HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M500306-JLR200v1 47/1/134    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tulenko, T. N. Articles by Labelle, E. F. Search for Related Content PubMed PubMed Citation Articles by Tulenko, T. N. Articles by Labelle, E. F. Social Bookmarking                      What's this?

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. Tulenko^1,*, Kathy Boeze-Battaglia, R. Preston Mason, G. Stephen Tint^**, Robert D. Steiner, William E. Connor and Edward F. Labelle^***

^* Departments of Surgery and Biochemistry & Molecular Pharmacology, Thomas Jefferson University College of Medicine, Philadelphia, PA
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
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-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-⁷-reductase • birth defects • cell membrane • caveolae • rafts

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. T. Burke, P. L. Colvin, L. Myatt, G. A. Graf, F. Schroeder, and L. A. Woollett Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster J. Lipid Res., June 1, 2009; 50(6): 1146 - 1155. [Abstract] [Full Text] [PDF]

				T. Kitami, R. Rubio, W. O'Brien, J. Quackenbush, and J. H. Nadeau Gene-environment interactions reveal a homeostatic role for cholesterol metabolism during dietary folate perturbation in mice Physiol Genomics, October 8, 2008; 35(2): 182 - 190. [Abstract] [Full Text] [PDF]

				K. Boesze-Battaglia, M. Damek-Poprawa, D. C. Mitchell, L. Greeley, R. S. Brush, R. E. Anderson, M. J. Richards, and S. J. Fliesler Alteration of retinal rod outer segment membrane fluidity in a rat model of Smith-Lemli-Opitz syndrome J. Lipid Res., July 1, 2008; 49(7): 1488 - 1499. [Abstract] [Full Text] [PDF]

				A. S. Pappu, W. E. Connor, L. S. Merkens, J. M. Jordan, J. A. Penfield, D. R. Illingworth, and R. D. Steiner Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol J. Lipid Res., December 1, 2006; 47(12): 2789 - 2798. [Abstract] [Full Text] [PDF]

				F. Jiang and G. E. Herman Analysis of Nsdhl-deficient embryos reveals a role for Hedgehog signaling in early placental development Hum. Mol. Genet., November 15, 2006; 15(22): 3293 - 3305. [Abstract] [Full Text] [PDF]