsung SDS, Seoul 138-240, Korea.
authors.forename: Seong-Hyeuk
authors.initials: SH
authors.lastname: Nam
authors.affiliation: Samsung SDS, Seoul 138-240, Korea.
authors.forename: Yoojin
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Samsung SDS, Seoul 138-240, Korea.
authors.forename: Yong Seok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Sung-A
authors.initials: SA
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Shin Yi
authors.initials: SY
authors.lastname: Jang
authors.affiliation: Departments of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Lim
authors.affiliation: Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Ki-Sun
authors.initials: KS
authors.lastname: Sung
authors.affiliation: Department of Pediatric Dentistry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Ki-Tae
authors.initials: KT
authors.lastname: Park
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Byoung Joon
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Joo-Heung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Duk-Kyung
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. Electronic address: ckee@skku.edu.
authors.forename: Changwon
authors.initials: C
authors.lastname: Kee
authors.affiliation: Departments of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. Electronic address: changski@skku.edu.
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Ki
mesh_terms: D000328:Adult; D001018:Aortic Diseases / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002478:Cells, Cultured; D002675:Child, Preschool; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics*; D003744:Dental Enamel Hypoplasia / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D005901:Glaucoma / Q000235:genetics*; D006801:Humans; D008297:Male; D008663:Metacarpus / Q000002:abnormalities* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009139:Musculoskeletal Abnormalities / Q000000981:diagnostic imaging / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D018126:Odontodysplasia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D010024:Osteoporosis / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011859:Radiography; D011971:Receptors, Immunologic; D017422:Sequence Analysis, DNA; D061205:Vascular Calcification / Q000235:genetics* / Q000473:pathology
chemical_list: D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases