TSPAN12 is a tetraspanin protein that functions as a critical regulator of cell surface receptor signaling, particularly in retinal vascular development. Its primary mechanism involves orchestrating norrin (NDP)-dependent FZD4 activation and subsequent β-catenin accumulation through the canonical Wnt pathway 1. TSPAN12 stabilizes FZD4-LRP5 receptor complexes to promote β-catenin-dependent transcriptional programs essential for retinal endothelial cell function and angiogenesis 2. Additionally, TSPAN12 regulates membrane proteinases ADAM10 and MMP14, influencing proteolytic processing 1. Disease relevance is substantial: TSPAN12 mutations cause familial exudative vitreoretinopathy (FEVR), a retinal vascular disorder characterized by peripheral retinal avascularity, neovascularization, and potential retinal detachment 34. TSPAN12 mutations account for ~15% of FEVR cases, with both novel and recurrent variants identified 45. Mechanistically, TSPAN12 mutations often trigger nonsense-mediated decay, reducing protein expression and disrupting critical endothelial cell signaling 5. TSPAN12 expression in vascular endothelial cells makes it essential for cochlear vascular barrier function, with TSPAN12 mutations also implicated in Norrie disease hearing loss 6. Clinically, TSPAN12-mutated FEVR patients require early genetic diagnosis and monitoring for complications including tractional retinal detachment 7. Current management involves laser photocoagulation and anti-VEGF therapy, with emerging prospects for pathway-based therapeutics targeting the disrupted Norrin-Wnt signaling axis.