Our laboratory works on Smith-Lemli-Opitz syndrome,inborn errors of cholesterol biosynthesis and Niemann-Pick Disease, type C1. SLOS is a human autosomal recessive multiple congenital anomaly/cognitive impairment syndrome characterized by facial dysmorphology, cognitive impairment, 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 multiple mouse models for this disorder. We are using these mouse models 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. Our laboratory also works to understnad the pathological processes underlying Niemann-Pick disease, type C1 (NPC1). NPC1 is a genetic disorder due to impaired intracellular cholesterol and lipid transport. Patients with NPC1 die due to a progressive neurological disorder. The laboratory is applying proteomic techniques to understand pathophysiological processes underlying clinical problems found in NPC and to identify biomarkers that can be used in future clincal trials. 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.

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Tseng, Wei-Chia; Loeb, Hannah E; Pei, Wuhong et al. (2018) Modeling Niemann-Pick disease type C1 in zebrafish: a robust platform for in vivo screening of candidate therapeutic compounds. Dis Model Mech 11:
Cougnoux, Antony; Drummond, Rebecca A; Collar, Amanda L et al. (2018) Microglia activation in Niemann-Pick disease, type C1 is amendable to therapeutic intervention. Hum Mol Genet 27:2076-2089
Cougnoux, Antony; Movassaghi, Miyad; Picache, Jaqueline A et al. (2018) Gastrointestinal Tract Pathology in a BALB/c Niemann-Pick Disease Type C1 Null Mouse Model. Dig Dis Sci 63:870-880
Dai, Sheng; Dulcey, Andrés E; Hu, Xin et al. (2017) Methyl-?-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK. Autophagy :1-17
Newton, Jason; Hait, Nitai C; Maceyka, Michael et al. (2017) FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts. FASEB J 31:1719-1730
Chandler, Randy J; Williams, Ian M; Gibson, Alana L et al. (2017) Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1. Hum Mol Genet 26:52-64
Höglinger, Doris; Nadler, André; Haberkant, Per et al. (2017) Trifunctional lipid probes for comprehensive studies of single lipid species in living cells. Proc Natl Acad Sci U S A 114:1566-1571
Yergey, Alfred L; Blank, Paul S; Cologna, Stephanie M et al. (2017) Characterization of hydroxypropyl-beta-cyclodextrins used in the treatment of Niemann-Pick Disease type C1. PLoS One 12:e0175478
Wassif, Christopher A; Kratz, Lisa; Sparks, Susan E et al. (2017) A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. Genet Med 19:297-305
Salman, Alexander; Cougnoux, Antony; Farhat, Nicole et al. (2017) Association of NPC1 variant p.P237S with a pathogenic splice variant in two Niemann-Pick disease type C1 patients. Am J Med Genet A 173:1038-1040

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