Our laboratorys focus is the Smith-Lemli-Opitz syndrome (SLOS) and other inborn errors of cholesterol biosynthesis. SLOS is a human autosomal recessive multiple congenital anomaly/mental retardation syndrome characterized by facial dysmorphology, mental retardation with a characteristic behavioral phenotype, growth retardation, and variable structural anomalies of the heart, lungs, brain, gastrointestinal tract, limbs, genitalia and kidneys. SLOS also has a distinct behavioral phenotype which includes self-injurious and autistic features. Biochemically, patients with SLOS have an inborn error of cholesterol biosynthesis; specifically they have a defect in the conversion of 7-dehydrocholesterol to cholesterol. However, we do not know why these children have such a variety of congenital malformations, and neurological problems. We cloned the gene encoding the 7-dehydrocholesterol reductase, and have subsequently identified mutations in this gene in more than fifty patients with Smith-Lemli-Opitz syndrome. Our laboratory continues to identify mutations in SLOS patients, and to determine residual enzymatic function in patient fibroblasts. This information is being used to establish genotype/enzymatic activity/phenotype correlations for this disorder. We have also isolated the mouse gene encoding this enzyme, and have produced a mouse model for this disorder. We are using this mouse model to further our understanding of how the malformations seen in this syndrome develop, and to further our understanding of the neurophysiological basis of the neurological problems associated with this syndrome. A hypomorphic mouse model of SLOS has also been developed. This mouse model is being used to investigate therapeutic interventions including dietary cholesterol supplementation, simvastatin therapy, and gene therapy. Our SLOS mouse models continue to be used to understand the pathophysiological processes that underlie the birth defects and clinical problems found in SLOS. Various biochemical, molecular, and proteomic approaches are being utilized to investigate these issues. These mouse models are being used to test various prenatal and postnatal therapeutic interventions. One of the most intriguing aspects of SLOS is the distinct behavioral phenotype. Most patients with SLOS have autistic features. We are currently working in collaboration with groups from Kennedy Krieger Institute in Baltimore and NHGRI to further analyze this association and to study whether abnormalities of cholesterol metabolism contribute to autism in general. In addition to SLOS, we have developed mouse models of lathosterolosis, desmosterolosis, and HEM dysplasia. These human syndromes all involve defects in cholesterol synthesis. We are using these mouse models to further our understanding of the biological processes which cause the birth defects found in these syndromes. The basic science work done in this laboratory supports and complements the clinical work also being performed by this Section. The combination of basic science and clinical science work in one Section facilitates the rapid translation of findings from the bench to the bedside and vice versa.