文章基本信息
- 标题：A membrane defect in the pathogenesis of the Smith-Lemli-Opitz syndrome
- 本地全文：下载
- 作者：Tulenko, Thomas N. ; Boeze-Battaglia, Kathy ; Mason, R. Preston 等
- 期刊名称：JLR Papers In Press
- 印刷版ISSN：0022-2275
- 电子版ISSN：1539-7262
- 出版年度：2006
- 卷号：47
- 期号：1
- 页码：134-143
- DOI：10.1194/jlr.M500306-JLR200
- 出版社：American Society for Biochemistry and Molecular Biology
- 摘要：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
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