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

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.

Selective antibody immune deficiency in a patient with Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome is a rare autosomal recessive disorder characterized by multiple congenital anomalies and various degrees of cognitive deficits. This condition results from a deficiency of 7-dehydrocholesterol reductase, a critical step in cholesterol biosynthesis. Children with Smith-Lemli-Opitz syndrome have frequent infections, particularly of the respiratory tract. Immunodeficiency, however, is not recognized as a part of this metabolic condition. Frequent infections are usually attributed to a decreased patient mobility and reduced respiratory effort secondary to muscular hypotonia and mental retardation, which are often present in affected individuals. We describe a patient with Smith-Lemli-Opitz syndrome and recurrent respiratory infections who was found to have a selective antibody deficiency. The immunological diagnosis was based on an absent immune response to Pneumovax. She also had no immunological response to hepatitis B vaccine and was unable to break down red cells with isoagglutinin B. Therapy with intravenous IgG (IVIG) was initiated. Infections were less severe, although they still occurred in a high frequency after initiation of the IVIG therapy. This finding prompts the need for a higher index of suspicion for an underlying immune deficiency in patients with Smith-Lemli-Opitz syndrome who present with recurrent and chronic infections. Early recognition and appropriate therapeutic interventions may decrease the severity of infections, prevent potentially fatal infections, and eventually improve the quality of life in these patients.