Impaired glutamylation of RPGRORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants
Impaired glutamylation of RPGRORF15 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 the photoreceptor-specific RPGRORF15 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 RPGRORF15 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 RPGRORF15 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 RPGRORF15 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.
cone dystrophy, gene therapy, glutamylation, RPGR, TTLL5
Cehajic-Kapetanovic, Jasmina
58f9cc83-5a9c-419b-9532-709367cc319e
de la Camara, Cristina Martinez Fernandez
4fdabdd8-d735-4110-ac96-755f870b3864
Birtel, Johannes
d9b4d729-36be-430c-8ae2-ae47e878853d
Rehman, Salwah
22e42e4a-006c-40e0-8468-124d68b7f7c2
McClements, Michelle E.
c07e03f0-60d6-44a9-b0b0-637e410b8256
Issa, Peter Charbel
b40844c7-19ad-4762-b922-7b1dfdd65e60
Lotery, Andrew J.
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
MacLaren, Robert E.
c7a2f458-a7b1-4b96-b88e-d376c90ec059
6 December 2022
Cehajic-Kapetanovic, Jasmina
58f9cc83-5a9c-419b-9532-709367cc319e
de la Camara, Cristina Martinez Fernandez
4fdabdd8-d735-4110-ac96-755f870b3864
Birtel, Johannes
d9b4d729-36be-430c-8ae2-ae47e878853d
Rehman, Salwah
22e42e4a-006c-40e0-8468-124d68b7f7c2
McClements, Michelle E.
c07e03f0-60d6-44a9-b0b0-637e410b8256
Issa, Peter Charbel
b40844c7-19ad-4762-b922-7b1dfdd65e60
Lotery, Andrew J.
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
MacLaren, Robert E.
c7a2f458-a7b1-4b96-b88e-d376c90ec059
Cehajic-Kapetanovic, Jasmina, de la Camara, Cristina Martinez Fernandez, Birtel, Johannes, Rehman, Salwah, McClements, Michelle E., Issa, Peter Charbel, Lotery, Andrew J. and MacLaren, Robert E.
(2022)
Impaired glutamylation of RPGRORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants.
Proceedings of the National Academy of Sciences of the United States of America, 119 (49), [e2208707119].
(doi:10.1073/pnas.2208707119).
Abstract
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 RPGRORF15 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 RPGRORF15 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 RPGRORF15 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 RPGRORF15 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.
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cehajic-kapetanovic-et-al-2022-impaired-glutamylation-of-rpgrorf15-underlies-the-cone-dominated-phenotype-associated
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Accepted/In Press date: 18 October 2022
e-pub ahead of print date: 29 November 2022
Published date: 6 December 2022
Keywords:
cone dystrophy, gene therapy, glutamylation, RPGR, TTLL5
Identifiers
Local EPrints ID: 494718
URI: http://eprints.soton.ac.uk/id/eprint/494718
ISSN: 0027-8424
PURE UUID: 841d5cb5-6685-433c-96e8-c48fe7c0f857
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Date deposited: 14 Oct 2024 16:54
Last modified: 15 Oct 2024 01:38
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Contributors
Author:
Jasmina Cehajic-Kapetanovic
Author:
Cristina Martinez Fernandez de la Camara
Author:
Johannes Birtel
Author:
Salwah Rehman
Author:
Michelle E. McClements
Author:
Peter Charbel Issa
Author:
Robert E. MacLaren
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