NAALAD2 mutations disrupt the fate of photoreceptor cells and retinal pigment epithelial cells during early retinal development.

In recent years, the global incidence of myopia has steadily increased, highlighting the importance of prevention and early intervention, particularly in the absence of effective treatments. Here, we identified a previously unreported mutation in the human N-acetylated alpha-linked acidic dipeptidase 2 (NAALAD2) gene (c.2109 T > G, p.F703L) considered in a Chinese family with pathological myopia (PM). We explored the potential link between NAALAD2 mutation and the development of PM by using the Naalad2 point mutation knock-in mouse models. Through single-cell RNA sequencing, we analyzed the retinal cell composition and transcriptional profiles both in Naalad2+/+ and Naalad2+/- mice, especially the changes in Cone photoreceptor cells, Rod photoreceptor cells and retinal pigment epithelial (RPE) cells. We found that the Naalad2 mutation led to a reduction in the abundance of Cone and Rod photoreceptor cells, along with upregulation of immediate early genes and abnormal differentiation of certain cell subpopulations. Additionally, RPE cell subpopulations exhibited a fibrotic tendency, disrupting their interactions with photoreceptor cells. Moreover, this study suggests that NAALAD2 mutation may accelerate retinal degeneration by influencing photoreceptor cell apoptosis, stress responses, and the epithelial-mesenchymal transition process in RPE cells. These findings provide new insights into the pathogenic mechanisms of NAALAD2 mutations in PM and offer potential therapeutic targets for future PM research.