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7-Dehydrocholesterol Reductase

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Forbes D. Porter – One of the best experts on this subject based on the ideXlab platform.

  • altered cerebrospinal fluid proteins in smith lemli opitz syndrome patients
    American Journal of Medical Genetics Part A, 2016
    Co-Authors: Stephanie M Cologna, Christopher A. Wassif, Simona Bianconi, Christine Shieh, Cynthia L Toth, Antony Cougnoux, Kathryn R Burkert, Forbes D. Porter
    Abstract:

    Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation syndrome with neurocognitive impairment. SLOS arises from mutations in the 7-Dehydrocholesterol Reductase gene which results in impaired enzymatic conversion of 7-Dehydrocholesterol to cholesterol. In the current work, we sought to measure proteins that were altered in the cerebrospinal fluid from SLOS patients compared to pediatric controls. Using a multi-analyte antibody-based assay, we found that 12 proteins are altered in SLOS patients. Validation studies were carried out and the findings from this study suggest alterations in extracellular matrix remodeling and further evidence of oxidative stress within the disease pathophysiology. The results of this study will be used to explore biological pathways altered in SLOS and identifies a set of CSF proteins that can be evaluated as biomarkers in future therapeutic trials. © 2016 Wiley Periodicals, Inc.

  • Altered cerebrospinal fluid proteins in Smith–Lemli–Opitz syndrome patients
    American journal of medical genetics. Part A, 2016
    Co-Authors: Stephanie M Cologna, Christopher A. Wassif, Simona Bianconi, Christine Shieh, Cynthia L Toth, Antony Cougnoux, Kathryn R Burkert, Forbes D. Porter
    Abstract:

    Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation syndrome with neurocognitive impairment. SLOS arises from mutations in the 7-Dehydrocholesterol Reductase gene which results in impaired enzymatic conversion of 7-Dehydrocholesterol to cholesterol. In the current work, we sought to measure proteins that were altered in the cerebrospinal fluid from SLOS patients compared to pediatric controls. Using a multi-analyte antibody-based assay, we found that 12 proteins are altered in SLOS patients. Validation studies were carried out and the findings from this study suggest alterations in extracellular matrix remodeling and further evidence of oxidative stress within the disease pathophysiology. The results of this study will be used to explore biological pathways altered in SLOS and identifies a set of CSF proteins that can be evaluated as biomarkers in future therapeutic trials. © 2016 Wiley Periodicals, Inc.

  • Discordant phenotype and sterol biochemistry in Smith-Lemli-Opitz syndrome.
    American journal of medical genetics. Part A, 2010
    Co-Authors: Grace Koo, Christopher A. Wassif, Sandra K Conley, Forbes D. Porter
    Abstract:

    Smith-Lemli-Opitz syndrome (SLOS) is a malformation syndrome resulting from mutations of the 7-Dehydrocholesterol Reductase (DHCR7) gene. During cholesterol biosynthesis, DHCR7 catalyzes the conversion of 7-Dehydrocholesterol (7DHC) to cholesterol. A clinical diagnosis of SLOS is confirmed biochemically by the presence of elevated levels of 7DHC. Phenotypic severity of SLOS has previously been shown to correlate with the 7DHC/cholesterol ratio. We describe a patient with a severe SLOS phenotype, but a very low serum 7DHC/cholesterol ratio. We show that this discordance is due to alternative splicing of a previously unreported IVS5+3 A>T mutation. This mutation results in the transcription of both normal and mutant mRNA transcripts. We postulate that alternative splicing of the IVS5+3 A>T results in insufficient DHCR7 activity during embryogenesis, but sufficient DHCR7 activity once cholesterol synthetic rates decrease postnatally. This unique case underscores the adjunctive use of fibroblast and molecular testing in ambiguous cases of SLOS and may provide insight into the potential efficacy of therapeutic interventions altering postnatal cholesterol biosynthesis.

Andrew J Brown – One of the best experts on this subject based on the ideXlab platform.

