Eyes shut homolog (EYS): Connecting molecule to disease

Eyes shut homologue (EYS) stands out as one of the most commonly mutated genes causing autosomal recessive retinitis pigmentosa (arRP), with a worldwide prevalence ranging from 1.2 % to 23.5 %. The EYS gene is predominantly expressed in retinal photoreceptor cells, where four transcripts have been identified, each varying in length. The human EYS protein initiates with a signal peptide and comprises 21 epidermal growth factor (EGF)-like domains in its N-terminal followed by five C-terminal LamG domains, interspersed among additional EGF repeats. The existence of different isoforms suggests potential variations in their functions within the human body. EYS-associated retinopathies present with a severe clinical phenotype and currently have no treatment options. The limited understanding of the role of EYS in the healthy and diseased retina remains a significant barrier to translating current advances into viable therapeutic interventions. This review consolidates existing knowledge on the molecular characteristics of EYS, animal and disease models, the clinical impact of EYS disease-causing variants, and the potential of emerging technologies in future therapeutic strategies for EYS-related diseases. Additionally, we contribute to the field by further elucidating the localization of EYS in the human retina, analyzing the most frequent variants and their positions within the gene, and proposing antisense oligonucleotides, and Prime and Base Editing strategies to correct some of the most recurrent pathogenic variants in EYS.