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Article
Nature Genetics  35, 158 - 164 (2003)
Published online: 21 September 2003; | doi:10.1038/ng1246

Spontaneous activity of opsin apoprotein is a cause of Leber congenital amaurosis

Michael L Woodruff1, 6, Zhongyan Wang2, 6, Hae Yun Chung2, T Michael Redmond3, Gordon L Fain1, 4, 6 & Janis Lem2, 5, 6

1  Department of Physiological Science, University of California Los Angeles, Los Angeles, California 90095, USA.

2  Molecular Cardiology Research Institute, Tufts-New England Medical Center, 750 Washington St. Box 5045, Boston, Massachusetts 02111, USA.

3  Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

4  Department of Ophthalmology, University of California Los Angeles, Los Angeles, California 90095, USA.

5  Department of Ophthalmology, Program in Genetics, and Tufts Center for Vision Research, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

6  These authors contributed equally to this work.

Correspondence should be addressed to Janis Lem jlem@tufts-nemc.org
Mutations in Rpe65 disrupt synthesis of the opsin chromophore ligand 11-cis-retinal and cause Leber congenital amaurosis (LCA), a severe, early-onset retinal dystrophy. To test whether light-independent signaling by unliganded opsin causes the degeneration, we used Rpe65-null mice, a model of LCA. Dark-adapted Rpe65-/- mice behaved as if light adapted, exhibiting reduced circulating current, accelerated response turn-off, and diminished intracellular calcium. A genetic block of transducin signaling completely rescued degeneration irrespective of an elevated level of retinyl ester. These studies clearly show that activation of sensory transduction by unliganded opsin, and not the accumulation of retinyl esters, causes light-independent retinal degeneration in LCA. A similar mechanism may also be responsible for degeneration induced by vitamin A deprivation.

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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