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Open AccessArticle

Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59

Research Service, VA Western NY Healthcare System, Buffalo, NY 14215, USA
Departments of Ophthalmology and Biochemistry and Neuroscience Graduate Program, The State University of New York- University at Buffalo, Buffalo, NY 14209, USA
Department of Optometry and Vision Science, Vision Science Research Center, University of Alabama at Birmingham, School of Optometry, Birmingham, AL 35294, USA
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2020, 9(4), 896;
Received: 17 February 2020 / Revised: 30 March 2020 / Accepted: 4 April 2020 / Published: 7 April 2020
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
Dehydrodolichyl diphosphate synthase (DHDDS) is required for protein N-glycosylation in eukaryotic cells. A K42E point mutation in the DHDDS gene causes an autosomal recessive form of retinitis pigmentosa (RP59), which has been classified as a congenital disease of glycosylation (CDG). We generated K42E Dhdds knock-in mice as a potential model for RP59. Mice heterozygous for the Dhdds K42E mutation were generated using CRISPR/Cas9 technology and crossed to generate DhddsK42E/K42E homozygous mice. Spectral domain-optical coherence tomography (SD-OCT) was performed to assess retinal structure, relative to age-matched wild type (WT) controls. Immunohistochemistry against glial fibrillary acidic protein (GFAP) and opsin (1D4 epitope) was performed on retinal frozen sections to monitor gliosis and opsin localization, respectively, while lectin cytochemistry, plus and minus PNGase-F treatment, was performed to assess protein glycosylation status. Retinas of DhddsK42E/K42E mice exhibited grossly normal histological organization from 1 to 12 months of age. Anti-GFAP immunoreactivity was markedly increased in DhddsK42E/K42E mice, relative to controls. However, opsin immunolocalization, ConA labeling and PNGase-F sensitivity were comparable in mutant and control retinas. Hence, retinas of DhddsK42E/K42E mice exhibited no overt signs of degeneration, yet were markedly gliotic, but without evidence of compromised protein N-glycosylation. These results challenge the notion of RP59 as a DHDDS loss-of-function CDG and highlight the need to investigate unexplored RP59 disease mechanisms. View Full-Text
Keywords: retinitis pigmentosa; knock-in mouse model; congenital disorder of glycosylation; retina retinitis pigmentosa; knock-in mouse model; congenital disorder of glycosylation; retina
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Ramachandra Rao, S.; Fliesler, S.J.; Kotla, P.; Nguyen, M.N.; Pittler, S.J. Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59. Cells 2020, 9, 896.

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