PUBLICATION
Deletion of POMT2 in Zebrafish Causes Degeneration of Photoreceptors
- Authors
- Liu, Y., Rittershaus, J.M., Yu, M., Sager, R., Hu, H.
- ID
- ZDB-PUB-221212-6
- Date
- 2022
- Source
- International Journal of Molecular Sciences 23(23): (Journal)
- Registered Authors
- Keywords
- congenital muscular dystrophy, inherited retinal degeneration, photoreceptor degeneration, retina, retinitis pigmentosa, zebrafish
- MeSH Terms
-
- Animals
- Dystroglycans/genetics
- Dystroglycans/metabolism
- Muscular Dystrophies*/metabolism
- Retinal Cone Photoreceptor Cells/metabolism
- Retinal Degeneration*/genetics
- Retinal Degeneration*/metabolism
- Retinitis Pigmentosa*/genetics
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 36499139 Full text @ Int. J. Mol. Sci.
Citation
Liu, Y., Rittershaus, J.M., Yu, M., Sager, R., Hu, H. (2022) Deletion of POMT2 in Zebrafish Causes Degeneration of Photoreceptors. International Journal of Molecular Sciences. 23(23):.
Abstract
Mutations in the extracellular matrix protein eyes shut homolog (EYS) are a common cause of retinitis pigmentosa, a blinding disease characterized by photoreceptor degeneration. EYS binds to matriglycan, a carbohydrate modification on O-mannosyl glycan substitutions of the cell-surface glycoprotein α-dystroglycan. Patients with mutations in enzymes required for the biosynthesis of matriglycan exhibit syndromic retinal atrophy, along with brain malformations and congenital muscular dystrophy. Protein O-mannosyltransferase 2 (POMT2) is an enzyme required for the synthesis of O-mannosyl glycans. To evaluate the roles of O-mannosyl glycans in photoreceptor health, we generated protein O-mannosyltransferase 2 (pomt2) mutant zebrafish by CRISPR. pomt2 mutation resulted in a loss of matriglycan and abolished binding of EYS protein to α-dystroglycan. Mutant zebrafish presented with hydrocephalus and hypoplasia of the cerebellum, as well as muscular dystrophy. EYS protein was enriched near photoreceptor connecting cilia in the wild-type, but its presence and proper localization was significantly reduced in mutant animals. The mutant retina exhibited mis-localization of opsins and increased apoptosis in both rod and cone photoreceptors. Immunofluorescence intensity of G protein subunit alpha transducin 2 (GNAT2) antibody (a general cone marker) and 1D4 antibody (a long double cone marker) in mutant retinas did not differ from wild-type retinas at 1-month post fertilization, but was reduced at 6 months post fertilization, indicating significant cone degeneration. These data suggest that POMT2-mediated O-mannosyl glycosylation is required for EYS protein localization to the connecting cilium region and photoreceptor survival.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping