No 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.

Background:The aim was to evaluate changes in choroidal thickness, intraocular pressure (IOP) and other parameters of optical coherence tomography, such as central foveal thickness (CFT), macular volume, peripapillary retinal nerve fibre layer (RNFL) thickness after haemodialysis (HD). Methods: Thirty-four eyes of 34 chronic renal failure patients (9 eyes with diabetic patients) who underwent haemodialysis in the Dialysis Unit of Gangneung Asan Hospital were included. CFT, macular volume, peripapillary RNFL and choroidal thickness were measured before and after haemodialysis by optical coherence tomography (OCT, Spectralis; Heidelberg Engineering). Changes in the IOP were evaluated with Goldmann applanation tonometry before and after haemodialysis. Results: The average choroidal thickness decreased significantly, from 233.1 Ϯ 77.5 mm to 219.1 Ϯ 76.8 mm (paired t-test, p < 0.001). This change correlated with the amount of body weight lost (Pearson's correlation coefficient = 0.348, p = 0.044). The mean IOP decreased from 15.1 Ϯ 2.6 mmHg to 13.9 Ϯ 2.2 mmHg after haemodialysis (paired t-test, p = 0.03). The change in macular volume and the small decrease in CFT (214.0 Ϯ 21.0 mm to 213.8 Ϯ 21.8 mm) were not significant. The measured overall change in RNFL thickness from 93.6 Ϯ 15.5 mm to 94.7 Ϯ 14.6 mm was not significant. Conclusions: Haemodialysis can affect various ocular parameters, particularly choroidal thickness and IOP.