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3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome.

Unit on Molecular Dysmorphology, Heritable Disorders Branch, Department of Health and Human Services, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Molecular Genetics and Metabolism (Impact Factor: 2.83). 03/2005; 84(2):112-26. DOI: 10.1016/j.ymgme.2004.09.017
Source: PubMed

ABSTRACT In the final step of cholesterol synthesis, 7-dehydrocholesterol reductase (DHCR7) reduces the double bond at C7-8 of 7-dehydrocholesterol to yield cholesterol. Mutations of DHCR7 cause Smith-Lemli-Opitz syndrome (SLOS). Over 100 different mutations of DHCR7 have been identified in SLOS patients. SLOS is a classical multiple malformation, mental retardation syndrome, and was the first human malformation syndrome shown to result from an inborn error of cholesterol synthesis. This paper reviews the biochemical, molecular, and mutational aspects of DHCR7.

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    ABSTRACT: Smith–Lemli–Opitz Syndrome (SLOS) is a congenital, autosomal recessive metabolic and developmental disorder caused by mutations in the enzyme which catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. Herein we show that dermal fibroblasts obtained from SLOS children display increased basal levels of LC3B-II, the hallmark protein signifying increased autophagy. The elevated LC3B-II is accompanied by increased beclin-1 and cellular autophagosome content. We also show that the LC3B-II concentration in SLOS cells is directly proportional to the cellular concentration of 7DHC, suggesting that the increased autophagy is caused by 7DHC accumulation secondary to defective DHCR7. Further, the increased basal LC3B-II levels were decreased significantly by pretreating the cells with antioxidants implicating a role for oxidative stress in elevating autophagy in SLOS cells. Considering the possible source of oxidative stress, we examined mitochondrial function in the SLOS cells using JC-1 assay and found significant mitochondrial dysfunction compared to mitochondria in control cells. In addition, the levels of PINK1 which targets dysfunctional mitochondria for removal by the autophagic pathway are elevated in SLOS cells, consistent with mitochondrial dysfunction as a stimulant of mitophagy in SLOS. This suggests that the increase in autophagic activity may be protective, i.e., to remove dysfunctional mitochondria. Taken together, these studies are consistent with a role for mitochondrial dysfunction leading to increased autophagy in SLOS pathophysiology.
    01/2014; 1:431–442. DOI:10.1016/j.ymgmr.2014.09.005
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    ABSTRACT: Smith-Lemli-Opitz Syndrome (SLOS) is a malformation syndrome inherited in an autosomal recessive fashion. It is due to a metabolic defect in the conversion of 7-dehydrocholesterol to cholesterol, which leads to an accumulation of 7-dehydrocholesterol and frequently a deficiency of cholesterol. The syndrome is characterized by typical dysmorphic facial features, multiple malformations, and intellectual disability. In this paper we provide an overview of the clinical phenotype and discuss how the manifestations of the syndrome vary depending on the age of the patients. We then explore the underlying biochemical defect and pathophysiological alterations that may contribute to the many disease manifestations. Subsequently we explore the epidemiology and succinctly discuss population genetics as they relate to SLOS. The next section presents the diagnostic possibilities. Thereafter, the treatment and management as is standard of care are presented. Even though the knowledge of the underlying molecular mutations and the biochemical alterations is being rapidly accumulated, there is currently no efficacious therapy addressing neurological dysfunction. We discuss the difficulty of treating this disorder, which manifests as a combination of a malformation syndrome and an inborn error of metabolism. A very important factor in developing new therapies is the need to rigorously establish efficacy in controlled trials.
    02/2015; 3(3). DOI:10.1517/21678707.2015.1014472
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    ABSTRACT: The enzyme 7-dehydrocholesterol reductase (DHCR7) catalyzes the final step of cholesterol synthesis via the Kandutsch-Russell pathway, and is crucial in maintaining cellular cholesterol levels. Its absence leads to the devastating fetal developmental disorder Smith-Lemli-Optiz Syndrome (SLOS). How this enzyme is regulated has implications in not only controlling cholesterol synthesis, but also the synthesis of Vitamin D - another product of 7-dehydrocholesterol. In this study, we look specifically at how DHCR7 is regulated by the sterol regulatory element binding protein-2 (SREBP-2) transcription factor. Sterol regulation has previously been studied in the rat DHCR7 promoter, but we have found that its regulatory elements are not all conserved in humans. Rather, the human promoter contains two binding sites for SREBP-2 (at -155 and -55) and a binding site for the nuclear factor-Y (NF-Y) cofactor (at -136). The -155 site is a particularly responsive sterol regulatory element (SRE) which is well conserved in mammals, and was possibly overlooked in the rat promoter study. The exact location of the weaker -55 site (close to the known rat SRE) may have shifted during evolution. Furthermore, we established that the two SREs that bind SREBP-2 work in cooperation to synergistically activate DHCR7. We have previously characterized the SREs in DHCR24, the final enzyme in the alternate Bloch pathway of cholesterol synthesis. Here, comparison of the sterol regulation of these terminal enzymes demonstrates the unique cooperative system that helps to control cholesterol synthesis.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 07/2014; 1841(10). DOI:10.1016/j.bbalip.2014.07.006 · 4.50 Impact Factor

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