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CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms
Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 5...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657784/ https://www.ncbi.nlm.nih.gov/pubmed/34884448 http://dx.doi.org/10.3390/ijms222312642 |
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author | Mairot, Kévin Smirnov, Vasily Bocquet, Béatrice Labesse, Gilles Arndt, Carl Defoort-Dhellemmes, Sabine Zanlonghi, Xavier Hamroun, Dalil Denis, Danièle Picot, Marie-Christine David, Thierry Grunewald, Olivier Pégart, Mako Huguet, Hélèna Roux, Anne-Françoise Kalatzis, Vasiliki Dhaenens, Claire-Marie Meunier, Isabelle |
author_facet | Mairot, Kévin Smirnov, Vasily Bocquet, Béatrice Labesse, Gilles Arndt, Carl Defoort-Dhellemmes, Sabine Zanlonghi, Xavier Hamroun, Dalil Denis, Danièle Picot, Marie-Christine David, Thierry Grunewald, Olivier Pégart, Mako Huguet, Hélèna Roux, Anne-Françoise Kalatzis, Vasiliki Dhaenens, Claire-Marie Meunier, Isabelle |
author_sort | Mairot, Kévin |
collection | PubMed |
description | Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 50 patients with regards to the recently identified CRB1 isoforms: a canonical long isoform A localized in Müller cells (12 exons) and a short isoform B predominant in photoreceptors (7 exons). Twenty-eight patients with early onset retinal dystrophy (EORD) consistently had a severe Müller impairment, with variable impact on the photoreceptors, regardless of isoform B expression. Among them, two patients expressing wild type isoform B carried one variant in exon 12, which specifically damaged intracellular protein interactions in Müller cells. Thirteen retinitis pigmentosa patients had mainly missense variants in laminin G-like domains and expressed at least 50% of isoform A. Eight patients with the c.498_506del variant had macular dystrophy. In one family homozygous for the c.1562C>T variant, the brother had EORD and the sister macular dystrophy. In contrast with the mouse model, these data highlight the key role of Müller cells in the severity of CRB1-related dystrophies in humans, which should be taken into consideration for future clinical trials. |
format | Online Article Text |
id | pubmed-8657784 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86577842021-12-10 CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms Mairot, Kévin Smirnov, Vasily Bocquet, Béatrice Labesse, Gilles Arndt, Carl Defoort-Dhellemmes, Sabine Zanlonghi, Xavier Hamroun, Dalil Denis, Danièle Picot, Marie-Christine David, Thierry Grunewald, Olivier Pégart, Mako Huguet, Hélèna Roux, Anne-Françoise Kalatzis, Vasiliki Dhaenens, Claire-Marie Meunier, Isabelle Int J Mol Sci Article Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 50 patients with regards to the recently identified CRB1 isoforms: a canonical long isoform A localized in Müller cells (12 exons) and a short isoform B predominant in photoreceptors (7 exons). Twenty-eight patients with early onset retinal dystrophy (EORD) consistently had a severe Müller impairment, with variable impact on the photoreceptors, regardless of isoform B expression. Among them, two patients expressing wild type isoform B carried one variant in exon 12, which specifically damaged intracellular protein interactions in Müller cells. Thirteen retinitis pigmentosa patients had mainly missense variants in laminin G-like domains and expressed at least 50% of isoform A. Eight patients with the c.498_506del variant had macular dystrophy. In one family homozygous for the c.1562C>T variant, the brother had EORD and the sister macular dystrophy. In contrast with the mouse model, these data highlight the key role of Müller cells in the severity of CRB1-related dystrophies in humans, which should be taken into consideration for future clinical trials. MDPI 2021-11-23 /pmc/articles/PMC8657784/ /pubmed/34884448 http://dx.doi.org/10.3390/ijms222312642 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mairot, Kévin Smirnov, Vasily Bocquet, Béatrice Labesse, Gilles Arndt, Carl Defoort-Dhellemmes, Sabine Zanlonghi, Xavier Hamroun, Dalil Denis, Danièle Picot, Marie-Christine David, Thierry Grunewald, Olivier Pégart, Mako Huguet, Hélèna Roux, Anne-Françoise Kalatzis, Vasiliki Dhaenens, Claire-Marie Meunier, Isabelle CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms |
title | CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms |
title_full | CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms |
title_fullStr | CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms |
title_full_unstemmed | CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms |
title_short | CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms |
title_sort | crb1-related retinal dystrophies in a cohort of 50 patients: a reappraisal in the light of specific müller cell and photoreceptor crb1 isoforms |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657784/ https://www.ncbi.nlm.nih.gov/pubmed/34884448 http://dx.doi.org/10.3390/ijms222312642 |
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