We propose a study of cholesterol metabolism and the effects of cholesterol deficiency in Smith-Lemli-Opitz Syndrome (SLOS). SLOS is a disorder of cholesterol synthesis caused by mutations in the DHCR7 gene encoding 7-dehydrocholesterol (7DHC) reductase, the final enzyme in the cholesterol synthetic pathway. Affected individuals exhibit multiple malformations and mental retardation. The features of SLOS are thought to be primarily related to cholesterol deficiency and accumulation of 7DHC. However, the clinical phenotype is not well characterized, the biochemical pathogenesis is incompletely understood, and there is no proven therapy for this devastating condition. Thus our first objective is to better define the phenotype of SLOS using a natural history study design. We hypothesize that impaired cholesterol homeostasis leads to measurable behavioral and neurocognitive deficits, impaired brain myelination and cholesterol turnover, and retinal dysfunction. To test this hypothesis we will assess cholesterol homeostasis using state-of-the-art methods in parallel with clinical observation, testing, and imaging. This natural history sub-study will contribute to creating a comprehensive SLOS natural history registry and to the development of end-points for clinical trials. Our second objective is to test the efficacy of simvastatin as a complementary therapeutic strategy in patients supplemented with cholesterol. We hypothesize that SLOS patients will respond favorably to simvastatin treatment by improving brain cholesterol synthesis and increasing whole body cholesterol pool size. To test this hypothesis, we will treat SLOS patients supplemented with cholesterol for 2 years with simvastatin. Treatment efficacy will be judged primarily on changes in cognition and behavior (clinical) but also on surrogate biochemical and other measures (i.e. sterols and oxysterols, ERG, and brain MRI), in comparison with patients receiving only cholesterol supplementation. This intervention study will test the feasibility of clinical treatment trials in SLOS and the likelihood of efficacy of a promising intervention, as well as provide a foundation for future multicenter clinical trials. In this project, we plan to proceed with translation of in vitro studies from bench to bedside. Our third objective is to elucidate SLOS pathogenesis, probe the consequences of DCHR7 deficiency on cell functions and evaluate the cellular benefit of compounds with therapeutic potential in vitro. We hypothesize that DCHR7 deficiency causes metabolic diversion away from cholesterol synthesis, alters the structure, composition and signaling function of plasma membrane caveolae, impairs ER-specific protein folding activity, and causes cellular oxidative stress and apoptosis. We further hypothesize that statins, bile acids, antioxidants and molecular chaperones selectively restore SLOS cell metabolism and function. These latter studies will be conducted in vitro using SLOS and control skin fibroblasts, SLOS mouse brain-derived cells, and SLOS human brain tissues. Together, the in vivo and in vitro studies proposed should shed light on the pathogenesis of SLOS, and offer insights into treatment that to date have eluded investigators.

Public Health Relevance

This research project represents an attempt to learn as much as we can about a condition called Smith-Lemli- Opitz syndrome (SLOS) in order to develop treatment. SLOS is a defect in cholesterol production;affected patients have mental retardation and birth defects. Unlike most cholesterol diseases which have excess cholesterol, SLOS is characterized by cholesterol deficiency. Studying this rare disease should yield insights into cholesterol metabolism in general, which should prove useful in fighting more common cholesterol related problems.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Ershow, Abby
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Marshfield Clinic Research Foundation
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Merkens, Mark J; Sinden, Nancy L; Brown, Christine D et al. (2014) Feeding impairments associated with plasma sterols in Smith-Lemli-Opitz syndrome. J Pediatr 165:836-41.e1
Chang, Shaohua; Ren, Gongyi; Steiner, Robert D et al. (2014) Elevated Autophagy and Mitochondrial Dysfunction in the Smith-Lemli-Opitz Syndrome. Mol Genet Metab Rep 1:431-442
Arya, Divya; Chang, Shaohua; DiMuzio, Paul et al. (2014) Sphingosine-1-phosphate promotes the differentiation of adipose-derived stem cells into endothelial nitric oxide synthase (eNOS) expressing endothelial-like cells. J Biomed Sci 21:55
Liu, Wei; Xu, Libin; Lamberson, Connor R et al. (2013) Assays of plasma dehydrocholesteryl esters and oxysterols from Smith-Lemli-Opitz syndrome patients. J Lipid Res 54:244-53
Freeman, Kurt A; Eagle, Rose; Merkens, Louise S et al. (2013) Challenging behavior in Smith-Lemli-Opitz syndrome: initial test of biobehavioral influences. Cogn Behav Neurol 26:23-9
Ren, Gongyi; Jacob, Robert F; Kaulin, Yuri et al. (2011) Alterations in membrane caveolae and BKCa channel activity in skin fibroblasts in Smith-Lemli-Opitz syndrome. Mol Genet Metab 104:346-55
DeBarber, Andrea E; Eroglu, Yasemen; Merkens, Louise S et al. (2011) Smith-Lemli-Opitz syndrome. Expert Rev Mol Med 13:e24
Merkens, Louise S; Wassif, Christopher; Healy, Kristy et al. (2009) Smith-Lemli-Opitz syndrome and inborn errors of cholesterol synthesis: summary of the 2007 SLO/RSH Foundation scientific conference sponsored by the National Institutes of Health. Genet Med 11:359-64
Merkens, Louise S; Jordan, Julia M; Penfield, Jennifer A et al. (2009) Plasma plant sterol levels do not reflect cholesterol absorption in children with Smith-Lemli-Opitz syndrome. J Pediatr 154:557-561.e1
Chan, Yen-Ming; Merkens, Louise S; Connor, William E et al. (2009) Effects of dietary cholesterol and simvastatin on cholesterol synthesis in Smith-Lemli-Opitz syndrome. Pediatr Res 65:681-5

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