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Terri L Young, Kristina Whisenhunt, Yasmin Bradfield, Nickie Stangel, Sarah Lamartina, Stuart Tompson; Novel DDX58 Gene Mutation Associated With Childhood Glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2835.
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© ARVO (1962-2015); The Authors (2016-present)
Singleton-Merten syndrome 2 (SMS2), an autosomal dominant disorder, is defined by variable expression of childhood glaucoma (CG), aortic calcification, psoriasis, and skeletal abnormalities. To date, SMS2 has only been described in association with Dead Box Polypeptide 58 (DDX58) gene mutations in 2 Korean families. We report a novel DDX58 mutation in a Caucasian with severe early CG.
A Caucasian male diagnosed at age 18 months with severe bilateral glaucoma and bicuspid valve was ascertained with both parents for gene screening. Whole exome sequencing (WES) of subject DNA using a Nimblegen capture kit with 2x100bp reads on an Illumina platform was performed. Sequences were aligned to the UCSC hg19/GRCh37human genome assembly. Variants were filtered/analyzed using Golden Helix SNP and Variation Suite software. Sanger sequencing validated candidate variants and co-segregation.Ocular tissue gene expression data was also obtained from the Iowa Ocular Tissue database (IOTD).DDX58 signaling function was assessed in HEK293T cells transfected with either FLAG-DDX58-WT or FLAG-DDX58-E330K constructs. Downstream NFkB activity was assayed by dual-luciferase reporter and phosphorylation of Interferon Regulatory Factor 3 (IRF3) was determined by Western blotting.
WES identified a heterozygous de novo p.E330K (c.988G>A; NM_014314.3) missense mutation in DDX58, substituting a highly conserved residue within the Hel-1 core helicase domain. The mutation was not found in 250,973 unrelated control alleles (gnomAD database v2.1), or in 37 in-house WES CG pedigrees.The IOTD showed highest expression of DDX58 in choroid/retinal pigment epithelium and trabecular meshwork.Protein over-expression assays demonstrated the E330K-harboring form of DDX58 to be constitutively active, resulting in increased NFkB reporter activity and increased phosphorylation of IRF3.
A novel heterozygous de novo DDX58 missense mutation was identified in association with CG in a non-Korean family. The heterozygosity expands the prevailing paradigm of homozygous autosomal recessive inheritance for CG. Our findings identify DDX58 mutations as a cause of ocular-only disease, although the bicuspid valve may be related. DDX58 should be considered for inclusion in any CG gene screening panel. We recommend that mutation-positive individuals undergo cardiac surveillance.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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