Schnyder Corneal Dystrophy Research Articles

Schnyders corneal dystrophy: A case report

Schnyder corneal dystrophy (SCD) is a rare, autosomal dominant inherited dystrophy affecting the anterior stroma of the cornea. It is caused by a local metabolic defect mapped on the UBIAD1 gene chromosome 1p36. It is known to causes progressive bilateral opacification of the cornea due to an abnormal accumulation of phospholipids and cholesterol in the cornea. In our case a 22-year-old male with vision loss and ocular discomfort revelled multiple grey, infiltrates or disc like opacities in both eyes arranged in circinate manner on slit-lamp, involving the sub-epithelium and stroma. On anterior segment OCT, involvement of the entire stroma was noted with Increased deposits seen in the anterior 1/3rd of the stroma. Central corneal thickness was also increased in the areas of depositions, while systemic evaluation showed dyslipidemia. Clinical as well as anterior segment OCT findings suggest of intrastromal deposits in a ring like pattern, suggestive of schnyders corneal dystrophy. AS-OCT is vital in such cases to help differentiate epithelial involvement from stromal, thus altering the therapeutic approach. Patients can be planned for penetrating keratoplasty if visual acquits is affected.

Lipid Keratopathy: Histopathology, Major Differential Diagnoses and The Importance of Clinical Correlation.

Lipid keratopathy (LK) is a rare ophthalmological condition characterized by a progressive reduction in visual acuity caused by corneal opacification due to central lipid accumulation. LK is characterized by lipid deposits, cholesterol clefts, and neovascularization (NV) leading to disruption in corneal optical quality. LK classification includes a primary and secondary form which depend on pre-existing corneal or systemic disorders and the evidence of NV. Secondary LK is typically associated with a prior occurrence of herpetic infection, such as herpes zoster keratitis. Patients with LK usually present with progressive vision loss and dense cream-colored corneal opacification. Treatment modalities include conservative and surgical approaches focused on corneal NV elimination. When evaluating corneal lipidosis, it is crucial to consider a range of differential diagnoses, including corneal arcus, Schnyder corneal dystrophy, and other corneal deposit conditions. We report a case of a 62-year-old male with herpes zoster keratitis complicated with LK. He presented with painless progressive vision loss and corneal scarring, which raised suspicion about LK diagnosis. This paper emphasizes the importance of correlating clinical and histological findings for accurate LK diagnosis.

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) variant c.695A > G identified in a multigenerational Japanese family with Schnyder corneal dystrophy.

We aimed to identify pathogenic variations in the UbiA prenyltransferase domain-containing protein 1 (UBIAD1) gene in a Japanese family with Schnyder corneal dystrophy (SCD). Clinical study METHODS: Three clinically diagnosed SCD patients from a single pedigree participated. Patients 1 and 2 were 69- and 65-year-old sisters, and patient 3 was the 42-year-old daughter of patient 1. Blood samples from the patients were obtained for genetic analysis. Mutation screening of the two UBIAD1 exons was performed using polymerase chain reaction (PCR)-based DNA sequencing. All participants were found to be heterozygous for the pathogenic missense variation c.695A > G (p.Asn232Ser) in exon 2 of UBIAD1. This is the first report on the pathogenic UBIAD1 variation c.695A > G (p.Asn232Ser) in a Japanese population. SCD is a rare corneal dystrophy, and further research on additional cases will aid in the elucidation of disease mechanisms and development of therapeutic strategies.

