Dysregulated Retinal DPP10 Expression with Single Cell-based Next Genomic Sequencing Profiling in X-linked Juvenile...

X-linked juvenile retinoschisis (XLRS) is a hereditary retinal dystrophy resulting from mutations in the retinoschisin (RS1) gene, which lead to progressive structural abnormalities in the retina and consequent visual impairment. Despite this, the molecular mechanisms through which RS1 mutations induce cell type-specific transcriptional remodeling during disease progression remain inadequately elucidated. To delineate transcriptional changes associated with RS1 mutations, we conducted single-cell RNA sequencing (scRNA-seq) on a CRISPR/Cas9-engineered Rs1^emR209C knock-in mouse model. Integrative analysis with the Mouse Retina Cell Atlas demonstrated that rod photoreceptors exhibited the most significant transcriptional dysregulation among retinal cell types. Notably, dipeptidyl peptidase-like protein 10 (DPP10) was progressively and markedly upregulated, predominantly within photoreceptors, as the disease advanced. These findings were corroborated by immunofluorescence staining, quantitative PCR, and western blot analyses, which confirmed increased retinal DPP10 expression concurrent with a gradual decline in RS1 levels. To explore the functional implications of DPP10 dysregulation, we developed Y79 retinal cell models expressing either wild-type RS1 or the XLRS-associated RS1 R209C variant. Cells expressing the RS1 R209C mutation exhibited elevated DPP10 expression alongside reduced viability. Crucially, siRNA-mediated knockdown of DPP10 partially rescued cell viability and was associated with reduced GRP78/BiP expression in RS1 R209C-expressing cells, supporting potential functional relevance between DPP10 upregulation and mutant RS1-induced cellular stress. Furthermore, circulating DPP10 concentrations were significantly increased in patients with XLRS compared to control subjects. Collectively, these results identify DPP10 as a molecular alteration associated with RS1 mutation and suggest its potential as a circulating biomarker candidate for XLRS.