Smith-Lemli-Opitz Syndrome: A Longitudinal Clinical Study of Patients Receiving Cholesterol Supplementation - STAIR 7001
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PROVIDER: PRJNA398583 | ENA |
REPOSITORIES: ENA
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Project description:7-dehydrocholesterol reductase catalyzes the reduction of 7-dehydrocholesterol to cholesterol. In Smith-Lemli-Opitz syndrome, mutations in DHCR7 prevents this conversion. We have found iPS cells derived from SLOS patients exhibit accelerated differentiation under cholesterol poor conditions. In this dataset, we include expression data obtained from comparision of a control iPS cell line (BJ) and a SLOS iPS cell line (A2). Cell line gene expression was compared in cholesterol rich conditions where the SLOS phenotype is suppressed. Cholesterol deficient culture of control and SLOS iPS cells demonstrated enhanced differentiation of SLOS cells over 7 days. These data are used to obtain 308 genes that are differentially expressed upon cholesterol deficient culture. time-course expression data obtained from control and SLOS patient iPS cells after transfer from cholesterol rich to cholesterol deficient culture.
2015-09-18 | GSE61203 | GEO
Project description:Smith-Lemli-Opitz Syndrome: A Longitudinal Clinical Study of Patients Receiving Cholesterol Supplementation - STAIR 7001
| PRJNA398584 | ENA
Project description:7-dehydrocholesterol reductase catalyzes the reduction of 7-dehydrocholesterol to cholesterol. In Smith-Lemli-Opitz syndrome, mutations in DHCR7 prevents this conversion. We have found iPS cells derived from SLOS patients exhibit accelerated differentiation under cholesterol poor conditions. In this dataset, we include expression data obtained from comparision of a control iPS cell line (BJ) and a SLOS iPS cell line (A2). Cell line gene expression was compared in cholesterol rich conditions where the SLOS phenotype is suppressed. Cholesterol deficient culture of control and SLOS iPS cells demonstrated enhanced differentiation of SLOS cells over 7 days. These data are used to obtain 308 genes that are differentially expressed upon cholesterol deficient culture. time-course expression data obtained from control and SLOS patient iPS cells after transfer from cholesterol rich to cholesterol deficient culture. 48 total RNA samples were isolated and hybridized on Affymetrix arrays. We generated the following pairwise comparisons using Partek: BJ 0hr vs A2 0hr; BJ 2Day vs A2 2Day; BJ 3Day vs A2 3Day; BJ 4Day vs A2 4Day; BJ 5Day vs A2 5Day; BJ 7Day vs A2 7Day. Genes with an FDR≤10% and a fold-change ≥3 were identified as significantly different. We also performed pairwise comparison of BJ and A2 samples within each cell line between subsequent isolations (i.e. BJ 0hr vs BJ 2Day; A2 3Day vs A2 4Day; etc.)
2015-09-18 | E-GEOD-61203 | biostudies-arrayexpress
Project description:BACKGROUND:Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by diminished cholesterol and increased 7-dehydrocholesterol (7-DHC) levels. 7-Dehydrocholesterol is highly reactive, giving rise to biologically active oxysterols. METHODS:7-DHC-derived oxysterols were measured in fibroblasts from SLOS patients and an in vivo SLOS rodent model using high-performance liquid chromatography tandem mass spectrometry. Expression of lipid biosynthesis genes was ascertained by quantitative polymerase chain reaction and Western blot. The effects of an antioxidant mixture of vitamin A, coenzyme Q10, vitamin C, and vitamin E were evaluated for their potential to reduce formation of 7-DHC oxysterols in fibroblast from SLOS patients. Finally, the effect of maternal feeding of vitamin E enriched diet was ascertained in the brain and liver of newborn SLOS mice. RESULTS:In cultured human SLOS fibroblasts, the antioxidant mixture led to decreased levels of the 7-DHC-derived oxysterol, 3?,5?-dihydroxycholest-7-en-6-one. Furthermore, gene expression changes in SLOS human fibroblasts were normalized with antioxidant treatment. The active ingredient appeared to be vitamin E, as even at low concentrations, it significantly decreased 3?,5?-dihydroxycholest-7-en-6-one levels. In addition, analyzing a mouse SLOS model revealed that feeding a vitamin E enriched diet to pregnant female mice led to a decrease in oxysterol formation in brain and liver tissues of the newborn Dhcr7-knockout pups. CONCLUSIONS:Considering the adverse effects of 7-DHC-derived oxysterols in neuronal and glial cultures and the positive effects of antioxidants in patient cell cultures and the transgenic mouse model, we believe that preventing formation of 7-DHC oxysterols is critical for countering the detrimental effects of DHCR7 mutations.
