Membrane frizzled-related protein (MFRP), present in the retinal pigment epithelium (RPE), is an integral membrane protein essential for ocular development and the normal physiology of the retina. Mutations in *MFRP* are associated with autosomal recessive nonsyndromic nanophthalmos, leading to severe hyperopia and early-onset retinitis pigmentosa. This study investigated MFRP's biochemical properties and the molecular consequences of its loss of function in the *rd6* mouse model. Using transcriptomic and lipidomic approaches, researchers found that docosahexaenoic acid (DHA) accumulation is a primary defect in MFRP-deficient RPE. MFRP was shown to undergo extensive glycosylation and bind to various lipids and transmembrane proteins, including ADIPOR1 and KCNJ13, influencing their subcellular localization. Gene therapy restored some features lost due to MFRP deficiency, suggesting MFRP is a crucial interaction hub in the RPE apical membrane, coordinating protein trafficking and lipid homeostasis.

Aleksander Tworak, Roman Smidak, Carolline Rodrigues Menezes, Samuel W. Du, Susie Suh, Elliot H. Cho, Sanae S. Imanishi, Zhiqian Dong, Dominik Lewandowski, Kristen E. Fong, Gabriela Grigorean, Antonio F. M. Pinto, Qianlan Xu, Dorota Skowronska-Krawczyk, Seth Blackshaw, Yoshikazu Imanishi, Krzysztof Palczewski