The Vitamin K2Synthetic Enzyme UBIAD1 Moonlights as a Key Regulator of Cholesterol Synthesis

UbiA prenyltransferase domain‐containing protein‐1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone‐4 (MK‐4). Mutations in UBIAD1 cause Schnyder corneal dystrophy (SCD), which is characterized by corneal opacification owing to over‐accumulation of cholesterol. Our studies disclosed a key role for UBIAD1 in regulating endoplasmic reticulum (ER)‐localized HMG CoA reductase, the rate‐limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids including GGpp. Feedback control of reductase involves sterol‐induced ubiquitination, an obligatory reaction for its ER‐associated degradation (ERAD) that is augmented by GGpp. Sterols also cause UBIAD1 to bind reductase, which inhibits ERAD and allows continued synthesis of nonsterol isoprenoids in sterol‐replete cells. GGpp triggers release of reductase from UBIAD1, enhancing ERAD and stimulating translocation of UBIAD1 to Golgi. SCD‐associated UBIAD1 resists GGpp‐induced release from reductase and becomes sequestered in ER to inhibit ERAD.Gene knockout studies in mice were attempted to explore the in vivo function of UBIAD1; however, homozygous germ‐line deletion of Ubiad1 caused embryonic lethality. We generated homozygous deletion of Ubiad1 in knock‐in mice expressing ubiquitination‐resistant HMGCR, implying embryonic lethality results from enhanced ERAD of HMGCR. The study of Ubiad1‐deficient mice offers the opportunity to determine the physiological significance of UBIAD1‐mediated synthesis of MK‐4.

Schnyder Crystalline Corneal Dystrophy: A Case Report

Schnyder crystalline corneal dystrophy (SCCD) is a rare hereditary corneal pathology, the clinical forms of which can be varied. It is classically characterized by the presence of central corneal disc or ring opacities, with or without the presence of crystals, and sometimes the association with a peripheral corneal arch or the limbic belt of Vogt. Its pathogenesis is linked to an abnormality in lipid metabolism with accumulation of lipids (phospholipids or cholesterol) in the cornea. We report the case of a 30-year-old patient, with no particular history, presenting a progressive decrease in visual acuity linked to central corneal opacities, in disc form following an accumulation of iridescent crystals in the central portion of the stroma, with a peripheral lipid arc all evolving for 15 years, and we describe its aspects in anterior segment optical coherence tomography and in vivo confocal microscopy. The purpose of our case is to recall the clinical and biological characteristics of Schnyder crystalline corneal dystrophy, and to underline the risk of occurrence of diffuse vascular damage secondary to a lipid disorder favoring cardiovascular accidents. Ophthalmologists should be aware of the ocular and general signs of Schnyder's dystrophy in order to preserve functional visual and vital cardiovascular prognosis.

Schnyder corneal dystrophy

We present the case of a 45-year-old African male patient, who presented to the ophthalmic consultation for decreased bilateral visual acuity and complaints of blurred vision for 5 years. The ophthalmological examination included a measure of visual acuity using Snellen’s distance vision chart. We did a complete and bilateral biomicroscopic examination of the anterior and the posterior segments. The clinical examination found a reduced visual acuity to counting fingers in the right eye and 2/10 in the left eye. Intraocular pressure was normal in both eyes. Slitlamp examination revealed corneal arcus or a disk-like lesion and polychromatic crystalline depositions in both eyes in the subepithelial and the anterior 1/3 of the stroma (A). The mild onset of arcus lipoides was seen but the Midperipheral stromal haze was absent. Central corneal thickness results were 513 μm in the right eye and 509 μm in the left eye. A diagnosis of Schnyder corneal dystrophy was based on clinical presentation and the coexistence dyslipidemia of the patient. Schnyder corneal dystrophy (SCD) is a rare, autosomal dominant, anterior stromal dystrophy described as progressive bilateral corneal opacification due to abnormal accumulation of cholesterol and phospholipids in the cornea. SCD with different presentations may actually be misdiagnosed. Early diagnosis would help to rule out other potentially sight threatening or treatable conditions like infectious keratitis or drug toxicity. SCD should be discerned from other lipid keratopathies.

Naturally occurring UBIAD1 mutations differentially affect menaquinone biosynthesis and vitamin K-dependent carboxylation.

