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

Mi-Ae Jang, Eun Kyoung Kim, Hesung Now, Nhung T.H. Nguyen, Woo-Jong Kim, Joo-Yeon Yoo, Jinhyuk Lee, Yun-Mi Jeong, Cheol-Hee Kim, Ok-Hwa Kim, Seongsoo Sohn, Seong-Hyeuk Nam, Yoojin Hong, Yong Seok Lee, Sung-A Chang, Shin Yi Jang, Jong-Won Kim, Myung-Shik Lee, So Young Lim, Ki-Sun Sung, Ki-Tae Park, Byoung Joon Kim, Joo-Heung Lee, Duk-Kyung Kim, 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.