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Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration

Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59; OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement. The DHDDS enzyme is ubiquitously required for several...

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Autores principales: DeRamus, Marci L., Davis, Stephanie J., Rao, Sriganesh Ramachandra, Nyankerh, Cyril, Stacks, Delores, Kraft, Timothy W., Fliesler, Steven J., Pittler, Steven J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140717/
https://www.ncbi.nlm.nih.gov/pubmed/32245241
http://dx.doi.org/10.3390/cells9030771
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author DeRamus, Marci L.
Davis, Stephanie J.
Rao, Sriganesh Ramachandra
Nyankerh, Cyril
Stacks, Delores
Kraft, Timothy W.
Fliesler, Steven J.
Pittler, Steven J.
author_facet DeRamus, Marci L.
Davis, Stephanie J.
Rao, Sriganesh Ramachandra
Nyankerh, Cyril
Stacks, Delores
Kraft, Timothy W.
Fliesler, Steven J.
Pittler, Steven J.
author_sort DeRamus, Marci L.
collection PubMed
description Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59; OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement. The DHDDS enzyme is ubiquitously required for several pathways of protein glycosylation. We wish to understand the basis for selective ocular pathology associated with certain DHDDS mutations and the contribution of specific ocular cell types to the pathology of mutant Dhdds-mediated retinal degeneration. To circumvent embryonic lethality associated with Dhdds knockout, we generated a Cre-dependent knockout allele of murine Dhdds (Dhdds(flx/flx)). We used targeted Cre expression to study the importance of the enzyme in the RPE. Structural alterations of the RPE and retina including reduction in outer retinal thickness, cell layer disruption, and increased RPE hyper-reflectivity were apparent at one postnatal month. At three months, RPE and photoreceptor disruption was observed non-uniformly across the retina as well as RPE transmigration into the photoreceptor layer, external limiting membrane descent towards the RPE, and patchy loss of photoreceptors. Functional loss measured by electroretinography was consistent with structural loss showing scotopic a- and b-wave reductions of 83% and 77%, respectively, at three months. These results indicate that RPE dysfunction contributes to DHDDS mutation-mediated pathology and suggests a more complicated disease mechanism than simply disruption of glycosylation.
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spelling pubmed-71407172020-04-13 Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration DeRamus, Marci L. Davis, Stephanie J. Rao, Sriganesh Ramachandra Nyankerh, Cyril Stacks, Delores Kraft, Timothy W. Fliesler, Steven J. Pittler, Steven J. Cells Article Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59; OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement. The DHDDS enzyme is ubiquitously required for several pathways of protein glycosylation. We wish to understand the basis for selective ocular pathology associated with certain DHDDS mutations and the contribution of specific ocular cell types to the pathology of mutant Dhdds-mediated retinal degeneration. To circumvent embryonic lethality associated with Dhdds knockout, we generated a Cre-dependent knockout allele of murine Dhdds (Dhdds(flx/flx)). We used targeted Cre expression to study the importance of the enzyme in the RPE. Structural alterations of the RPE and retina including reduction in outer retinal thickness, cell layer disruption, and increased RPE hyper-reflectivity were apparent at one postnatal month. At three months, RPE and photoreceptor disruption was observed non-uniformly across the retina as well as RPE transmigration into the photoreceptor layer, external limiting membrane descent towards the RPE, and patchy loss of photoreceptors. Functional loss measured by electroretinography was consistent with structural loss showing scotopic a- and b-wave reductions of 83% and 77%, respectively, at three months. These results indicate that RPE dysfunction contributes to DHDDS mutation-mediated pathology and suggests a more complicated disease mechanism than simply disruption of glycosylation. MDPI 2020-03-21 /pmc/articles/PMC7140717/ /pubmed/32245241 http://dx.doi.org/10.3390/cells9030771 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
DeRamus, Marci L.
Davis, Stephanie J.
Rao, Sriganesh Ramachandra
Nyankerh, Cyril
Stacks, Delores
Kraft, Timothy W.
Fliesler, Steven J.
Pittler, Steven J.
Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration
title Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration
title_full Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration
title_fullStr Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration
title_full_unstemmed Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration
title_short Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration
title_sort selective ablation of dehydrodolichyl diphosphate synthase in murine retinal pigment epithelium (rpe) causes rpe atrophy and retinal degeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140717/
https://www.ncbi.nlm.nih.gov/pubmed/32245241
http://dx.doi.org/10.3390/cells9030771
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