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) is responsible for the biosynthesis of menaquinone-4 (MK-4), a cofactor for extrahepatic carboxylation of vitamin K-dependent (VKD) proteins. Genetic variations of UBIAD1 are mainly associated with Schnyder corneal dystrophy (SCD), a disease characterized by abnormal accumulation of cholesterol in the cornea. Results from in vitro studies demonstrate that SCD-associated UBIAD1 mutations are defective in MK-4 biosynthesis. However, SCD patients do not exhibit typical phenotypes associated with defects of MK-4 or VKD carboxylation. Here, we coupled UBIAD1's biosynthetic activity of MK-4 with VKD carboxylation in HEK293 cells that stably express a chimeric VKD reporter protein. The endogenous Ubiad1 gene in these cells was knocked out by CRISPR-Cas9-mediated genome editing. The effect of UBIAD1 mutations on MK-4 biosynthesis and VKD carboxylation was evaluated in Ubiad1-deficient reporter cells by determining the production of MK-4 or by measuring the efficiency of reporter-protein carboxylation. Our results show that the hot-spot mutation N102S has a moderate impact on MK-4 biosynthesis (retained ˜ 82% activity) but does not affect VKD carboxylation. However, the G186R mutation significantly affected both MK-4 biosynthesis and VKD carboxylation. Other mutations exhibit varying degrees of effects on MK-4 biosynthesis and VKD carboxylation. These results are consistent with in vivo results obtained from gene knock-in mice and SCD patients. Our findings suggest that UBIAD1's MK-4 biosynthetic activity does not directly correlate with the phenotypes of SCD patients. The established cell-based assays in this study provide a powerful tool for the functional studies of UBIAD1 in a cellular milieu.

Functional study of SCCD pathogenic gene UBIAD1 (Review).

Schnyder's crystalline corneal dystrophy (SCCD) is a rare autosomal dominant genetic disorder that is characterized by progressive corneal opacity, owing to aberrant accumulation of cholesterol and phospholipids in the cornea. A number of SCCD affected families have been reported in the world since 1924, when it was first described. In 2007, the molecular basis of SCCD was demonstrated to be associated with a tumor suppressor, UbiA prenyltransferase domain-containing 1 (UBIAD1), which was isolated from the bladder mucosa and demonstrated to be involved in vitamin K2 and CoQ10 biosynthesis. This sterol triggers the binding of UBIAD1 to 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR) at endoplasmic reticulum (ER) membranes, which is regulated by an intracellular geranylgeranyl diphosphate (GGpp) molecule. The inability of SCCD-associated UBIAD1 to bind GGpp results in the consistent binding of UBIAD1 to HMGCR at ER membranes. This binding leads to HMGCRs being redundant. Therefore, they cannot be degraded through ER-associated degradation to synthesize abundant cholesterol in tissue cells. Excess corneal cholesterol accumulation thus leads to SCCD disease. After decades, the efforts of numerous ophthalmologists and scientists have helped clarify the molecular basis and pathogenesis of SCCD, which has guided the effective diagnosis and treatment of this genetic disorder. However, more studies need to be conducted to understand the pathogenesis of SCCD disease from a genetic basis by studying the defective gene, UBIAD1. Results would guide effective diagnosis and treatment of the inherited eye disease.

High expression of Matrix Gla Protein in Schnyder corneal dystrophy patients points to an active role of vitamin K in corneal health.

