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

Abstract

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.

Six new cases of CRB2‐related syndrome and a review of clinical findings in 28 reported patients

“…Recurrent variants are in bold. The location of the variants illustrates clustering in specific exons [Colour figure can be viewed at wileyonlinelibrary.com]bridge 5. This finding is compatible with the CRB2 variant data, as many of the missense variants in CRB2 involve cysteine residues.…”

Retinitis Pigmentosa in the Puerto Rican Population: A Geographic Distribution

“…Both the p.Ile205Aspfs*13 and p.Ile167_Gly169del variants identified in the township of Ciales have previously been identified in France. 13 Meanwhile, the p.Ile167_Gly169del variant has been identified in Brazilian and Spanish cohorts. 14,15 A study based on a small European cohort of patients identified this variant in all their patients indicating further European influence.…”

Biallelic Heterozygous Mutations in Crumbs Homolog-1 Gene Associated With Macular Retinoschisis and Angle-Closure Glaucoma: A Case Report and Literature Review

“…Therefore, the positions of mutation may also affect distinct isoforms and lead to different phenotypes. Indeed, Mairot et al (30) reported that the phenotype in CRB1 patients might be dependent on the severity of Müller cell impairment related to isoform diversity. In addition, experiments based on gene knockout mouse models indicated a modifying role of CRB2 (31)(32)(33)(34).…”