Data from: MFRP is a molecular hub that organizes the apical membrane of RPE cells by engaging in interactions with specific proteins and lipids

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. While several
preclinical gene-augmentation and gene-editing trials hold promise for
future therapies aimed at stopping degeneration and restoring retinal
function, the molecular mechanisms involved in MFRP biology are still not
well understood. Here, we studied the biochemical properties of MFRP and
the molecular consequences of its loss of function in the retinal
degeneration 6 (rd6) mouse model. Using transcriptomic and lipidomic
approaches, we observed that accumulation of docosahexaenoic acid (DHA)
constitutes a primary defect in the MFRP-deficient RPE. In biochemical
assays, we showed that MFRP undergoes extensive glycosylation, and it
preferentially binds lipids of several classes, including
phosphatidylserine and phosphatidylinositol-4-phosphate; as well as
binding to several transmembrane proteins, notably adiponectin receptor 1
(ADIPOR1) and inward rectifier potassium channel 13 (KCNJ13). Moreover,
MFRP determines the subcellular localization of ADIPOR1 and KCNJ13 in the
RPE in vivo. This feature is altered by MFRP deficiency and can be
restored by gene-therapy approaches. Overall, our observations suggest
that MFRP constitutes an important interaction hub within the apical
membrane of RPE cells, coordinating protein trafficking and subcellular
localization within the RPE, and lipid homeostasis within the entire
retina.