Discovery of a novel missense mutation in the RIMS1 gene potentially enhances the severity of retinitis pigmentosa (RP) caused by RP1 mutation in humans

Abstract

Retinitis pigmentosa (RP) is a genetically diverse disorder characterized by the progressive degeneration of photoreceptors, ultimately leading to vision impairment and potential blindness. Understanding the disease progression and developing effective therapies is challenging due to its complex genetic landscape. This study unveils a di-genic complexity in RP involving a novel missense mutation in the RIMS1 and RP1 genes, traditionally associated with Cone-Rod Dystrophy. This mutation potentially enhances the RP phenotype, particularly in cases caused by RP1 mutations. We conducted a comprehensive genetic analysis on a family with a severe form of RP, focusing on the combined effects of RIMS1 and RP1. Using a targeted gene panel of 322 inherited retinal dystrophy (IRD) genes, we discovered a significant interaction between the RIMS1 variant and RP1 mutation within the cohort. Interestingly, patients with identical mutations exhibited substantial disease severity and progression differences. This discrepancy was particularly apparent in Patient E_1, who experienced rapid vision decline, emphasizing the impact of the mutation when combined with RP1. Biological network analysis shed light on the intricate genetic interplay, indicating a complex mechanism of disease modulation. Our findings contribute to a more nuanced understanding of RP's genetic heterogeneity. The RIMS1 variant may serve as a modifier of the disease phenotype. This discovery expands our comprehension of the genetic factors influencing RP and underscores the importance of considering digenic interactions in future research and therapy development for retinal dystrophies.