Cargando…

Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype–Phenotype Correlation in 228 Patients

Purpose: RPGRIP1 encodes a ciliary protein expressed in the photoreceptor connecting cilium. Mutations in this gene cause ∼5% of Leber congenital amaurosis (LCA) worldwide, but are also associated with cone–rod dystrophy (CRD) and retinitis pigmentosa (RP) phenotypes. Our purpose was to clinically c...

Descripción completa

Detalles Bibliográficos
Autores principales: Beryozkin, Avigail, Aweidah, Hamzah, Carrero Valenzuela, Roque Daniel, Berman, Myriam, Iguzquiza, Oscar, Cremers, Frans P. M., Khan, Muhammad Imran, Swaroop, Anand, Amer, Radgonde, Khateb, Samer, Ben-Yosef, Tamar, Sharon, Dror, Banin, Eyal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551679/
https://www.ncbi.nlm.nih.gov/pubmed/34722527
http://dx.doi.org/10.3389/fcell.2021.746781
_version_ 1784591212836028416
author Beryozkin, Avigail
Aweidah, Hamzah
Carrero Valenzuela, Roque Daniel
Berman, Myriam
Iguzquiza, Oscar
Cremers, Frans P. M.
Khan, Muhammad Imran
Swaroop, Anand
Amer, Radgonde
Khateb, Samer
Ben-Yosef, Tamar
Sharon, Dror
Banin, Eyal
author_facet Beryozkin, Avigail
Aweidah, Hamzah
Carrero Valenzuela, Roque Daniel
Berman, Myriam
Iguzquiza, Oscar
Cremers, Frans P. M.
Khan, Muhammad Imran
Swaroop, Anand
Amer, Radgonde
Khateb, Samer
Ben-Yosef, Tamar
Sharon, Dror
Banin, Eyal
author_sort Beryozkin, Avigail
collection PubMed
description Purpose: RPGRIP1 encodes a ciliary protein expressed in the photoreceptor connecting cilium. Mutations in this gene cause ∼5% of Leber congenital amaurosis (LCA) worldwide, but are also associated with cone–rod dystrophy (CRD) and retinitis pigmentosa (RP) phenotypes. Our purpose was to clinically characterize RPGRIP1 patients from our cohort, collect clinical data of additional RPGRIP1 patients reported previously in the literature, identify common clinical features, and seek genotype–phenotype correlations. Methods: Clinical data were collected from 16 patients of our cohort and 212 previously reported RPGRIP1 patients and included (when available) family history, best corrected visual acuity (BCVA), refraction, comprehensive ocular examination, optical coherence tomography (OCT) imaging, visual fields (VF), and full-field electroretinography (ffERG). Results: Out of 228 patients, the majority (197, 86%) were diagnosed with LCA, 18 (7%) with RP, and 13 (5%) with CRD. Age of onset was during early childhood (n = 133, average of 1.7 years). All patients but 6 had moderate hyperopia (n = 59, mean of 4.8D), and average BCVA was 0.06 Snellen (n = 124; only 10 patients had visual acuity [VA] > 0.10 Snellen). On funduscopy, narrowing of blood vessels was noted early in life. Most patients had mild bone spicule-like pigmentation starting in the midperiphery and later encroaching upon the posterior pole. OCT showed thinning of the outer nuclear layer (ONL), while cystoid changes and edema were relatively rare. VF were usually very constricted from early on. ffERG responses were non-detectable in the vast majority of cases. Most of the mutations are predicted to be null (363 alleles), and 93 alleles harbored missense mutations. Missense mutations were identified only in two regions: the RPGR-interacting domain and the C2 domains. Biallelic null mutations are mostly associated with a severe form of the disease, whereas biallelic missense mutations usually cause a milder disease (mostly CRD). Conclusion: Our results indicate that RPGRIP1 biallelic mutations usually cause severe retinal degeneration at an early age with a cone–rod pattern. However, most of the patients exhibit preservation of some (usually low) BCVA for a long period and can potentially benefit from gene therapy. Missense changes appear only in the conserved domains and are associated with a milder phenotype.
format Online
Article
Text
id pubmed-8551679
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-85516792021-10-29 Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype–Phenotype Correlation in 228 Patients Beryozkin, Avigail Aweidah, Hamzah Carrero Valenzuela, Roque Daniel Berman, Myriam Iguzquiza, Oscar Cremers, Frans P. M. Khan, Muhammad Imran Swaroop, Anand Amer, Radgonde Khateb, Samer Ben-Yosef, Tamar Sharon, Dror Banin, Eyal Front Cell Dev Biol Cell and Developmental Biology Purpose: RPGRIP1 encodes a ciliary protein expressed in the photoreceptor connecting cilium. Mutations in this gene cause ∼5% of Leber congenital amaurosis (LCA) worldwide, but are also associated with cone–rod dystrophy (CRD) and retinitis pigmentosa (RP) phenotypes. Our purpose was to clinically