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.
Highlights
Inherited retinal dystrophies (IRDs), despite clinical and genetic heterogeneity, share progressive degeneration of photoreceptors and/or retinal pigment epithelium cells
41 different pathogenic variants are reported: 26 missense (63% of the total variants), nine indel, four nonsense variants, one splice variation and one leading to the loss of the final stop codon, resulting in a protein extended by 110 amino acids
We demonstrate that CRB1-related maculopathy is not a rare phenotype
Summary
Inherited retinal dystrophies (IRDs), despite clinical and genetic heterogeneity, share progressive degeneration of photoreceptors and/or retinal pigment epithelium cells. IRDs affect about 2 million people worldwide among the 300 million patients with inherited diseases. They account for 10% of the causes of visual impairment in Western countries. IRDs are classified according to the predominant cell type affected (rod-cone dystrophy, RCD, versus cone-rod dystrophy, CRD) and/or topography of the lesions (maculopathy versus generalized retinal dystrophy). Maculopathies account for 20% of cases, with Stargardt disease being the most prevalent [1,2]. A distinction is made between IRDs with an early onset (early onset retinal dystrophy, EORD), including Leber congenital amaurosis (LCA), and those with a later onset after the age of 5 years. All modes of inheritance have been reported in these disorders, autosomal recessive (aR), dominant (aD), X-linked or, more rarely, mitochondrial
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