<i>CRB1</i>-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor <i>CRB1</i> Isoforms
Pathogenic variants in <i>CRB1</i> 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-genoty...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/23/12642 |
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| author | Kévin Mairot Vasily Smirnov Béatrice Bocquet Gilles Labesse Carl Arndt Sabine Defoort-Dhellemmes Xavier Zanlonghi Dalil Hamroun Danièle Denis Marie-Christine Picot Thierry David Olivier Grunewald Mako Pégart Hélèna Huguet Anne-Françoise Roux Vasiliki Kalatzis Claire-Marie Dhaenens Isabelle Meunier |
| author_facet | Kévin Mairot Vasily Smirnov Béatrice Bocquet Gilles Labesse Carl Arndt Sabine Defoort-Dhellemmes Xavier Zanlonghi Dalil Hamroun Danièle Denis Marie-Christine Picot Thierry David Olivier Grunewald Mako Pégart Hélèna Huguet Anne-Françoise Roux Vasiliki Kalatzis Claire-Marie Dhaenens Isabelle Meunier |
| author_sort | Kévin Mairot |
| collection | DOAJ |
| description | Pathogenic variants in <i>CRB1</i> 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 <i>CRB1</i> 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 <i>CRB1</i>-related dystrophies in humans, which should be taken into consideration for future clinical trials. |
| first_indexed | 2024-03-10T04:53:07Z |
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| id | doaj.art-40828ac7e7714ecb9a2c7357e1ad0888 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:53:07Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-40828ac7e7714ecb9a2c7357e1ad08882023-11-23T02:25:41ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231264210.3390/ijms222312642<i>CRB1</i>-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor <i>CRB1</i> IsoformsKévin Mairot0Vasily Smirnov1Béatrice Bocquet2Gilles Labesse3Carl Arndt4Sabine Defoort-Dhellemmes5Xavier Zanlonghi6Dalil Hamroun7Danièle Denis8Marie-Christine Picot9Thierry David10Olivier Grunewald11Mako Pégart12Hélèna Huguet13Anne-Françoise Roux14Vasiliki Kalatzis15Claire-Marie Dhaenens16Isabelle Meunier17Department of Ophthalmology, University North Hospital of Marseille, Sensgene Care Network, 13915 Marseille, FranceDepartment of Visual Exploration and Neuro-Ophthalmology, Robert Salengro Hospital, Sensgene Care Network, 59045 Lille, FranceNational Reference Centre for Inherited Sensory Diseases, University of Montpellier, Montpellier University Hospital, Sensgene Care Network, ERN-EYE Network, 34000 Montpellier, FranceStructural Biochemistry Centre, University of Montpellier, INSERM, CNRS, 34000 Montpellier, FranceDepartment of Ophthalmology, Reims University Hospital, 51000 Reims, FranceDepartment of Visual Exploration and Neuro-Ophthalmology, Robert Salengro Hospital, Sensgene Care Network, 59045 Lille, FranceDepartment of Ophthalmology, Rennes University Hospital, 35000 Rennes, FranceDepartment of Research and Innovation, University of Montpellier, Montpellier University Hospital, 34000 Montpellier, FranceDepartment of Ophthalmology, University North Hospital of Marseille, Sensgene Care Network, 13915 Marseille, FranceClinical Investigation Center (CIC), Clinical Research and Epidemiology Unit (URCE), University of Montpellier, 34000 Montpellier, FranceDepartment of Ophthalmology, University North Hospital of Marseille, Sensgene Care Network, 13915 Marseille, FranceInserm, Lille University Hospital, U1172-LilNCog-Lille Neuroscience and Cognition, University of Lille, 59045 Lille, FranceNational Reference Centre for Inherited Sensory Diseases, University of Montpellier, Montpellier University Hospital, Sensgene Care Network, ERN-EYE Network, 34000 Montpellier, FranceClinical Investigation Center (CIC), Clinical Research and Epidemiology Unit (URCE), University of Montpellier, 34000 Montpellier, FranceInstitute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, 34000 Montpellier, FranceInstitute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, 34000 Montpellier, FranceInserm, Lille University Hospital, U1172-LilNCog-Lille Neuroscience and Cognition, University of Lille, 59045 Lille, FranceNational Reference Centre for Inherited Sensory Diseases, University of Montpellier, Montpellier University Hospital, Sensgene Care Network, ERN-EYE Network, 34000 Montpellier, FrancePathogenic variants in <i>CRB1</i> 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 <i>CRB1</i> 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 <i>CRB1</i>-related dystrophies in humans, which should be taken into consideration for future clinical trials.https://www.mdpi.com/1422-0067/22/23/12642<i>CRB1</i>isoformsearly onset retinal dystrophyLeber congenital amaurosismacular dystrophyMüller cells |
| spellingShingle | Kévin Mairot Vasily Smirnov Béatrice Bocquet Gilles Labesse Carl Arndt Sabine Defoort-Dhellemmes Xavier Zanlonghi Dalil Hamroun Danièle Denis Marie-Christine Picot Thierry David Olivier Grunewald Mako Pégart Hélèna Huguet Anne-Françoise Roux Vasiliki Kalatzis Claire-Marie Dhaenens Isabelle Meunier <i>CRB1</i>-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor <i>CRB1</i> Isoforms International Journal of Molecular Sciences <i>CRB1</i> isoforms early onset retinal dystrophy Leber congenital amaurosis macular dystrophy Müller cells |
| title | <i>CRB1</i>-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor <i>CRB1</i> Isoforms |
| title_full | <i>CRB1</i>-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor <i>CRB1</i> Isoforms |
| title_fullStr | <i>CRB1</i>-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor <i>CRB1</i> Isoforms |
| title_full_unstemmed | <i>CRB1</i>-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor <i>CRB1</i> Isoforms |
| title_short | <i>CRB1</i>-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor <i>CRB1</i> Isoforms |
| title_sort | i crb1 i related retinal dystrophies in a cohort of 50 patients a reappraisal in the light of specific muller cell and photoreceptor i crb1 i isoforms |
| topic | <i>CRB1</i> isoforms early onset retinal dystrophy Leber congenital amaurosis macular dystrophy Müller cells |
| url | https://www.mdpi.com/1422-0067/22/23/12642 |
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