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Jessica Gomez, Darcy L. Welch, Kendal Kernstine, Chinatsu Tosha, Gabriel H. Travis, Steven Nusinowitz, Roxana A. Radu; Characterization Of The Phenotype In Elovl4-tg2 Mice On The rpe65-Leu450 Background. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3329.
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Mutations in the ELOVL4 gene are responsible for autosomal dominant Stargardt macular degeneration (STGD3). The ELOVL4 gene encodes an enzyme involved in the elongation of long-chain fatty acids in outer-segment membranes. The role of ELOVL4 in retinal function and the mechanisms of ELOVL4-dependent retinal degeneration remain unclear. We are using a transgenic Elovl4-tg2 mouse on the rpe65-Leu450 (normal allele) background to investigate the role of ELOVL4. Characterization of these mice may shed light on the pathophysiology of STGD3 and other forms of macular degeneration.
Elovl4-tg2 (rpe65-Met450) mice were crossed with 129/Sv wild-type (rpe65-Leu450) to yield Elovl4-tg2 mice on rpe65-Leu450. Retinas and RPE-containing eyecups were collected from age-matched 129/Sv and Elovl4-tg2 mice at different time points. Levels of the complement-regulatory (CRRY, CFH) and oxidative-stress (HO1, GSTT, CAT1, SOD1) mRNA’s were measured by qRT-PCR. Rpe65 and GAPDH protein levels were measured by quantitative immunoblotting. Retinoids and lipofuscin pigments were quantified by HPLC. Retina structure was evaluated in vivo byoptical coherence tomography (OCT). Electroretinography (ERG) was used to evaluate retinal function.
Rpe65 levels were similar at four-weeks and ~30% reduced in two-month-old Elovl4-tg2 versus 129/Sv mice. CFH and CRRY mRNA levels were two- and three-fold lower in Elovl4-tg2 mice at P21 days and two months. At P21, all oxidative stress genes were 2-3-fold lower in Elovl4-tg2 compared to 129/Sv mice. Fourteen-week-old Elovl4-tg2 mice showed ~25% reduced retinal thickness. ERG-response amplitudes were ~60% reduced compared to 129/Sv mice. Visual retinoids were significantly reduced in both four-week- and two-month-old transgenic mice. A2E levels were elevated in four-week- and two-month-old Elovl4-tg2 mice.
The Elovl4-tg2 mouse showed significant functional, biochemical, and structural defects in the retina. Decreased expression of complement regulatory protein mRNA’s may signify dysregulation of the complement system in common with age-related macular degeneration.
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