  • DHCR7: A vital enzyme switch between cholesterol and vitamin D production.
    Progress in lipid research, 2016
    Co-Authors: Anika V Prabhu, Laura J Sharpe, Winnie Luu, Andrew J Brown
    Abstract:

    The conversion of 7-Dehydrocholesterol to cholesterol, the final step of cholesterol synthesis in the Kandutsch-Russell pathway, is catalyzed by the enzyme 7-Dehydrocholesterol Reductase (DHCR7). Homozygous or compound heterozygous mutations in DHCR7 lead to the developmental disease Smith-Lemli-Opitz syndrome, which can also result in fetal mortality, highlighting the importance of this enzyme in human development and survival. Besides serving as a substrate for DHCR7, 7-Dehydrocholesterol is also a precursor of vitamin D via the action of ultraviolet light on the skin. Thus, DHCR7 exerts complex biological effects, involved in both cholesterol and vitamin D production. Indeed, we argue that DHCR7 can act as a switch between cholesterol and vitamin D synthesis. This review summarizes current knowledge about the critical enzyme DHCR7, highlighting recent findings regarding its structure, transcriptional and post-transcriptional regulation, and its links to vitamin D synthesis. Greater understanding about DHCR7 function, regulation and its place within cellular metabolism will provide important insights into its biological roles.

  • Phosphorylation regulates activity of 7-Dehydrocholesterol Reductase (DHCR7), a terminal enzyme of cholesterol synthesis.
    The Journal of steroid biochemistry and molecular biology, 2016
    Co-Authors: Anika V Prabhu, Laura J Sharpe, Winnie Luu, Andrew J Brown
    Abstract:

    Cholesterol is essential for survival, but too much or too little can cause disease. Thus, cholesterol levels must be kept within close margins. 7-Dehydrocholesterol Reductase (DHCR7) is a terminal enzyme of cholesterol synthesis, and is essential for embryonic development. Largely, DHCR7 research is associated with the developmental disease Smith-Lemli-Opitz syndrome, which is caused by mutations in the DHCR7 gene. However, little is known about what regulates DHCR7 activity. Here we provide evidence that phosphorylation plays a role in controlling DHCR7 activity, which may provide a means to divert flux from cholesterol synthesis to vitamin D production. DHCR7 activity was significantly decreased when we used pharmacological inhibitors against two important kinases, AMP-activated protein kinase and protein kinase A. Moreover, mutating a known phosphorylated residue, S14, also decreased DHCR7 activity. Thus, we demonstrate that phosphorylation modulates DHCR7 activity in cells, and contributes to the overall synthesis of cholesterol, and probably vitamin D.

  • Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis
    The Journal of biological chemistry, 2016
    Co-Authors: Anika V Prabhu, Laura J Sharpe, Winnie Luu, Andrew J Brown
    Abstract:

    Cholesterol is detrimental to human health in excess but is also essential for normal embryogenesis. Hence, enzymes involved in its synthesis possess many layers of regulation to achieve balanced cholesterol levels. 7-Dehydrocholesterol Reductase (DHCR7) is the terminal enzyme of cholesterol synthesis in the Kandutsch-Russell pathway, converting 7-Dehydrocholesterol (7DHC) to cholesterol. In the absence of functional DHCR7, accumulation of 7DHC and a lack of cholesterol production leads to the devastating developmental disorder, Smith-Lemli-Opitz syndrome. This study identifies that statin treatment can ameliorate the low DHCR7 expression seen with common Smith-Lemli-Opitz syndrome mutations. Furthermore, we show that wild-type DHCR7 is also relatively labile. In an example of end-product inhibition, cholesterol accelerates the proteasomal degradation of DHCR7, resulting in decreased protein levels and activity. The loss of enzymatic activity results in the accumulation of the substrate 7DHC, which leads to an increased production of vitamin D. Thus, these findings highlight DHCR7 as an important regulatory switch between cholesterol and vitamin D synthesis.

Young Ki Paik – One of the best experts on this subject based on the ideXlab platform.

