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Updated: Aug 9, 2026
Analyzing the Functions of Mast Cells In Vivo Using 'Mast Cell Knock-in' Mice
Published on: May 27, 2015
Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness
Martina Kovarova1, Christopher A Wassif, Sandra Odom
1Molecular 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.
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.
Insights
Smith-Lemli-Opitz syndrome (SLOS) causes cholesterol deficiency, leading to immune cell dysfunction. In SLOS mast cells, 7-dehydrocholesterol disrupts lipid rafts, increasing allergic responses.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Smith-Lemli-Opitz syndrome (SLOS) results from 3beta-hydroxysterol delta7-reductase gene (Dhcr7) mutations, causing cholesterol deficiency and 7-dehydrocholesterol (DHC) accumulation.
- SLOS is associated with developmental abnormalities and immune system anomalies, including allergies.
- Cholesterol is crucial for lipid rafts, membrane domains regulating mast cell activation.
Purpose of the Study:
- To investigate mast cell responsiveness in a mouse model of Smith-Lemli-Opitz syndrome (SLOS).
- To determine the role of 7-dehydrocholesterol (DHC) in lipid raft function and mast cell activation in SLOS.
Main Methods:
- Mast cells were derived from Dhcr7-/- mice (DHCR KO) and wild-type littermates.
- Mast cell degranulation and cytokine production were assessed after Fc epsilonRI stimulation.
- Lipid raft composition, stability, and associated kinase activity (Lyn, Fyn, Akt) were analyzed in DHCR KO and wild-type mast cells.
Main Results:
- DHCR KO mast cells exhibited constitutive cytokine production and hyper-degranulation.
- Accumulation of 7-dehydrocholesterol (DHC) in lipid rafts of DHCR KO mast cells was observed.
- DHC disrupted lipid raft stability, altered Lyn and Fyn kinase activity, and affected downstream signaling, mimicking Lyn-null mast cell characteristics.
Conclusions:
- This study provides the first evidence of lipid raft dysfunction in Smith-Lemli-Opitz syndrome (SLOS).
- Altered lipid raft function in SLOS mast cells contributes to immune anomalies, potentially explaining the association with allergies.
- Targeting lipid raft integrity may offer therapeutic strategies for SLOS-related immune disorders.
