CRUMBS-associated mutations in Retinitis Pigmentosa and its impact on molecular scaffolding.

The death of photoreceptors is a primary driver of retinal degenerative diseases, leading to irreversible vision loss. In Retinitis Pigmentosa (RP), a wide spectrum of mutations has been identified. Among these, the Crumbs (CRB) family of proteins, comprising CRB1, CRB2, and CRB3, plays a critical role in maintaining retinal homeostasis. The distribution of CRB mutations indicates population-specific variations, which may be influenced by factors such as founder effects, consanguinity, and geographic isolation. These findings suggest that genetic diagnostics and therapeutic strategies could benefit from considering population diversity. However, genotype-phenotype correlations remain complex, suggesting a modulatory role for genetic modifiers and environmental factors. Dysfunction of the CRB proteins disrupts apicobasal polarity of Retinal Pigment Epithelia (RPE) and photoreceptors, weakening their interaction and impairing phototransduction. This review highlights how mutations in conserved domains, especially the Epidermal Growth Factor (EGF)-like and Laminin G-like regions, compromise structural integrity and trigger degenerative cascades, establishing them as critical biomarkers and promising therapeutic targets for retinal degenerations.