*14.2. Phosphatases*

The phosphoinositide phosphatases encoded by Inpp1, Inpp4a, Inpp4b, Inpp5e, Mtmr2 and Synj1 (synaptojanin-1) have also been detected in retina by proteomics [134]. As noted below, defects in synaptojanin-1 and INPP5E are associated with retinal defects, as is the phosphoinositide 5-phosphatase, OCRL (oculocerebrorenal syndrome of Lowe) [135,136]. Among the other enzymes detected, almost none were enriched in the rod outer segmen<sup>t</sup> fraction as compared to the rest of the retina, consistent with the relatively low PI content of that organelle. One exception was Pip4k2c, the PI(5)P-4-kinase Type II γ isoform. Inactivation of the mouse *Pip4kc2* gene was found to lead to hyperactivation of the immune system, but the retinal phenotype was not examined [137].

### **15. Retinal Phenotypes of Genetic Defects in Genes Related to Phosphoinositide Metabolism and Signaling**

Rods and cones have a very high rate of metabolism and biosynthesis of membrane components, due to the energetic demands of the phototransduction cascade and the daily shedding of ~10% of the disk membranes (based on observation of a rate of 9%–13% in the rhesus monkey [138], which have to be engulfed and recycled by the RPE. As highly polarized cells, their function and health depend critically on e fficient and accurate transport of the correct proteins and lipids to the correct compartments. A host of human blinding diseases have been linked to defects in membrane transport and sorting [139,140]. In RPE cells, massive amounts of membrane tra ffic are associated with their role as professional phagophores. Defects in RPE phagocytosis, as in MERTK deficiency [111,141] and Bestrophin deficiency [142–145], cause retinal degeneration in humans and animal models and have been proposed to play a role in age-related macular degeneration [146].
