Nl. Mata et al., Delayed. dark-adaptation and lipofuscin accumulation in abcr+/- mice: Implications for involvement of ABCR in age-related macular degeneration, INV OPHTH V, 42(8), 2001, pp. 1685-1690
PURPOSE. TO examine the ocular phenotype in mice heterozygous for a null mu
tation in the abcr gene.
METHODS. Retinas and retinal pigment epithelia (RPE) were prepared from wil
d-type, abcr+/-, and abcr-/- mice. Fresh tissues were homogenized and analy
zed by normal phase highperformance liquid chromatography (HPLC) for the pr
esence of retinoids and phospholipids. In another study, fixed tissues were
sectioned and analyzed by light and electron microscopy. Finally, anesthet
ized mice were studied by electroretinography (ERG) at different times afte
r exposure to strong light.
RESULTS. A2E, the major fluorophore of lipofuscin, and its precursors, A2PE
-H-2 and A2PE, were approximately fourfold more abundant in 8-month-old abc
r+/- than in the wild-type retina and RPE. The levels of these substances i
n abcr+/- mice were approximately 40% those in abcr-/- mice. Lipofuscin pig
ment-granules were also visible in abcr+/- RPE cells by electron microscopy
. Accumulation of A2PF-H-2 and A2E in abcr+/- retina and RPE, respectively,
was strongly dependent on light exposure. Heterozygous mutants also exhibi
ted delayed recovery of rod sensitivity by FRG. This delay was correlated w
ith elevated levels of all-trans-retinaldehyde (all-trans-RAL) in retina af
ter a photobleach and was not caused by a reduction in quantum-catch due to
depletion of Il-cis-retinaldehyde (11-cis-RAL).
CONCLUSIONS. Partial loss of the ABCR or rim protein is sufficient to cause
a phenotype in mice similar to recessive Stargardt's disease (STGD) and ag
e-related macular degeneration (AMD) in humans. These data are consistent w
ith the suggestion that the STGD carrier-state may predispose to the develo
pment of AMD.