July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Deletion of Fatty Acids Transport Protein 4 (FATP4) Improves Cone-Mediated Vision in a Mouse Model of Leber Congenital Amaurosis (LCA)
Author Affiliations & Notes
  • Minghao Jin
    Neuroscience Center and Department of Ophthalmology, LSU School of Medicine, New Orleans, Louisiana, United States
  • Songhua Li
    Neuroscience Center, LSU School of Medicine, New Orleans, Louisiana, United States
  • Footnotes
    Commercial Relationships   Minghao Jin, None; Songhua Li, None
  • Footnotes
    Support  NIH Grants EY028572, EY021208, P30GM103340 and LSU School of Medicine Research Enhancement Fund
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2338. doi:
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      Minghao Jin, Songhua Li; Deletion of Fatty Acids Transport Protein 4 (FATP4) Improves Cone-Mediated Vision in a Mouse Model of Leber Congenital Amaurosis (LCA). Invest. Ophthalmol. Vis. Sci. 2019;60(9):2338.

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

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Abstract

Purpose : FATP4 is a negative regulator of 11-cis-retinol synthesis catalyzed by RPE65 in the retinal pigment epithelium (RPE). The purpose of this study is to test our hypothesis that deletion of FATP4 preserves cone survival and function in a mouse model of LCA caused by hypomorphic R91W-RPE65.

Methods : All experiments were performed using young adult (6~16-week-old) R91W knock-in (KI) and KI;Fatp4-/- mice that harbor the Leu450 alleles in the Rpe65 gene. Expression levels of proteins in the RPE and cones were analyzed by immunoblot analysis and immunohistochemistry. Cone survival rate was assessed by counting cone arrestin (CAR)-positive cells in retinal sections taken from the dorsal-ventral midline of the eye. S-opsin mislocalization was quantified according the following formula, after measuring fluorescence intensities of the opsin in the outer segments (OS) and outer plexiform layer (OPL): mislocalization = [OPL fluorescence/(OS fluorescence + OPL fluorescence)] X100%. Retinoids from mouse eyes were analyzed by high performance liquid chromatography. Cone visual function was evaluated by photopic electroretinograms (ERG) evoked by a series of white light flashes (-2~2 log cd.s/m2).

Results : Expression levels of RPE65 and LRAT in the KI mouse RPE were similar to those in age-matched KI;Fatp4-/- mouse RPE, whereas expression levels of CAR and S-opsin were significantly increased in the KI;Fatp4-/- retinas as compared to the KI retinas. CAR-positive cone numbers in 4-month-old KI;Fatp4-/- inferior retinas were at least 8-fold greater than those in the KI retinas. Mislocalization of S-opsin was reduced approximately 40% in the KI;Fatp4-/- mice compared to KI mice. Amounts of all-trans-retinal, all-trans-retinol and all-trans retinyl ester in dark-adapted the KI mouse eyes were similar to those in the KI;Fatp4-/- eyes. However, amounts of 11-cis-retinal and 9-cis-retinal (a functional iso-chromophore) in dark-adapted KI;Fatp4-/- mice were increased at least 2-fold compare to those in KI mice. Consistent with these results, cone visual function was significantly rescued in KI;Fatp4-/- mice compared to KI mice.

Conclusions : Deletion of FATP4 improves the visual cycle, cone survival and visual function in the mouse models of LCA, indicating that FATP4 is a new therapeutic target for patients with Rpe65 mutations.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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