Schnyder corneal dystrophy (SCD) is a rare autosomal dominant disorder characterized by corneal lipid accumulation and caused by UBIAD1 pathogenic variants. UBIAD1 encodes a vitamin K (VK) biosynthetic enzyme. To assess the corneal and vascular VK status in SCD patients, we focused on matrix Gla protein (MGP), a VK-dependent protein. Conformation-specific immunostainings of different MGP maturation forms were performed on corneal sections and primary keratocytes from corneal buttons of two SCD patients with UBIAD1 p.Asp112Asn and p.Asn102Ser pathogenic variants and unrelated donors. Native or UBIAD1-transfected keratocytes were used for gene expression analysis. Plasma samples from SCD patients (n=12) and control individuals (n=117) were subjected for inactive desphospho-uncarboxylated MGP level measurements with an ELISA assay. Substantial amounts of MGP were identified in human cornea and most of it in its fully matured and active form. The level of mature MGP did not differ between SCD and control corneas. In primary keratocytes from SCD patients, a highly increased MGP expression and presence of immature MGP forms were detected. Significantly elevated plasma concentration of inactive MGP was found in SCD patients. High amount of MGP and the predominance of mature MGP forms in human cornea indicate that VK metabolism is active in the visual system. Availability of MGP seems of vital importance for a healthy cornea and may be related to protection against corneal calcification. Systemic MGP findings reveal a poor vascular VK status in SCD patients and indicate that SCD may lead to cardiovascular consequences.

Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation

The autosomal dominant disorder Schnyder corneal dystrophy (SCD) is caused by mutations in UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which uses geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4 (MK-4). SCD is characterized by opacification of the cornea, owing to aberrant build-up of cholesterol in the tissue. We previously discovered that sterols stimulate association of UBIAD1 with ER-localized HMG-CoA reductase, which catalyzes a rate-limiting step in the synthesis of cholesterol and nonsterol isoprenoids, including GGpp. Binding to UBIAD1 inhibits sterol-accelerated ER-associated degradation (ERAD) of reductase and permits continued synthesis of GGpp in cholesterol-replete cells. GGpp disrupts UBIAD1-reductase binding and thereby allows for maximal ERAD of reductase as well as ER-to-Golgi translocation of UBIAD1. SCD-associated UBIAD1 is refractory to GGpp-mediated dissociation from reductase and remains sequestered in the ER to inhibit ERAD. Here, we report development of a biochemical assay for UBIAD1-mediated synthesis of MK-4 in isolated membranes and intact cells. Using this assay, we compared enzymatic activity of WT UBIAD1 with that of SCD-associated variants. Our studies revealed that SCD-associated UBIAD1 exhibited reduced MK-4 synthetic activity, which may result from its reduced affinity for GGpp. Sequestration in the ER protects SCD-associated UBIAD1 from autophagy and allows intracellular accumulation of the mutant protein, which amplifies the inhibitory effect on reductase ERAD. These findings have important implications not only for the understanding of SCD etiology but also for the efficacy of cholesterol-lowering statin therapy, which becomes limited, in part, because of UBIAD1-mediated inhibition of reductase ERAD.

Multimodal Imaging Features of Schnyder Corneal Dystrophy.

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.

Schnyder corneal dystrophy-associated UBIAD1 mutations cause corneal cholesterol accumulation by stabilizing HMG-CoA reductase.

Schnyder corneal dystrophy (SCD) is a rare genetic eye disease characterized by corneal opacification resulted from deposition of excess free cholesterol. UbiA prenyltransferase domain-containing protein-1 (UBIAD1) is an enzyme catalyzing biosynthesis of coenzyme Q10 and vitamin K2. More than 20 UBIAD1 mutations have been found to associate with human SCD. How these mutants contribute to SCD development is not fully understood. Here, we identified HMGCR as a binding partner of UBIAD1 using mass spectrometry. In contrast to the Golgi localization of wild-type UBIAD1, SCD-associated mutants mainly resided in the endoplasmic reticulum (ER) and competed with Insig-1 for HMGCR binding, thereby preventing HMGCR from degradation and increasing cholesterol biosynthesis. The heterozygous Ubiad1 G184R knock-in (Ubiad1G184R/+) mice expressed elevated levels of HMGCR protein in various tissues. The aged Ubiad1G184R/+ mice exhibited corneal opacification and free cholesterol accumulation, phenocopying clinical manifestations of SCD patients. In summary, these results demonstrate that SCD-associated mutations of UBIAD1 impair its ER-to-Golgi transportation and enhance its interaction with HMGCR. The stabilization of HMGCR by UBIAD1 increases cholesterol biosynthesis and eventually causes cholesterol accumulation in the cornea.

Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice.

Autosomal-dominant Schnyder corneal dystrophy (SCD) is characterized by corneal opacification owing to overaccumulation of cholesterol. SCD is caused by mutations in UBIAD1, which utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. Using cultured cells, we previously showed that sterols trigger binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase (HMGCR), thereby inhibiting its endoplasmic reticulum (ER)-associated degradation (ERAD) (Schumacher et al. 2015). GGpp triggers release of UBIAD1 from HMGCR, allowing maximal ERAD and ER-to-Golgi transport of UBIAD1. SCD-associated UBIAD1 resists GGpp-induced release and is sequestered in ER to inhibit ERAD. We now report knockin mice expressing SCD-associated UBIAD1 accumulate HMGCR in several tissues resulting from ER sequestration of mutant UBIAD1 and inhibition of HMGCR ERAD. Corneas from aged knockin mice exhibit signs of opacification and sterol overaccumulation. These results establish the physiological significance of UBIAD1 in cholesterol homeostasis and indicate inhibition of HMGCR ERAD contributes to SCD pathogenesis.

In vivo confocal microscopy as a diagnostic tool in Schnyder Corneal Dystrophy’s case

Schnyder’s corneal dystrophy (SCD) is a rare corneal condition characterized by cholesterol and phospholipids deposition in the stroma and Bowman’s layer. We present a case report of a patient who had a progressive corneal stromal haze in both eyes since he was 15 years old. Etiological diagnosis of SCD was well established by In Vivo Confocal Microscopy (IVCM). In vivo confocal microscopy as a diagnostic tool in Schnyder Corneal Dystrophy’s case

Schnyder corneal dystrophy and associated phenotypes caused by novel and recurrent mutations in the UBIAD1 gene

BackgroundThe purpose of this study was to identify the genetic cause and describe the clinical phenotype of Schnyder corneal dystrophy (SCD) in six unrelated probands.MethodsWe identified two white Czech, two white British and two South Asian families with a clinical diagnosis of SCD. Ophthalmic assessment included spectral domain optical coherence tomography (SD-OCT) of one individual with advanced disease, and SD-OCT and confocal microscopy of a child with early stages of disease. UBIAD1 coding exons were amplified and Sanger sequenced in each proband. A fasting serum lipid profile was measured in three probands. Paternity testing was performed in one family.ResultsA novel heterozygous c.527G>A; p.(Gly176Glu) mutation in UBIAD1 was identified in one Czech proband. In the second Czech proband, aged 6 years when first examined, a previously described de novo heterozygous c.289G>A; p.(Ala97Thr) mutation was found. Two probands of South Asian descent carried a known c.305G>A; p.(Asn102Ser) mutation in the heterozygous state. Previously reported heterozygous c.361C>T; p.(Leu121Phe) and c.308C>T; p.(Thr103Ile) mutations were found in two white British families. Although crystalline deposits were present in all probands the affected area was small in some individuals. Corneal arcus and stromal haze were the most prominent phenotypical feature in two probands. In the Czech probands, SD-OCT confirmed accumulation of reflective material in the anterior stroma. Crystalline deposits were visualized by confocal microscopy. Mild dyslipidemia was found in all three individuals tested.ConclusionAlthough de novo occurrence of mutations in UBIAD1 is extremely rare, SCD should be considered in the differential diagnosis of bilateral corneal haze and/or crystal deposition, especially in children.