| S-EPMC3874268 | biostudies-literature
Project description:Smith-Lemli-Opitz syndrome is an autosomal recessive disorder that arises from mutations in the gene DHCR7, which encodes the terminal enzyme of cholesterol biosynthesis, leading to decreased production of cholesterol and accumulation of the cholesterol precursor, 7-dehydrocholesterol, and its oxysterol metabolites. The disorder displays a wide range of neurodevelopmental defects, intellectual disability and behavioral problems. However, an in-depth study on the temporal changes of gene expression in the developing brains of SLOS mice has not been done before. In this work, we carried out the transcriptomic analysis of whole brains from WT and Dhcr7-KO mice at four time points through postnatal day 0. First, we observed the expected downregulation of the Dhcr7 gene in the Dhcr7-KO mouse model, as well as gene expression changes of several other genes involved in cholesterol biosynthesis throughout all time points. Pathway and GO term enrichment analyses revealed affected signaling pathways and biological processes that were shared amongst time points and unique to individual time points. Specifically, the pathways important for embryonic development, including Hippo, Wnt, and TGF-β signaling pathways are the most significantly affected at the earliest time point, E12.5. Additionally, neurogenesis-related GO terms were enriched in earlier time points, consistent with the timing of development. Conversely, pathways related to synaptogenesis, which occurs later in development compared to neurogenesis, are significantly affected at the later time points, E16.5 and PND0, including the cholinergic, glutamatergic, and GABAergic synapses. The impact of these transcriptomic changes and enriched pathways is discussed in the context of known biological phenotypes of SLOS.
2024-02-15 | GSE247566 | GEO
Project description:<p>Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol production by the body. It is caused by changes in the DHCR7 gene, which is the blueprint for an enzyme called 7-dehydrocholesterol- delta7-reductase. This enzyme is necessary for the production of cholesterol by all cells in the body. People with SLOS often have malformations of major organs, slow growth, feeding difficulties and intellectual disability or learning problems.</p> <p>Because patients with SLOS cannot make enough cholesterol, it has been proposed that cholesterol supplementation (either with egg yolk or liquid suspensions of cholesterol) could help improve the symptoms of the disease. However, despite the widespread use of cholesterol supplementation, it is still not known whether it works or not. The study will try to provide an answer to this question by studying the disease and its progression while patients are receiving cholesterol.</p> <p>The clinical features of SLOS are thought to be related to low cholesterol and buildup of toxic cholesterol precursors (substances from which cholesterol is formed). But how exactly low cholesterol and toxic precursors contribute to the disease is poorly understood. This knowledge is critically important because it should help discover new therapeutic targets and develop treatments of the disease in the long run. The study will try to fill this gap with a comprehensive clinical and biochemical testing of the study participants over the course of several years.</p> <p>Last, a limitation of previous SLOS research studies has been their low number of participants. This is understandable because SLOS is a rare diseases and few research groups are working on it. However, in order to fully understand the disease, researchers need to study as many patients as possible. This study is unique in that it is run by a network of several highly specialized clinical research sites across the country. Having several sites involved increases the researcher's ability to recruit and study large number of patients, and centralize patients' information in a comprehensive SLOS clinical registry. This registry will be key to identify markers for diagnostic testing, screening and measuring outcomes in future studies of treatment.</p> <p>The purpose of this study is to learn as much as possible about Smith-Lemli-Opitz Syndrome (SLOS) by following a large group of affected children and adults over time. In this study, we will measure cholesterol and other similar chemicals in blood and urine, evaluate development and behavior, do limited medical evaluation, and carry out brain imaging studies.This study will help researchers: <ul> <li>learn more about what causes SLOS and how SLOS changes with age,</li> <li>note differences in features of SLOS among those affected,</li> <li>evaluate the effect of giving extra cholesterol in this condition, and</li> <li>develop ways to evaluate whether treatments developed in the future will be helpful.</li> </ul> </p>
| phs001430 | dbGaP
Project description:Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital malformation and intellectual disability syndrome, with clinical characteristics that encompass a wide spectrum and great variability. Elucidation of the biochemical and genetic basis for SLOS, specifically understanding SLOS as a cholesterol deficiency syndrome caused by mutation in DHCR7, opened up enormous possibilities for therapeutic intervention. When cholesterol was discovered to be the activator of sonic hedgehog, cholesterol deficiency with inactivation of this developmental patterning gene was thought to be the cause of SLOS malformations, yet this explanation is overly simplistic. Despite these important research breakthroughs, there is no proven treatment for SLOS. Better animal models are needed to allow potential treatment testing and the study of disease pathophysiology, which is incompletely understood. Creation of human cellular models, especially models of brain cells, would be useful, and in vivo human studies are also essential. Biomarker development will be crucial in facilitating clinical trials in this rare condition, because the clinical phenotype can change over many years. Additional research in these and other areas is critical if we are to make headway towards ameliorating the effects of this devastating condition.
| S-EPMC3366105 | biostudies-literature
Project description:The Smith-Lemli-Opitz syndrome (SLOS) is one of the archetypical multiple congenital malformation syndromes. The recent discovery of the biochemical cause of SLOS and the subsequent redefinition of SLOS as an inborn error of cholesterol metabolism have led to important new treatment possibilities for affected patients. Moreover, the recent recognition of the important role of cholesterol in vertebrate embryogenesis, especially with regard to the hedgehog embryonic signalling pathway and its effects on the expression of homeobox genes, has provided an explanation for the abnormal morphogenesis in the syndrome. The well known role of cholesterol in the formation of steroid hormones has also provided a possible explanation for the abnormal behavioural characteristics of SLOS.
| S-EPMC1734573 | biostudies-other
Project description:Cellular and molecular characterization of iPSC-derived human RPE cells from normal and Smith-Lemil-Opitz syndrome patients
| PRJNA767404 | ENA
Project description:Temporal gene expression changes and affected pathways in neurodevelopment of a mouse model of Smith-Lemli-Opitz syndrome
| PRJNA1039744 | ENA