Temporal gene expression changes and affected pathways in neurodevelopment of a mouse model of Smith-Lemli-Opitz syndrome
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PROVIDER: PRJNA1039744 | ENA |
REPOSITORIES: ENA
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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: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.
| S-EPMC10690207 | biostudies-literature
Project description:Neurodevelopment is an intricately orchestrated program of cellular events that occurs with tight temporal and spatial regulation. While it is known that the development and proper functioning of the brain, which is the second most lipid rich organ behind adipose tissue, greatly rely on lipid metabolism and signaling, the temporal lipidomic changes that occur throughout the course of neurodevelopment have not been investigated. Smith-Lemli-Opitz syndrome is a metabolic disorder caused by genetic mutations in the DHCR7 gene, leading to defective 3β-hydroxysterol-Δ7-reductase (DHCR7), the enzyme that catalyzes the last step of the Kandutsch-Russell pathway of cholesterol synthesis. Due to the close regulatory relationship between sterol and lipid homeostasis, we hypothesize that altered or dysregulated lipid metabolism beyond the primary defect of cholesterol biosynthesis is present in the pathophysiology of SLOS. Herein, we applied our HILIC-IM-MS method and LiPydomics Python package to streamline an untargeted lipidomics analysis of developing mouse brains in both wild-type and Dhcr7-KO mice, identifying lipids at Level 3 (lipid species level: lipid class/subclass and fatty acid sum composition). We compared relative lipid abundances throughout development, from embryonic day 12.5 to postnatal day 0 and determined differentially expressed brain lipids between wild-type and Dhcr7-KO mice at specific developmental time points, revealing lipid metabolic pathways that are affected in SLOS beyond the cholesterol biosynthesis pathway, such as glycerolipid, glycerophospholipid, and sphingolipid metabolism. Implications of the altered lipid metabolic pathways in SLOS pathophysiology are discussed.
| S-EPMC9018458 | biostudies-literature
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: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:Smith-Lemli-Opitz Syndrome: A Longitudinal Clinical Study of Patients Receiving Cholesterol Supplementation - STAIR 7001
| PRJNA398583 | ENA
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:This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: 1. To evaluate the efficacy of statin therapy in reducing the frequency or severity of the neurobehavioral abnormalities seen in people with SLOS (e.g. aggression, anxiety, irritability, self-mutilation, autistic behaviors, sleep disturbances, etc.) (Wassif 2017). 2. To evaluate the potential effects of statin therapy on survival.
| S-EPMC7055734 | biostudies-literature