Phenotype–Genotype Correlation in Patients With Schnyder Corneal Dystrophy

Nowińska, Anna; Wylęgała, Edward; Teper, Sławomir; Lyssek-Boroń, Anita; Aragona, Pasquale; Roszkowska, Anna M.; Micali, Antonio; Pisani, Antonina; Puzzolo, Domenico

doi:10.1097/ico.0000000000000090

Cited by 20 publications

(22 citation statements)

References 27 publications

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“…Twenty-four mutations that alter twenty amino acid residues in UBIAD1 protein have been identified in SCD families (8,9). Asparagine-102 (N102) and glycine-177 (G177) are the most frequently altered UBIAD1 residues in SCD.…”

Section: Resultsmentioning

confidence: 99%

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Schumacher

Jun

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgUbiA prenyltransferase domain-containing protein-1 (UBIAD1) belongs to the UbiA superfamily of integral membrane prenyltransferases (1). These enzymes contain 8-10 transmembrane helices and catalyze transfer of isoprenyl groups to aromatic acceptors, producing a wide range of molecules such as ubiquinones, hemes, chlorophylls, vitamin E, and vitamin K. In animals, UBIAD1 catalyzes transfer of the 20-carbon geranylgeranyl moiety from geranylgeranyl pyrophosphate (GGpp) to menadione released from plant-derived phylloquinone, thereby generating the vitamin K 2 subtype, menaquinone-4 (MK-4) (2, 3).Mutations in the UBIAD1 gene are associated with Schnyder corneal dystrophy (SCD), an autosomal dominant human eye disease characterized by progressive opacification of the cornea, owing to abnormal accumulation of cholesterol and other lipids (4,5). Systemic dyslipidemia appears to be associated with some, but not all, SCD cases (6, 7). Missense mutations that alter 20 amino acid residues in UBIAD1 have been identified in 50 SCD families (8, 9). Several of these altered amino acids reside within the active site of UBIAD1 (10, 11). A link between UBIAD1 and cholesterol metabolism was first provided by coimmunoprecipitation studies that showed an association of UBIAD1 with the cholesterol biosynthetic enzyme, HMGCoA reductase (8). More recently, we showed that UBIAD1 inhibits sterol-accelerated endoplasmic reticulum (ER)-associated degradation (ERAD) of reductase (12), one of several feedback mechanisms that converge on the enzyme to maintain cholesterol homeostasis (13).Abstract UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K 2 subtype menaquinone-4. Previously, we found that sterols trigger binding of UBIAD1 to endoplasmic reticulum (ER)-localized HMG-CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids, including GGpp. This binding inhibits sterol-accelerated degradation of reductase, which contributes to feedback regulation of the enzyme. The addition to cells of geranylgeraniol (GGOH), which can become converted to GGpp, triggers release of UBIAD1 from reductase, allowing for its maximal degradation and permitting ER-to-Golgi transport of UBIAD1. Here, we further characterize geranylgeranyl-regulated transport of UBIAD1.

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Section: Resultsmentioning

confidence: 99%

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Schumacher

Jun

et al. 2016

Journal of Lipid Research

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“…However, the number of patients examined was relatively low compared with that of the previous studies [13]. Absence of crystals renders the diagnosis of SCD more challenging and previous studies have shown the ability of modern imaging techniques such as SD-OCT and IVCM to identify the corneal features of SCD by allowing an in-depth evaluation of corneal structures [13][14][15][16].…”

Section: Discussionmentioning

confidence: 99%

“…Previously published data on SD-OCT in SCD included hyperreflective corneal opacities located under the epithelium and in the anterior stroma and a diffuse optical shadow from the stromal side [15].…”

Section: Discussionmentioning

confidence: 99%

Multimodal Imaging Features of Schnyder Corneal Dystrophy

Ghazal¹,

Georgeon²,

Grieve

et al. 2020

Journal of Ophthalmology

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Objective. To describe the multimodal imaging of Schnyder corneal dystrophy. Methods. Seven eyes of seven patients (5 female and 2 male patients) aged 52 to 92 years were included in this prospective observational study. Diagnosis of SCD was confirmed by histology after keratoplasty. In vivo multimodal imaging consisted of spectral domain-optical coherence tomography with cross sections, en face scans, corneal pachymetry, and epithelial mapping, and in vivo confocal microscopy was recorded. Ex vivo full-field optical coherence tomography scans of two corneal buttons were analyzed. The seven corneal buttons obtained during penetrating or deep anterior lamellar keratoplasty were processed for light microscopy. Results. Slit-lamp examination showed central stromal opacities, arcus lipoides, and midperipheral haze. Corneal crystals were found in 2 out of 7 eyes. SD-OCT cross sections and en face scans showed diffuse hyperreflectivity of the anterior, mid, and posterior stroma with a maximum in the anterior stroma, hyporeflective stromal striae, and epithelial hyperreflectivity. Central corneal thickness ranged from 507 to 635 μm. IVCM revealed hyperreflective deposits in the epithelium and throughout the stroma, thin subepithelial nerves, and needle-shaped and rectangular crystals. Keratocyte nuclei were rare or undetectable. FF-OCT scans confirmed the presence of small round and needle-shaped hyperreflective deposits in the epithelium and stroma. Histology revealed vacuolization of the basal epithelial cells and empty interlamellar stromal vacuoles. Conclusion. High-resolution multimodal imaging demonstrates the characteristic features of SCD which involve both the corneal epithelium and stroma, and it provides diagnosis confirmation even in eyes with no visible corneal crystals at slit-lamp examination.

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“…On slit lamp biomicroscopy, such deposition may manifest as stromal mid‐peripheral corneal haze, crystal deposition and arcus lipoides (Fig. ) . Patients under the age of 23 years usually only have a central corneal opacity, with or without sub‐epithelial and anterior stromal polychromatic crystals, and have normal corneal sensation.…”

Section: Lipidmentioning

confidence: 99%

“…In vivo confocal microscopy has shown decreased sub‐basal nerve density and increased stromal reflectivity. Cases with crystalline deposits exhibited numerous needle shaped and rectangular highly reflective opacities in the anterior stroma …”

Section: Lipidmentioning

confidence: 99%