title: Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness.
abstract: Mutation of the 3beta-hydroxysterol delta7-reductase gene (Dhcr7-/-) results in Smith-Lemli-Opitz syndrome (SLOS). Patients, and genetically altered mice, are unable to produce cholesterol and accumulate 7-dehydrocholesterol (DHC) in serum and tissue. This causes multiple growth and developmental abnormalities as well as immune system anomalies including allergy. Because cholesterol is a key component of liquid-ordered membranes (lipid rafts) and these domains have been implicated in regulating mast cell activation, we examined whether mast cell responsiveness is altered in this model. Mast cells derived from Dhcr7-/- mice (DHCR KO) showed constitutive cytokine production and hyper-degranulation after stimulation of the high affinity IgE receptor (Fc epsilonRI). DHCR KO mast cells, but not wild-type mast cells, accumulated DHC in lipid rafts. DHC partially disrupted lipid raft stability and displaced Lyn kinase protein and activity from lipid rafts. This led to down-regulation of some Lyn-dependent signaling events but increased Fyn kinase activity and Akt phosphorylation. The Lyn-dependent phosphorylation of Csk-binding protein, which negatively regulates Fyn activity, was decreased. This phenotype reproduces some of the characteristics of Lyn-null mast cells, which also demonstrate hyper-degranulation. These findings provide the first evidence of lipid raft dysfunction in SLOS and may explain the observed association of allergy with SLOS.
authors.affiliation: Molecular Inflammation Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Kovarova
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.forename: Sandra
authors.initials: S
authors.lastname: Odom
authors.forename: Katherine
authors.initials: K
authors.lastname: Liao
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.forename: Juan
authors.initials: J
authors.lastname: Rivera
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000276:immunology*; D002478:Cells, Cultured; D003684:Dehydrocholesterols / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051058:Oncogene Protein v-akt / Q000276:immunology / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency*; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D019082:Smith-Lemli-Opitz Syndrome / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019061:src-Family Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D003684:Dehydrocholesterols; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051058:Oncogene Protein v-akt