huRS1 Mouse

X-linked juvenile retinoschisis (XLRS), also known as X-linked retinoschisis, is an X-linked recessive inherited retinal dystrophy that primarily affects males. Patients typically present with splitting of the retinal layers (particularly in the macula and peripheral retina), progressive vision loss, retinal structural abnormalities, and potential complications, such as vitreous hemorrhage and retinal detachment. XLRS is one of the common inherited eye disorders causing visual impairment in young males, with an estimated prevalence of 1 in 5,000 to 1 in 25,000 ^[1]. Depending on the severity of the clinical phenotype, XLRS generally manifests as a single major phenotype, although the type of mutation can influence disease severity. Most patients experience vision decline in early childhood, along with foveal schisis and common peripheral retinal schisis; some may develop retinal detachment or hemorrhage, with further deterioration in adulthood. Female carriers are usually asymptomatic or exhibit only mild manifestations ^[1-2]. The primary causative gene for XLRS is RS1, which encodes retinoschisin, a secreted cell adhesion protein. Retinoschisin maintains cell-cell adhesion in the retina, stabilizes retinal laminar architecture and synaptic integrity, and plays a critical role in normal retinal development, structural maintenance, and functional homeostasis. It is essential for photoreceptor-bipolar cell synaptic transmission, retinal layer organization, and visual signal processing ^[3]. RS1 interacts with negatively charged membrane lipids and the Na/K-ATPase complex on the cell surface to maintain retinal cell adhesion and laminar integrity. Its oligomeric structure (homo-octamers and paired octamers) is crucial for its adhesive function ^[4]. The protein is predominantly expressed in retinal photoreceptors (rods and cones) and bipolar cells, with additional expression in the pineal gland ^[3]. Studies have shown that RS1 participates in the regulation of the MAPK signaling pathway and apoptosis, thereby influencing photoreceptor-bipolar cell synaptic function ^[5].

The huRS1 mouse is a humanized model generated via gene editing, in which the murine Rs1 locus (from upstream of exon 1 to downstream of exon 3) is replaced with the human RS1 sequence (from upstream of exon 1 to downstream of the 3'UTR). This model facilitates research into the pathogenesis of X-linked retinoschisis (XLRS) and supports the preclinical pharmacological evaluation of RS1-targeted therapeutics.