Clinical diversity in patients with Schnyder corneal dystrophy\u2014a novel and known UBIAD1 pathogenic variants

PurposeSchnyder corneal dystrophy (SCD) is a rare inherited disease that leads to gradual vision loss by the deposition of lipids in the corneal stroma. The aim of this study is to report a novel pathogenic variant in the UBIAD1 gene and present clinical and molecular findings in Polish patients with SCD.MethodsIndividuals (n = 37) originating from four Polish SCD families were subjected for a complete ophthalmological check-up and genetic testing. Corneal changes were visualized by slit-lamp examination, anterior segment optical coherent tomography (AS-OCT), and in vivo confocal microscopy (IVCM).ResultsIn a proband with primarily mild SCD that progressed rapidly at the end of the fifth decade of life, a novel missense pathogenic variant in UBIAD1 (p.Thr120Arg) was identified. The other studied SCD family represents the second family reported worldwide with the UBIAD1 p.Asp112Asn variant. SCD in the remaining two families resulted from a frequently identified p.Asn102Ser pathogenic variant. All affected subjects presented a crystalline form of SCD. The severity of corneal changes was age-dependent, and their morphology and localization are described in detail.ConclusionThe novel p.Thr120Arg is the fourth SCD-causing variant lying within the FARM motif of the UBIAD1 protein, which underlines a high importance of this motif for SCD pathogenesis. The current study provides independent evidence for the pathogenic potential of UBIAD1 p.Asp112Asn and new information useful for clinicians.

A Mouse Model of Schnyder Corneal Dystrophy with the N100S Point Mutation

Schnyder corneal dystrophy (SCD) is a rare autosomal dominant disease in humans, characterized by abnormal deposition of cholesterol and phospholipids in cornea caused by mutations in the UbiA prenyltransferase domain containing 1 (UBIAD1) gene. In this study, we generated a mouse line carrying Ubiad1 N100S point mutation using the CRISPR/Cas9 technique to investigate the pathogenesis of SCD. In vivo confocal microscopy revealed hyper-reflective dot-like deposits in the anterior cornea in heterozygotes and homozygotes. No significant change was found in corneal epithelial barrier function or wound healing. Electron microscopy revealed abnormal mitochondrial morphology in corneal epithelial, stromal, and endothelial cells. Mitochondrial DNA copy number assay showed 1.27 ± 0.07 fold change in homozygotes versus 0.98 ± 0.05 variation in wild type mice (P < 0.05). Lipidomic analysis indicated abnormal metabolism of glycerophosphoglycerols, a lipid class found in mitochondria. Four (34:1, 34:2, 36:2, and 44:8) of the 11 glycerophosphoglycerols species identified by mass spectrometry showed a significant increase in homozygous corneas compared with heterozygous and wild-type mouse corneas. Unexpectedly, we did not find a difference in the corneal cholesterol level between different genotypes by filipin staining or lipidomic analysis. The Ubiad1N100S mouse provides a promising animal model of SCD revealing that mitochondrial dysfunction is a prominent component of the disease. The different phenotype in human and mouse may due to difference in cholesterol metabolism between species.

Long-Term Outcome After Penetrating Keratoplasty in a Pedigree With the G177E Mutation in the UBIAD1 Gene for Schnyder Corneal Dystrophy.

To investigate the long-term surgical outcome after penetrating keratoplasty in 5 patients from 1 pedigree with Schnyder corneal dystrophy (SCD), resulting from the same UbiA prenyltransferase domain containing 1 (UBIAD1) mutation. This retrospective study involved 6 eyes of 5 patients who underwent penetrating keratoplasty for treatment of SCD. Postoperative surgical outcome measures included the analysis of best-corrected visual acuity (BCVA), corneal endothelial cell density, and the rates of corneal graft rejection and disease recurrence. Genomic DNA was extracted from whole peripheral blood samples obtained from each patient at the time of surgery, and mutation analysis of the UBIAD1 gene was then performed. All patients were found to have the same G177E mutation in the UBIAD1 gene. Mean patient age at the time of surgery was 61.5 ± 10.4 years (range, 49-72 yrs), and mean postoperative follow-up period was 8.8 ± 3.1 years (range, 3-11 yrs). Preoperatively, BCVA ranged from logarithm of the minimum angle of resolution (logMAR) 1.7 to logMAR 0.22; yet, it was found that BCVA had improved to logMAR 0.02 at 3 years postoperatively. Mean corneal endothelial cell density at 3, 5, and 8 years postoperatively was 2181, 1783, and 910 cells/mm, respectively. In all eyes, no disease recurrence or corneal graft rejection was observed during the follow-up period, and graft transparency was maintained. Our findings show that the corneal grafts in the reported SCD pedigree remained clear with no rejection or disease recurrence over the long term.

