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A Mouse Model of Schnyder Corneal Dystrophy with the N100S Point Mutation.
- Source :
-
Scientific reports [Sci Rep] 2018 Jul 05; Vol. 8 (1), pp. 10219. Date of Electronic Publication: 2018 Jul 05. - Publication Year :
- 2018
-
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 < 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 Ubiad1 <superscript>N100S</superscript> 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.
- Subjects :
- Animals
CRISPR-Cas Systems
Cornea metabolism
Corneal Dystrophies, Hereditary genetics
Corneal Dystrophies, Hereditary metabolism
Glycerophosphates metabolism
Humans
Male
Mice
Microscopy, Confocal
Microscopy, Electron
Mitochondria genetics
Mitochondria metabolism
Point Mutation
Cornea diagnostic imaging
Corneal Dystrophies, Hereditary diagnostic imaging
Dimethylallyltranstransferase genetics
Disease Models, Animal
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 29977031
- Full Text :
- https://doi.org/10.1038/s41598-018-28545-0