| Quantitative proteomics analysis of inborn errors of cholesterol synthesis: identification of altered metabolic pathways in DHCR7 and SC5D deficiency. | |
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MedLine Citation:
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PMID: 20305089 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Smith-Lemli-Opitz syndrome (SLOS) and lathosterolosis are malformation syndromes with cognitive deficits caused by mutations of 7-dehydrocholesterol reductase (DHCR7) and lathosterol 5-desaturase (SC5D), respectively. DHCR7 encodes the last enzyme in the Kandutsch-Russel cholesterol biosynthetic pathway, and impaired DHCR7 activity leads to a deficiency of cholesterol and an accumulation of 7-dehydrocholesterol. SC5D catalyzes the synthesis of 7-dehydrocholesterol from lathosterol. Impaired SC5D activity leads to a similar deficiency of cholesterol but an accumulation of lathosterol. Although the genetic and biochemical causes underlying both syndromes are known, the pathophysiological processes leading to the developmental defects remain unclear. To study the pathophysiological mechanisms underlying SLOS and lathosterolosis neurological symptoms, we performed quantitative proteomics analysis of SLOS and lathosterolosis mouse brain tissue and identified multiple biological pathways affected in Dhcr7(Delta3-5/Delta3-5) and Sc5d(-/-) E18.5 embryos. These include alterations in mevalonate metabolism, apoptosis, glycolysis, oxidative stress, protein biosynthesis, intracellular trafficking, and cytoskeleton. Comparison of proteome alterations in both Dhcr7(Delta3-5/Delta3-5) and Sc5d(-/-) brain tissues helps elucidate whether perturbed protein expression was due to decreased cholesterol or a toxic effect of sterol precursors. Validation of the proteomics results confirmed increased expression of isoprenoid and cholesterol synthetic enzymes. This alteration of isoprenoid synthesis may underlie the altered posttranslational modification of Rab7, a small GTPase that is functionally dependent on prenylation with geranylgeranyl, that we identified and validated in this study. These data suggested that although cholesterol synthesis is impaired in both Dhcr7(Delta3-5/Delta3-5) and Sc5d(-/-) embryonic brain tissues the synthesis of nonsterol isoprenoids may be increased and thus contribute to SLOS and lathosterolosis pathology. This proteomics study has provided insight into the pathophysiological mechanisms of SLOS and lathosterolosis, and understanding these pathophysiological changes will help guide clinical therapy for SLOS and lathosterolosis. |
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Authors:
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Xiao-Sheng Jiang; Peter S Backlund; Christopher A Wassif; Alfred L Yergey; Forbes D Porter |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-03-19 |
Journal Detail:
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Title: Molecular & cellular proteomics : MCP Volume: 9 ISSN: 1535-9484 ISO Abbreviation: Mol. Cell Proteomics Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-01 Completed Date: 2010-11-04 Revised Date: 2012-05-25 |
Medline Journal Info:
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Nlm Unique ID: 101125647 Medline TA: Mol Cell Proteomics Country: United States |
Other Details:
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Languages: eng Pagination: 1461-75 Citation Subset: IM |
Affiliation:
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NICHD, National Institutes of Health, United States Department of Health and Human Services, Bethesda, Maryland 20892, USA. jiangx@mail.nih.gov |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Brain / enzymology Caspase 3 / metabolism Cholesterol / biosynthesis*, chemistry, metabolism Enzyme Activation Female Metabolic Networks and Pathways / genetics* Mevalonic Acid / metabolism Mice Mice, Knockout Molecular Sequence Data Molecular Structure Oxidoreductases Acting on CH-CH Group Donors / deficiency*, genetics Proteomics / methods* Smith-Lemli-Opitz Syndrome / genetics*, metabolism*, pathology Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / methods rab GTP-Binding Proteins / metabolism rab5 GTP-Binding Proteins / metabolism |
| Chemical | |
Reg. No./Substance:
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150-97-0/Mevalonic Acid; 152989-05-4/rab7 protein; 57-88-5/Cholesterol; 80-99-9/lathosterol; EC 1.14.21.6/lathosterol delta-5-dehydrogenase; EC 1.3.-/Oxidoreductases Acting on CH-CH Group Donors; EC 1.3.1.21/7-dehydrocholesterol reductase; EC 3.4.22.-/Caspase 3; EC 3.6.1.-/rab GTP-Binding Proteins; EC 3.6.5.2/rab5 GTP-Binding Proteins |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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