Ablation of Fatty Acid Transport Protein-4 Enhances Cone Survival, M-cone Vision, and Synthesis of Cone-Tropic 9--Retinal in 12 Mouse Model of Leber Congenital Amaurosis.

The canonical visual cycle employing RPE65 as the retinoid isomerase regenerates 11--retinal to support both rod- and cone-mediated vision. Mutations of are associated with Leber congenital amaurosis that results in rod and cone photoreceptor degeneration and vision loss of affected patients at an early age. Dark-reared mouse has been known to form isorhodopsin that employs 9--retinal as the photosensitive chromophore. The mechanism regulating 9--retinal synthesis and the role of the endogenous 9--retinal in cone survival and function remain largely unknown. In this study, we found that ablation of fatty acid transport protein-4 (FATP4), a negative regulator of 11--retinol synthesis catalyzed by RPE65, increased the formation of 9--retinal, but not 11--retinal, in a light-independent mechanism in both sexes of RPE65-null 12 mice. Both 12 and 12; mice contained a massive amount of all--retinyl esters in the eyes, exhibiting comparable scotopic vision and rod degeneration. However, expression levels of M- and S-opsins as well as numbers of M- and S-cones surviving in the superior retinas of 12; mice were at least twofold greater than those in age-matched 12 mice. Moreover, FATP4 deficiency significantly shortened photopic -wave implicit time, improved M-cone visual function, and substantially deaccelerated the progression of cone degeneration in 12 mice, whereas FATP4 deficiency in mice with wild-type alleles neither induced 9--retinal formation nor influenced cone survival and function. These results identify FATP4 as a new regulator of synthesis of 9--retinal, which is a "cone-tropic" chromophore supporting cone survival and function in the retinas with defective RPE65.