  • Methylation of CpG islands in the rat 7-Dehydrocholesterol Reductase promoter suppresses transcriptional activation.
    Molecules and cells, 2005
    Co-Authors: Jai-hyun Kim, Eun-ha Hwang, Hye-jung Park, Young Ki Paik, Yhong-hee Shim
    Abstract:

    In mammals, 7-Dehydrocholesterol Reductase (Dhcr7) is the terminal enzyme in cholesterol biosynthesis. We previously reported that the Dhcr7 proximal promoter (-179 to +1), which contains CpG islands, is responsible for sterol-mediated expression of the rat gene. In the present study, we examined whether methylation of this region affects the transcriptional activity of the Dhcr7 gene. In vitro DNA methylation of the Dhcr7 promoter and luciferase-reporter assays showed that DNA methylation of the CpG islands suppressed transcription. Furthermore, treatment of the methylated Dhcr7 promoter with the demethylating agent, 5-aza-2′-deoxycytidine (5-Aza-CdR), reversed the suppression of promoter activity. These results indicate that methylation of the CpG islands is an important transcriptional regulatory mechanism in the Dhcr7 promoter.

  • A novel mutation of the human 7-Dehydrocholesterol Reductase gene reduces enzyme activity in patients with holoprosencephaly
    Biochemical and biophysical research communications, 2004
    Co-Authors: Yhong-hee Shim, Jai-hyun Kim, Soo-han Bae, Kyu-rae Kim, Chong Jai Kim, Young Ki Paik
    Abstract:

    Defects in cholesterol biosynthesis genes are recognized as a leading cause for holoprosencephaly (HPE). Previous reports suggest that mutations of human 7-Dehydrocholesterol Reductase (Dhcr7), which catalyzes the final step of cholesterol biosynthesis, may cause HPE [Clin. Genet. 53 (1998) 155]. To determine whether Dhcr7 mutations are involved in HPE pathogenesis, we analyzed the sequence of exon 9, which contains both a catalytic domain and a mutational hot spot. We examined 36 prematurely terminated fetuses with HPE at their gestation ages in the range from 21 to 33 weeks by single strand conformation polymorphism analysis and DNA sequencing. A novel missense mutation was identified: G344D. Dhcr7 enzyme assays using overexpressed recombinant mutant proteins revealed altered enzyme activity. Mutant G344D harbored less than 50% of enzyme activity compared with the control. Two previously reported mutations, R404C and G410S, abolished enzyme activity. These results suggest that mutation of the Dhcr7 gene is involved in HPE pathogenesis.

  • Structure and alternative splicing of the rat 7-Dehydrocholesterol Reductase gene.
    Biochimica et biophysica acta, 2002
    Co-Authors: Joon No Lee, Soo-han Bae, Young Ki Paik
    Abstract:

    The enzyme 7-Dehydrocholesterol Reductase (Dhcr7) catalyzes the reduction of 7-Dehydrocholesterol (DHC), the terminal reaction of the pathway of cholesterol biosynthesis. We report the isolation and characterization of the genomic DNA encoding rat Dhcr7 that contains nine exons and eight introns distributed over 15944 nucleotides (nts) and a consensus GT-AG at each exon/intron junction. Unexpectedly, we have found the occurrence of at least five isoforms of Dhcr7, designated as Dhcr7-AS (alternatively spliced)-1 (1474 nts), -2 (1595 nts), -3 (1602 nts), -4 (1723 nts) and -5 (1287 nts), which was believed to be caused by alternative usage of three 5′ noncoding exons. Furthermore, Dhcr7-AS-1 was found to be differentially expressed in six tissues examined while Dhcr7-AS-2 was expressed mainly in liver and brain. Interestingly, human Dhcr7 gene in HepG2 cells produced no detectable isoform while mouse Dhcr7 gene in L929 cells produced three isoforms, suggesting a difference in alternative splicing between species. Thus, regulation of Dhcr7 through the combined mechanisms of tissue-specific transcription and differential alternative splicing appears unique among enzymes characterized from the entire post-lanosterol pathway in cholesterol biosynthesis.