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Impaired glutamylation of RPGR(ORF15) underlies the cone-dominated phenotype associated with truncating distal ORF15 variants
Pathogenic variants in the Retinitis pigmentosa GTPase regulator (RPGR) gene lead to a clinically severe form of X-linked retinal dystrophy. However, it remains unclear why some variants cause a predominant rod, while others result in a cone-dominated phenotype. Post-translational glutamylation of t...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9897430/ https://www.ncbi.nlm.nih.gov/pubmed/36445968 http://dx.doi.org/10.1073/pnas.2208707119 |
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author | Cehajic-Kapetanovic, Jasmina Martinez-Fernandez de la Camara, Cristina Birtel, Johannes Rehman, Salwah McClements, Michelle E. Charbel Issa, Peter Lotery, Andrew J MacLaren, Robert E. |
author_facet | Cehajic-Kapetanovic, Jasmina Martinez-Fernandez de la Camara, Cristina Birtel, Johannes Rehman, Salwah McClements, Michelle E. Charbel Issa, Peter Lotery, Andrew J MacLaren, Robert E. |
author_sort | Cehajic-Kapetanovic, Jasmina |
collection | PubMed |
description | Pathogenic variants in the Retinitis pigmentosa GTPase regulator (RPGR) gene lead to a clinically severe form of X-linked retinal dystrophy. However, it remains unclear why some variants cause a predominant rod, while others result in a cone-dominated phenotype. Post-translational glutamylation of the photoreceptor-specific RPGR(ORF15) isoform by the TTLL5 enzyme is essential for its optimal function in photoreceptors, and loss of TTLL5 leads to retinal dystrophy with a cone phenotype. Here we show that RPGR retinal disease, studied in a single cohort of 116 male patients, leads to a clear progressive shift from rod- to cone-dominating phenotype as the RPGR(ORF15) variant location approaches the distal part of the Open Reading Frame 15 (ORF15) region. The rod photoreceptor involvement on the contrary diminishes along the RGPR sequence, and the variants associated with the cone only phenotype are located predominantly in the very distal part, including the C-terminal basic domain. Moreover, these distal truncating RPGR(ORF15) variants disrupt the interaction with TTLL5 and lead to a significant impairment of RPGR glutamylation. Thus, consistent with the phenotype of TTLL5 pathogenic variants, our study shows that RPGR(ORF15) variants, which disrupt its basic domain and the interaction with TTLL5, also impair RPGR glutamylation and lead to the cone phenotype. This has implications for ongoing gene therapy clinical trials where the application of RPGR with impaired glutamylation may be less effective in treating RGPR dystrophies and may even convert a rod–cone dystrophy into a cone dystrophy phenotype. |
format | Online Article Text |
id | pubmed-9897430 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-98974302023-02-04 Impaired glutamylation of RPGR(ORF15) underlies the cone-dominated phenotype associated with truncating distal ORF15 variants Cehajic-Kapetanovic, Jasmina Martinez-Fernandez de la Camara, Cristina Birtel, Johannes Rehman, Salwah McClements, Michelle E. Charbel Issa, Peter Lotery, Andrew J MacLaren, Robert E. Proc Natl Acad Sci U S A Biological Sciences Pathogenic variants in the Retinitis pigmentosa GTPase regulator (RPGR) gene lead to a clinically severe form of X-linked retinal dystrophy. However, it remains unclear why some variants cause a predominant rod, while others result in a cone-dominated phenotype. Post-translational glutamylation of the photoreceptor-specific RPGR(ORF15) isoform by the TTLL5 enzyme is essential for its optimal function in photoreceptors, and loss of TTLL5 leads to retinal dystrophy with a cone phenotype. Here we show that RPGR retinal disease, studied in a single cohort of 116 male patients, leads to a clear progressive shift from rod- to cone-dominating phenotype as the RPGR(ORF15) variant location approaches the distal part of the Open Reading Frame 15 (ORF15) region. The rod photoreceptor involvement on the contrary diminishes along the RGPR sequence, and the variants associated with the cone only phenotype are located predominantly in the very distal part, including the C-terminal basic domain. Moreover, these distal truncating RPGR(ORF15) variants disrupt the interaction with TTLL5 and lead to a significant impairment of RPGR glutamylation. Thus, consistent with the phenotype of TTLL5 pathogenic variants, our study shows that RPGR(ORF15) variants, which disrupt its basic domain and the interaction with TTLL5, also impair RPGR glutamylation and lead to the cone phenotype. This has implications for ongoing gene therapy clinical trials where the application of RPGR with impaired glutamylation may be less effective in treating RGPR dystrophies and may even convert a rod–cone dystrophy into a cone dystrophy phenotype. National Academy of Sciences 2022-11-29 2022-12-06 /pmc/articles/PMC9897430/ /pubmed/36445968 http://dx.doi.org/10.1073/pnas.2208707119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Cehajic-Kapetanovic, Jasmina Martinez-Fernandez de la Camara, Cristina Birtel, Johannes Rehman, Salwah McClements, Michelle E. Charbel Issa, Peter Lotery, Andrew J MacLaren, Robert E. Impaired glutamylation of RPGR(ORF15) underlies the cone-dominated phenotype associated with truncating distal ORF15 variants |
title | Impaired glutamylation of RPGR(ORF15) underlies the cone-dominated phenotype associated with truncating distal ORF15 variants |
title_full | Impaired glutamylation of RPGR(ORF15) underlies the cone-dominated phenotype associated with truncating distal ORF15 variants |
title_fullStr | Impaired glutamylation of RPGR(ORF15) underlies the cone-dominated phenotype associated with truncating distal ORF15 variants |
title_full_unstemmed | Impaired glutamylation of RPGR(ORF15) underlies the cone-dominated phenotype associated with truncating distal ORF15 variants |
title_short | Impaired glutamylation of RPGR(ORF15) underlies the cone-dominated phenotype associated with truncating distal ORF15 variants |
title_sort | impaired glutamylation of rpgr(orf15) underlies the cone-dominated phenotype associated with truncating distal orf15 variants |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9897430/ https://www.ncbi.nlm.nih.gov/pubmed/36445968 http://dx.doi.org/10.1073/pnas.2208707119 |
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