The Journal of Experimental Medicine
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Published online 17 April 2006 doi:10.1084/jem.20051701
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 5, 1161-1171
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ARTICLE

 Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness

Martina Kovarova1, Christopher A. Wassif2, Sandra Odom1, Katherine Liao1, Forbes D. Porter2, and Juan Rivera1

1 Molecular Inflammation Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and 2 Unit on Molecular Dysmorphology, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD 20892

CORRESPONDENCE Juan Rivera: juan_rivera{at}nih.gov

Mutation of the 3ß-hydroxysterol {Delta}7-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{varepsilon}RI). 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.

Abbreviations used: Ag, antigen; Cbp, Csk-binding protein; DHC, 7-dehydrocholesterol; GC, gas chromatography; LPDS, lipoprotein-deficient serum; MBCD, methyl-ß-cyclodextrin; PI3K, phosphatidylinositol 3-OH kinase; PLC{gamma}, phospholipase C-{gamma}; SLOS, Smith-Lemli-Opitz syndrome.


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