出版社：American Society for Biochemistry and Molecular Biology
摘要：The Smith-Lemli-Opitz syndrome (SLOS) is an often lethal birthdefect resulting from mutations in the gene responsible forthe synthesis of the enzyme 3ß-hydroxy-steroid-7-reductase,which catalyzes the reduction of the double bond at carbon 7on 7-dehydrocholesterol (7-DHC) to form unesterified cholesterol.We hypothesize that the deficiency in cholesterol biosynthesisand subsequent accumulation of 7-DHC in the cell membrane leadsto defective composition, organization, dynamics, and functionof the cell membrane. Using skin fibroblasts obtained from SLOSpatients, we demonstrate that the SLOS membrane has increased7-DHC and reduced cholesterol content and abnormal membranefluidity. X-ray diffraction analyses of synthetic membranesprepared to mimic SLOS membranes revealed atypical membraneorganization. In addition, calcium permeability is markedlyaugmented, whereas membrane-bound Na+/K+ATPase activity, folateuptake, inositol-1,4,5-trisphosphate signaling, and cell proliferationrates are markedly suppressed. These data indicate that thedisturbance in membrane sterol content in SLOS, likely at thelevel of membrane caveolae, directly contributes to the widespreadtissue abnormalities in this disease.Supplementary key words 7-dehydrocholesterol • 3ß-hydroxy-steroid-7-reductase • birth defects • cell membrane • caveolae • rafts
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-
