J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M500306-JLR200 on October 28, 2005

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Journal of Lipid Research, Vol. 47, 134-143, January 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

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

Thomas N. Tulenko1,*, Kathy Boeze-Battaglia{dagger}, R. Preston Mason§, G. Stephen Tint**, Robert D. Steiner{dagger}{dagger}, William E. Connor§§ and Edward F. Labelle***

* Departments of Surgery and Biochemistry & Molecular Pharmacology, Thomas Jefferson University College of Medicine, Philadelphia, PA
{dagger} Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA
§ Elucida Research LLC, Beverly, MA, and Brigham and Women's Hospital, Harvard Medical School, Boston, MA
** Research Service, Department of Veterans Affairs Medical Center, East Orange, NJ, and Department of Medicine, University of Medicine and Dentistry of New Jersey Medical School, Newark, NJ
{dagger}{dagger} Departments of Pediatrics and Molecular & Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital
§§ Department of Medicine, Oregon Health and Science University, Portland OR
*** Department of Physiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA

Published, JLR Papers in Press, October 28, 2005.

1 To whom correspondence should be addressed. e-mail: thomas.tulenko{at}jefferson.edu

The Smith-Lemli-Opitz syndrome (SLOS) is an often lethal birth defect resulting from mutations in the gene responsible for the synthesis of the enzyme 3ß-hydroxy-steroid-{Delta}7-reductase, 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 increased 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, whereas membrane-bound Na+/K+ATPase activity, folate uptake, inositol-1,4,5-trisphosphate 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.

Supplementary key words 7-dehydrocholesterol • 3ß-hydroxy-steroid-{Delta}7-reductase • birth defects • cell membrane • caveolae • rafts


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