The Specific Pathogenicity Pattern of the Different CRB1 Isoforms Conditions Clinical Severity in Inherited Retinal Dystrophies

Pathogenic variants in Crumbs homolog 1 (<i>CRB1</i>) cause a wide range of severe ocular diseases, most commonly Leber congenital amaurosis and other forms of adult-onset macular dystrophy that lead to vision loss. Despite this broad clinical spectrum, the expression and function of <i>CRB1</i> in retinal cells remains underexplored. In this study, we show a comprehensive characterization of <i>CRB1</i> isoforms in several human retinal models like retinal organoids. Although <i>CRB1</i> is predominantly expressed in photoreceptors and Müller glial cells, we also detected its expression in the human retinal pigment epithelium (RPE). Moreover, we observed defined expression patterns of <i>CRB1</i> isoforms depending on the maturation stage of retinal cells, suggesting a role for this protein in development and differentiation. In this context, the less abundant and less studied isoform <i>CRB1-C</i> was the most highly expressed in early undifferentiated stages of photoreceptors and in RPE. Additionally, clinical and genetic evaluation of a cohort of 25 probands carrying pathogenic <i>CRB1</i> variants allowed us to propose a genotype-phenotype correlation between isoforms involvement and disease severity, and to the identification of four novel pathogenic variants: p.Met70ArgfsTer17, p.Cys136Phe, p.Cys248Ser and p.Gln1094Ter. Collectively, our data elucidate previously undescribed expression patterns of <i>CRB1</i> isoforms during retinal cell differentiation and highlight key aspects of <i>CRB1</i>-associated inherited retinal dystrophies.