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.

Type I interferonopathies—an expanding disease spectrum of immunodysregulation

“…In addition, patients may suffer from psoriasis, early-onset glaucoma and recurrent infections. Singleton-Merton syndrome is inherited in an autosomal dominant manner and caused by heterozygous mutations in IFIH1 (SGMRT1; OMIM 182250) or RIGI (SGMRT2; OMIM 616298) encoding cytosolic pattern recognition receptors for dsRNA [74,75]. Functional studies have shown that IFIH1 or RIGI mutations in patients act as gain-offunction mutations which results in constitutive type IFN activation.…”

Newly recognized Mendelian disorders with rheumatic manifestations

“…Mutations in DDX58 encoding RIG-I, have recently been described in 11 patients from 2 families with glaucoma and skeletal abnormalities [12]*. The musculoskeletal manifestations include arthritis of hands and feet, joint contractures, calcific tendinitis, and, erosive changes in the terminal tufts of the distal phalanges.…”

“…The musculoskeletal manifestations include arthritis of hands and feet, joint contractures, calcific tendinitis, and, erosive changes in the terminal tufts of the distal phalanges. Four patients had aortic and valvular calcification; psoriasiform rashes were present in 8 individuals and most patients had glaucoma [12]*. Transfection of wildtype and mutant DDX58 into HEK293T cells showed increased basal reporter gene activity of NF-κB and of the IFNB1 enhancer region PRDIII-I [12]*.…”

“…Four patients had aortic and valvular calcification; psoriasiform rashes were present in 8 individuals and most patients had glaucoma [12]*. Transfection of wildtype and mutant DDX58 into HEK293T cells showed increased basal reporter gene activity of NF-κB and of the IFNB1 enhancer region PRDIII-I [12]*. An increased expression of IFNB1 and ISG15 in mutant compared to WT-construct transfected cells was further enhanced by poly I:C stimulation [12]*.…”

Nucleic acid-mediated autoinflammation and autoimmunity—type I interferonopathies

“…Deficiency of components of the immunoproteasome (PSMB8, PSMA3, PSMB4, PSMB9, POMP) causes chronic type I IFN activation by yet unknown mechanisms that may involve antigen presentation. AGS Aicardi-Goutières syndrome, RVCL retinal vasculopathy with cerebral leukodystrophy, CHBL familial chilblain lupus, XLPDR X-linked reticulate pigmentary disorder, SAVI STING-associated vasculopathy, infantile-onset, SGMRT SingletonMerton syndrome, SPENCD spondyloenchrondrodysplasia, CANDLE chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature SGMRT2), AGS and STING-associated vasculopathy (SAVI), respectively [20][21][22][23]. Finally, dysregulation of pathways that modulate type I IFN signaling can cause ISG15 or USP18 deficiency, spondyloenchondrodysplasia, or CANDLE syndrome [10,[24][25][26].…”