期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 38, 页码 15123-15128出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0706367104
关键词
optical coherence tomography; retinal degeneration; retinoid cycle; Leber congenital amaurosis; gene therapy
资金
- NEI NIH HHS [P30 EY11373, P30 EY011373-119005, EY017280, U10 EY017280, EY09339, R01 EY009339-18, R01 EY009339, P30 EY011373] Funding Source: Medline
The visual (retinoid) cycle, the enzymatic pathway that regenerates chromophore after light absorption, is located primarily in the retinal pigment epithelium (RPE) and is essential for rod photoreceptor survival. Whether this pathway also is essential for cone photoreceptor survival is unknown, and there are no data from man or monkey to address this question. The visual cycle is naturally disrupted in humans with Leber congenital amaurosis (LCA), which is caused by mutations in RPE65, the gene that encodes the retinoid isomerase. We investigated such patients over a wide age range (3-52 years) for effects on the cone-rich human fovea. In vivo microscopy of the fovea showed that, even at the youngest ages, patients with RPE65-LCA exhibited cone photoreceptor loss. This loss was incomplete, however, and residual cone photoreceptor structure and function persisted for decades. Basic questions about localization of RPE65 and isomerase activity in the primate eye were addressed by examining normal macaque. RPE65 was definitively localized by immunocytochemistry to the central RIPE and, by immunoblotting, appeared to concentrate in the central retina. The central retinal RIPE layer also showed a 4-fold higher retinoid isomerase activity than more peripheral RIPE. Early cone photoreceptor losses in RPE65-LCA suggest that robust RPE65-based visual chromophore production is important for cones; the residual retained cone structure and function support the speculation that alternative pathways are critical for cone photoreceptor survival.
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