Functional characterization of the UBIAD1 protein: The nodal point for vitamin K and cholesterol synthesis. From corneal dystrophies to lifestyle diseases

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is a transmembrane enzyme that plays an essential physiological role in the human body. The most important functions of the UBIAD1 protein include (i) the synthesis of endogenous vitamin K, (ii) direct and indirect participation in the cholesterol synthesis pathway and (iii) synthesis of the non-mitochondrial ubiquinone Q10 (CoQ10), a cellular antioxidant [27, 28, 30]. UBIAD1 is the only protein in the human body that is known to convert derivatives of the plant form of vitamin K1 to the endogenous vitamin K2 (MK-4). Mutations in the UBIAD1 gene and/or dysfunction of the UBIAD1 protein have severe consequences on cellular metabolism and are causative of many diseases, including Schnyder corneal dystrophy (SCD). It is an inherited disease that leads to gradual vision loss by the deposition of lipids in the cornea. The mechanism of the disease remains largely unknown. Importantly, dysfunction of UBIAD1 was also found in other diseases, such as (i) Parkinson’s disease, (ii) cardiovascular diseases and (iii) prostate and bladder cancer. In this paper we attempt to present a wide characterization of UBIAD1 metabolic functions at the cellular and tissue level. We also show the mechanisms that may lead to pathological changes observed in SCD. Based on previous research, we demonstrate the complexity of processes in which the UBIAD1 protein is involved. The aim of this review is to analyze possible causes and to present a probable explanation for the occurrence of various diseases related to the dysfunction of UBIAD1.

UbiA prenyltransferase domain–containing protein-1 modulates HMG-CoA reductase degradation to coordinate synthesis of sterol and nonsterol isoprenoids

UBIAD1 (UbiA prenyltransferase domain-containing protein-1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2 We previously reported that sterols stimulate binding of UBIAD1 to endoplasmic reticulum (ER)-localized 3-hydroxy-3-methylglutaryl (HMG) CoA reductase. UBIAD1 binding inhibits sterol-accelerated, ER-associated degradation (ERAD) of reductase, one of several mechanisms for feedback control of this rate-limiting enzyme in the branched pathway that produces cholesterol and nonsterol isoprenoids such as GGpp. Accumulation of GGpp in ER membranes triggers release of UBIAD1 from reductase, permitting its maximal ERAD and ER-to-Golgi transport of UBIAD1. Mutant UBIAD1 variants associated with Schnyder corneal dystrophy (SCD), a human disorder characterized by corneal accumulation of cholesterol, resist GGpp-induced release from reductase and remain sequestered in the ER to block reductase ERAD. Using lines of genetically manipulated cells, we now examine consequences of UBIAD1 deficiency and SCD-associated UBIAD1 on reductase ERAD and cholesterol synthesis. Our results indicated that reductase becomes destabilized in the absence of UBIAD1, resulting in reduced cholesterol synthesis and intracellular accumulation. In contrast, an SCD-associated UBIAD1 variant inhibited reductase ERAD, thereby stabilizing the enzyme and contributing to enhanced synthesis and intracellular accumulation of cholesterol. Finally, we present evidence that GGpp-regulated, ER-to-Golgi transport enables UBIAD1 to modulate reductase ERAD such that synthesis of nonsterol isoprenoids is maintained in sterol-replete cells. These findings further establish UBIAD1 as a central player in the reductase ERAD pathway and regulation of isoprenoid synthesis. They also indicate that UBIAD1-mediated inhibition of reductase ERAD underlies cholesterol accumulation associated with SCD.