July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Deletion of Fatty Acid Transport Protein 4 Rescues the Visual Cycle and Function of Rod Photoreceptors in the R91W Mouse Model of Leber Congenital Amaurosis
Author Affiliations & Notes
  • Songhua Li
    Neuroscience Center & Department of Ophthalmology, LSU Health Sciences Center, New Orleans, Louisiana, United States
  • Minghao Jin
    Neuroscience Center & Department of Ophthalmology, LSU Health Sciences Center, New Orleans, Louisiana, United States
  • Footnotes
    Commercial Relationships   Songhua Li, None; Minghao Jin, None
  • Footnotes
    Support  NIH Grants EY021208, P30GM103340, RPB and LSU Medical School Research Enhancement Fund
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4516. doi:
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      Songhua Li, Minghao Jin; Deletion of Fatty Acid Transport Protein 4 Rescues the Visual Cycle and Function of Rod Photoreceptors in the R91W Mouse Model of Leber Congenital Amaurosis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4516.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We have previously shown that fatty acid transport protein 4 (FATP4) inhibits 11-cis-retinol synthesis catalyzed by the RPE65 isomerase of the visual cycle. The purpose of this study is to test whether knockout of FATP4 can ameliorate the visual cycle and vision in the RPE65 R91W knock-in (KI) mouse model of Leber congenital amaurosis (LCA).

Methods : We generated a mutant mouse line (KI;Fatp4-/-) harboring the R91W knock-in and Fatp4-knockout mutations. Both KI and KI;Fatp4-/- mice are homozygous for the Leu450 allele in the Rpe65 gene. All experiments were performed using young adult mice. Expression levels of the retinal pigment epithelium (RPE) and rod photoreceptor proteins were analyzed by immunoblot analysis. The rates of the visual cycle were determined by measuring synthesis of 11-cis-retinal and 9-cis-retinal (a functional iso-chromophore) in mice dark-adapted for different times (30~120 min) following photobleaching of rhodopsin. Retinoids were analyzed by high performance liquid chromatography. Visual functions of the mice were evaluated by recording scotopic electroretinogram evoked by a series of light flashes (-1~2 log cd.s/m2).

Results : Expression levels of RPE65 and LRAT in the KI mice RPE were similar to those in age-matched KI;Fatp4-/- mice RPE, whereas expression levels of rhodopsin were increased in the KI;Fatp4-/- retinas as compared to the KI retinas. The eyes of age-matched KI and KI;Fatp4-/- mice under different light conditions contained comparable amounts of all-trans-retinal, all-trans-retinol and all-trans retinyl ester. Immediately after photobleaching, the KI and KI;Fatp4-/- eyes also had similar amounts of 11-cis- and 9-cis-retinals. However, the amounts of these visual chromophores in KI;Fatp4-/- mice dark-adapted for one hour after photobleaching were at least two-fold greater than those in the KI mice under the same light conditions. This difference was also observed in overnight dark-adapted mice, although the degree of difference was reduced ~15%. Consistent with these results, light responses of rod photoreceptors were increased at least 35% in the KI;Fatp4-/- mice, as compared to the KI mice.

Conclusions : FATP4 inhibits synthesis of the visual chromophores in the LCA-associated RPE. This finding identifies FATP4 as a new molecular target to improve the visual cycle in patients with RPE65 mutations.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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