characterize RPGRIP1 patients from our cohort, collect clinical data of additional RPGRIP1 patients reported previously in the literature, identify common clinical features, and seek genotype–phenotype correlations. Methods: Clinical data were collected from 16 patients of our cohort and 212 previously reported RPGRIP1 patients and included (when available) family history, best corrected visual acuity (BCVA), refraction, comprehensive ocular examination, optical coherence tomography (OCT) imaging, visual fields (VF), and full-field electroretinography (ffERG). Results: Out of 228 patients, the majority (197, 86%) were diagnosed with LCA, 18 (7%) with RP, and 13 (5%) with CRD. Age of onset was during early childhood (n = 133, average of 1.7 years). All patients but 6 had moderate hyperopia (n = 59, mean of 4.8D), and average BCVA was 0.06 Snellen (n = 124; only 10 patients had visual acuity [VA] > 0.10 Snellen). On funduscopy, narrowing of blood vessels was noted early in life. Most patients had mild bone spicule-like pigmentation starting in the midperiphery and later encroaching upon the posterior pole. OCT showed thinning of the outer nuclear layer (ONL), while cystoid changes and edema were relatively rare. VF were usually very constricted from early on. ffERG responses were non-detectable in the vast majority of cases. Most of the mutations are predicted to be null (363 alleles), and 93 alleles harbored missense mutations. Missense mutations were identified only in two regions: the RPGR-interacting domain and the C2 domains. Biallelic null mutations are mostly associated with a severe form of the disease, whereas biallelic missense mutations usually cause a milder disease (mostly CRD). Conclusion: Our results indicate that RPGRIP1 biallelic mutations usually cause severe retinal degeneration at an early age with a cone–rod pattern. However, most of the patients exhibit preservation of some (usually low) BCVA for a long period and can potentially benefit from gene therapy. Missense changes appear only in the conserved domains and are associated with a milder phenotype. Frontiers Media S.A. 2021-10-14 /pmc/articles/PMC8551679/ /pubmed/34722527 http://dx.doi.org/10.3389/fcell.2021.746781 Text en Copyright © 2021 Beryozkin, Aweidah, Carrero Valenzuela, Berman, Iguzquiza, Cremers, Khan, Swaroop, Amer, Khateb, Ben-Yosef, Sharon and Banin. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Beryozkin, Avigail
Aweidah, Hamzah
Carrero Valenzuela, Roque Daniel
Berman, Myriam
Iguzquiza, Oscar
Cremers, Frans P. M.
Khan, Muhammad Imran
Swaroop, Anand
Amer, Radgonde
Khateb, Samer
Ben-Yosef, Tamar
Sharon, Dror
Banin, Eyal
Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype–Phenotype Correlation in 228 Patients
title Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype–Phenotype Correlation in 228 Patients
title_full Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype–Phenotype Correlation in 228 Patients
title_fullStr Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype–Phenotype Correlation in 228 Patients
title_full_unstemmed Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype–Phenotype Correlation in 228 Patients
title_short Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype–Phenotype Correlation in 228 Patients
title_sort retinal degeneration associated with rpgrip1: a review of natural history, mutation spectrum, and genotype–phenotype correlation in 228 patients
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551679/
https://www.ncbi.nlm.nih.gov/pubmed/34722527
http://dx.doi.org/10.3389/fcell.2021.746781
work_keys_str_mv AT beryozkinavigail retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT aweidahhamzah retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT carrerovalenzuelaroquedaniel retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT bermanmyriam retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT iguzquizaoscar retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT cremersfranspm retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT khanmuhammadimran retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT swaroopanand retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT amerradgonde retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT khatebsamer retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT benyoseftamar retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT sharondror retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients
AT banineyal retinaldegenerationassociatedwithrpgrip1areviewofnaturalhistorymutationspectrumandgenotypephenotypecorrelationin228patients