Dataset Information

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

ABSTRACT: 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?

SUBMITTER: Dong F

PROVIDER: S-EPMC6033878 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Dong Fei F Jin Xueting X Boettler Michelle A MA Sciulli Harrison H Abu-Asab Mones M Del Greco Christina C Wang Shurong S Hu Yueh-Chiang YC Campos Maria M MM Jackson Shelley N SN Muller Ludovic L Woods Amina S AS Combs Christian A CA Zhang Jianhua J Nickerson Michael L ML Kruth Howard S HS Weiss Jayne S JS Kao Winston W WW

Scientific reports 20180705 1

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 hetero ...[more]

PMID: 29977031

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Project description:BACKGROUND:Mutations in a novel gene, UBIAD1, were recently found to cause the autosomal dominant eye disease Schnyder corneal dystrophy (SCD). SCD is characterized by an abnormal deposition of cholesterol and phospholipids in the cornea resulting in progressive corneal opacification and visual loss. We characterized lesions in the UBIAD1 gene in new SCD families and examined protein homology, localization, and structure. METHODOLOGY/PRINCIPAL FINDINGS:We characterized five novel mutations in the UBIAD1 gene in ten SCD families, including a first SCD family of Native American ethnicity. Examination of protein homology revealed that SCD altered amino acids which were highly conserved across species. Cell lines were established from patients including keratocytes obtained after corneal transplant surgery and lymphoblastoid cell lines from Epstein-Barr virus immortalized peripheral blood mononuclear cells. These were used to determine the subcellular localization of mutant and wild type protein, and to examine cholesterol metabolite ratios. Immunohistochemistry using antibodies specific for UBIAD1 protein in keratocytes revealed that both wild type and N102S protein were localized sub-cellularly to mitochondria. Analysis of cholesterol metabolites in patient cell line extracts showed no significant alteration in the presence of mutant protein indicating a potentially novel function of the UBIAD1 protein in cholesterol biochemistry. Molecular modeling was used to develop a model of human UBIAD1 protein in a membrane and revealed potentially critical roles for amino acids mutated in SCD. Potential primary and secondary substrate binding sites were identified and docking simulations indicated likely substrates including prenyl and phenolic molecules. CONCLUSIONS/SIGNIFICANCE:Accumulating evidence from the SCD familial mutation spectrum, protein homology across species, and molecular modeling suggest that protein function is likely down-regulated by SCD mutations. Mitochondrial UBIAD1 protein appears to have a highly conserved function that, at least in humans, is involved in cholesterol metabolism in a novel manner.

Dataset Information

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

Publications

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

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