More insights from Abca4(-/-) mouse models of recessive Stargardt disease.

Mutations in the ABC transporter ABCA4 (ABC, subfamily A, member 4) are responsible for recessive Stargardt disease 1 (STGD1), a juvenile form of macular degeneration. In preclinical and clinical studies, it has been shown that deficiency in ABCA4 leads to accelerated formation of the toxic bisretinoid fluorophores that form as the product of nonenzymatic reactions of retinaldehyde with phosphatidylethanolamine (2:1 ratio). Here, by comparing photoreceptor cell viability in albino versus agouti Abca4(-/-) mice and by dark-rearing albino Abca4(-/-) mice, we show that photoreceptor cell degeneration in the Abca4(-/-) mouse is at least partially driven by light. Elevated vitamin A in chow and a high-fat diet reduced photoreceptor cell viability. Phosphatidylethanolamine and N-retinylidiene-phosphatidylethanolamine were reduced, as were steady-state levels of retinoid in light-adapted eyes. As expected, bisretinoids, measured as short-wavelength fundus autofluorescence (AF), were elevated in both pigmented and albino Abca4(-/-) mice. Hyperautofluorescent puncta in fundus AF images colocalized in spectral domain optical coherence tomography scans with aberrant hyper-reflectivity that occupied photoreceptor-attributable bands and extended anteriorly to interrupt the ellipsoid zone and external limiting membrane. In epifluorescence images of Abca4(-/-) retina, retinal pigment epithelium was autofluorescent because of bisretinoid accumulation. Occasionally, AF lesions extended anteriorly from the retinal pigment epithelium to a horizontal band exhibiting less pronounced AF at the level of photoreceptor inner and outer segments. These lesions did not colocalize with IBA1 (ionized calcium-binding adaptor molecule)-labeled microglia. The hyperautofluorescent foci that presented as hyper-reflective lesions in spectral domain optical coherence tomography form in photoreceptor inner segments and are reminiscent of fundus flecks in STGD1.