IMPG2 is a chondroitin sulfate- and hyaluronic acid-binding proteoglycan that functions as a critical structural component of the interphotoreceptor matrix (IPM), the extracellular mesh surrounding photoreceptor outer and inner segments 1. IMPG2 undergoes proteolytic maturation in its SEA domain, generating membrane-attached and extracellular peptides that traffic from inner to outer segment IPM in an IMPG1-dependent manner 2. This proteolysis is essential for normal IPM organization and cone-specific glycocalyx formation 1. Mechanistically, IMPG2 loss-of-function impairs photoreceptor homeostasis through multiple pathways. In mouse models, Impg2 deletion causes progressive degeneration of both rod and cone photoreceptors, mislocalization of rhodopsin, and activation of endoplasmic reticulum (ER) stress responses including elevated CHOP, BIP, and PDI levels, alongside impaired autophagy 3. Critically, IMPG2 absence prevents proper IMPG1 integration into the IPM, leading to aberrant IMPG1 accumulation and subretinal lesion formation 1. Clinically, IMPG2 variants cause inherited retinal dystrophies with variable penetrance. Mono-allelic variants manifest as vitelliform maculopathy with foveal elevation and subretinal material accumulation, often remaining stable or partially resolving with preserved moderate vision 4. Biallelic mutations cause early-onset severe retinitis pigmentosa with photoreceptor outer segment loss in human disease 5. IMPG2 mutations represent a notable genetic cause of pediatric inherited retinal disease 6.