Advisor(s)
Steven Pittler
Committee Member(s)
Lawrence Sincich
Marina Gorbatyuk
Timothy Kraft
Yuchen Wang
School
School of Optometry
Document Type
Dissertation
Department (new version)
Vision Science
Date of Award
1-7-2025
Abstract
Cis-prenyltransferase (CPT), a prenyl chain elongation enzyme made up of two copies of dehydrodolichyl diphosphate synthase (DHDDS) and two copies of Nogo-B Receptor (NgBR), condenses metabolites from the mevalonate pathway to create dolichol, a sugar carrier required for glycosylation in all cells of the body. However, certain missense mutations in DHDDS cause non-syndromic retinitis pigmentosa (RP59). Three missense mutations, K42E, T206A, and R98W have been found in RP59 patients that present the cardinal phenotypes of RP – diminished ERG responses, attenuated retinal vessels, bone spicule-like pigmentation, and retinal thinning due to photoreceptor loss. However, no global changes in glycosylation are observed, despite a shift to shorter dolichol chain lengths of the main dolichol species. Our lab has created RP59 knock-in mouse models (DhddsK42E/K42E, DhddsT206A/K42E, and DhddsT206A/T206A) using CRISPR-Cas technology and has characterized the structural and functional phenotypes found in the progression of the disease. We found several phenotypic changes in our mouse models that parallel most of the changes found in patients, including reduced retinal degeneration, reduced ERG signals, lower visual acuity, and shorter dolichol lengths. Negative ERG b-waves were found at PN 8-mo, in addition to reductions in c-waves, d- waves, and oscillatory potentials. Although there was no structural modification in the ONL, a phenotype normally found in IRD patients, total retinal thickness and INL of mutant mice were reduced by PN 12-mo compared to WT. In fact, bipolar cell densities in mutant mice were at least 23% reduced compared to WT and amacrine cell densities were at least 14% reduced in older mice. Although defects in DHDDS are classified as congenital defects of glycosylation, our studies showed that global glycosylation was not affected despite truncated dolichol species. Our RP59 knock-in mice are promising models for the sight-threatening disease found in humans. Because no direct effects on glycosylation were observed, we hypothesize that the DHDDS mutations cause abnormal interaction(s) with one or more retina-specific proteins, leading to the observed retinal phenotypes. Although no mechanism has been identified yet, our mouse models pave the way for further studies not possible in patients, that will allow drug and/or genetic intervention to be developed.
ProQuest ID
Recommended Citation
Nguyen, Mai Ngoc, "Characterization Of Dhdds Rp59 Knock-In Mouse Models Of Retinitis Pigmentosa" (2025). All ETDs from UAB. 7300.
https://digitalcommons.library.uab.edu/etd-collection/7300
