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Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome: Thinking Beyond Cholesterol Deficiency

  • Steven J. Fliesler
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 664)

Abstract

Smith-Lemli-Opitz Syndrome (SLOS) is a recessive hereditary disease caused by a defect in the last step in cholesterol biosynthesis – the reduction of the Δ7 double bond of 7-dehydrocholesterol (7DHC) – resulting in the abnormal accumulation of 7DHC and diminished levels of Chol in all bodily tissues. Treatment of rats with AY9944 – a drug that inhibits the same enzyme that is genetically defective in SLOS (i.e., DHCR7, 3β-hydroxysterol-Δ7-reductase) – starting in utero and continuing throughout postnatal life, provides a convenient animal model of SLOS for understanding the disease mechanism and also for testing the efficacy of therapeutic intervention strategies. Herein, the biochemical, morphological, and electrophysiological hallmarks of retinal degeneration in this animal model are reviewed. A high-cholesterol diet partially ameliorates the associated visual function deficits, but not the morphological degeneration. Recent studies using this model suggest that the disease mechanism in SLOS goes well beyond the initial cholesterol pathway defect, including global metabolic alterations, lipid and protein oxidation, and differential expression of hundreds of genes in multiple ontological gene families. These findings may have significant implications with regard to developing more optimal therapeutic interventions for managing SLOS patients.

Keywords

Outer Segment Cholesterol Biosynthesis Retinal Degeneration Cholesterol Supplementation Cholesterol Deficiency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The author thanks the following collaborators for their significant contributions to the studies briefly summarized herein: Robert E. Anderson, Kathleen Boesze-Battaglia, R. Steven Brush, Deborah Ferrington, David Ford, Rebecca Kapphahn, Drake Mitchell, Barbara Nagel, Neal Peachey, Michael Richards, Akbar Siddiqui, and Dana Vaughan. This work was supported, in part, by U.S.P.H.S. (NEI/NIH) grant EY007361, by a departmental Challenge Grant and a Senior Scientific Investigator Award from Research to Prevent Blindness, and by a grant from the March of Dimes.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Veterans Administration Western New York Healthcare System, and the Department of Ophthalmology and BiochemistryUniversity at Buffalo (State University of New York)BuffaloUSA

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