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A more recent version of this article appeared on January 1, 2006

Papers In Press, published online ahead of print October 28, 2005
J. Lipid Res., doi:10.1194/jlr.M500306-JLR200
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Submitted on July 18, 2005
Revised on October 25, 2005
Accepted on October 28, 2005

A membrane defect in the pathogenesis of the Smith-Lemli-Opitz syndrome

Thomas N. Tulenko, Kathy Boeze-Battaglia, R. Preston Mason, G. Stephen Tint, Robert D. Steiner, William E. Connor, and Edward F. LaBelle

Surgery Dept., Thomas Jefferson University, Philadep[phia, PA 19107

Corresponding Author: thomas.tulenko{at}jefferson.edu

The Smith-Lemli-Opitz (SLO) syndrome is an often lethal birth defect resulting from mutations in the gene responsible for the synthesis of the enzyme 3b-hydroxy-steroid-D7-reductase (DHCR7) which catalyzes the reduction of the double bond at carbon 7 on 7-dehydrocholesterol (7-DHC) to form unesterified cholesterol. We hypothesize that the deficiency in cholesterol biosynthesis and subsequent accumulation of 7-DHC in the cell membrane leads to defective composition, organization, dynamics and function of the cell membrane. Using skin fibroblasts obtained from SLOS patients, we demonstrate that the SLOS membrane has elevated 7-DHC and reduced cholesterol content and abnormal membrane fluidity. X-ray diffraction analyses of synthetic membranes prepared to mimic SLOS membranes revealed atypical membrane organization. In addition, calcium permeability is markedly augmented while membrane-bound Na+/K+ATPase activity, folate uptake, IP3 signaling and cell proliferation rates are markedly suppressed. These data indicate that the disturbance in membrane sterol content in SLOS, likely at the level of membrane caveolae, directly contributes to the widespread tissue abnormalities in this disease


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