CRB1 -Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Mutation*; Ependymoglial Cells/*pathology ; Eye Proteins/*genetics ; Eye Proteins/*metabolism ; Macular Degeneration/*pathology ; Membrane Proteins/*genetics ; Membrane Proteins/*metabolism ; Nerve Tissue Proteins/*genetics ; Nerve Tissue Proteins/*metabolism ; Retinal Dystrophies/*pathology ; Retinitis Pigmentosa/*pathology; Adolescent ; Age of Onset ; Alternative Splicing ; Child ; Child, Preschool ; Ependymoglial Cells/metabolism ; Eye Proteins/chemistry ; Female ; Genetic Association Studies ; Humans ; Infant ; Macular Degeneration/genetics ; Macular Degeneration/metabolism ; Male ; Membrane Proteins/chemistry ; Models, Molecular ; Mutation, Missense ; Nerve Tissue Proteins/chemistry ; Point Mutation ; Retinal Dystrophies/genetics ; Retinal Dystrophies/metabolism ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/metabolism ; Retrospective Studies ; Sequence Deletion ; Young Adult

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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Keywords: CRB1; Leber congenital amaurosis; Müller cells; early onset retinal dystrophy; isoforms; macular dystrophy; pathogenic variant; photoreceptors; rod-cone dystrophy; spectral domain optical coherence tomography

0 (CRB1 protein, human)
0 (Eye Proteins)
0 (Membrane Proteins)
0 (Nerve Tissue Proteins)

Date Created: 20211210 Date Completed: 20211222 Latest Revision: 20211222

20231215

PMC8657784

10.3390/ijms222312642

34884448