DDX58 and Classic Singleton-Merten Syndrome

Carlos R Ferreira,Ji Woo Park,Yanick J Crow,Michele Nehrebecky,Adriana Almeida De Jesús,Pamela J Gardner,Raphaela Goldbach-Mansky,William A Gahl,Tracy A Briggs,Sun Hur

doi:10.1007/s10875-018-0572-1

Abstract

PurposeSingleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy. Pathogenic variants in IFIH1 have previously been associated with the classic Singleton-Merten syndrome, while variants in DDX58 has been described in association with a milder phenotype, which is suggested to have a better prognosis. We studied a family with severe, “classic” Singleton-Merten syndrome.MethodsWe undertook clinical phenotyping, next-generation sequencing, and functional studies of type I interferon production in patient whole blood and assessed the type I interferon promoter activity in HEK293 cells transfected with wild-type or mutant DDX58 stimulated with Poly I:C.ResultsWe demonstrate a DDX58 autosomal dominant gain-of-function mutation, with constitutive upregulation of type I interferon.ConclusionsDDX58 mutations may be associated with the classic features of Singleton-Merten syndrome including dental dysplasia, tendon rupture, and severe cardiac sequela.

Highlights

Singleton-Merten syndrome (SMS [MIM 182250]) is an autosomal dominant disorder, encompassing the cardinal features of dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities, including osteoporosis, contractures, and tendon rupture
Pathogenic variants in interferon-induced with helicase C domain 1 (IFIH1) had previously been associated with a variety of neuroinflammatory phenotypes including Aicardi-Goutières syndrome (AGS) and hereditary spastic
J Clin Immunol (2019) 39:75–80 paraparesis [2, 3]. Functional investigations in both the SMS and AGS studies demonstrated that the observed heterozygous IFIH1 pathogenic variants resulted in a gain-of-function with induction of type I interferon production and increased expression of interferon-stimulated genes (ISGs) [1,2,3]

Summary

Methods

Both patients were enrolled in clinical protocol 76-HG0238 (identifier: NCT00369421), approved by the NHGRI Institutional Review Board, and gave written informed consent. Whole exome sequencing was undertaken using SeqCap EZ Exome+UTR Library using a HiSeq 2500 (Illumina). Structural analysis was undertaken based on the structure of RIG-I [7, 8]. RIG-I wild-type and mutant plasmid constructs were devised and transiently co-transfected with an IFN-b promoter-driven firefly luciferase reporter plasmid into a HEK293 cell line. Significant P values were calculated using a one-tailed, unpaired t test, comparing mutant IFN production with WT RIG-I. Gene expression of selected interferon-stimulated genes (ISGs) was determined by Nanostring (NanoString Technologies, Seattle, WA) and an IFN-score was calculated. Standardized interferon score is the sum of 25 Nanostring counts that were standardized by subtracting the mean of healthy controls and dividing by standard deviation of the healthy controls. Means and SDs of the IFN score are depicted in parenthesis for each group of individuals, as per Kim et al [10]

Introduction

Results