title: A membrane defect in the pathogenesis of the Smith-Lemli-Opitz syndrome.
abstract: 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 3beta-hydroxy-steroid-Delta7-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.
authors.affiliation: Departments of Surgery and Biochemistry & Molecular Pharmacology, Thomas Jefferson University College of Medicine, Philadelphia, PA, USA. thomas.tulenko@jefferson.edu
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Tulenko
authors.forename: Kathy
authors.initials: K
authors.lastname: Boeze-Battaglia
authors.forename: R Preston
authors.initials: RP
authors.lastname: Mason
authors.forename: G Stephen
authors.initials: GS
authors.lastname: Tint
authors.forename: Robert D
authors.initials: RD
authors.lastname: Steiner
authors.forename: William E
authors.initials: WE
authors.lastname: Connor
authors.forename: Edward F
authors.initials: EF
authors.lastname: Labelle
mesh_terms: D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003684:Dehydrocholesterols / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008560:Membrane Fluidity; D008563:Membrane Lipids / Q000378:metabolism; D009154:Mutation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism; D019082:Smith-Lemli-Opitz Syndrome / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D003684:Dehydrocholesterols; D007295:Inositol Phosphates; D008563:Membrane Lipids; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium