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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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