DOCSLIB.ORG

And Mevalonate Kinase Deficiency Linda Henneman Uitnod Lind

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
And Mevalonate Kinase Deficiency Linda Henneman Uitnod Lind UvA-DARE (Digital Academic Repository) Isoprenoid biosynthesis and mevalonate kinase deficiency Henneman, L. Publication date 2011 Document Version Final published version Link to publication Citation for published version (APA): Henneman, L. (2011). Isoprenoid biosynthesis and mevalonate kinase deficiency. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:28 Sep 2021 Isoprenoid Biosynthesis and Mevalonate Kinase Deficiency Isoprenoid O Uitnodiging - O P O - P O O - O O Isoprenoid Biosynthesis voor het bijwonen van de openbare verdediging and van het proefschrift van HO Mevalonate Kinase Deficiency Linda Henneman N N FeII HN N N O HN N N O - N N O N P N O HO - O O P O - N H H O N O O HO H H OH O OH H OH O O H H O O H H OH H O O - H O P O O - H H P O O HO O P O - O O O O - O P O O P op woensdag 5 oktober 2011 - O - O - O Linda Henneman om 14.00 uur in de Agnietenkapel HN O P O - O Oudezijds Voorburgwal 231 N - N HO Amsterdam N N HO O H H Receptie ter plaatse N N H H OH H FeII na afloop van de promotie N N H O H H Paranimfen: HO Merel Ebberink 06-18411478 O H OH OH O Judith Henneman 06-55118408 H O 2011 H H HO Linda Henneman Isoprenoid Biosynthesis and Mevalonate Kinase Deficiency Author Linda Henneman Cover Image End products of isoprenoid biosynthesis with GGPP in red GGPP becomes limiting in MKD Printed by Gildeprint drukkerijen, Enschede, The Netherlands ISBN 978-94-6108-209-1 Isoprenoid Biosynthesis and Mevalonate Kinase Deficiency Academisch proefschrift ter verkrijging van de graad van doctor aan d­­e Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op woensdag 5 oktober 2011, te 14:00 uur door Linda Henneman geboren te Alkmaar Promotiecommissie Promotor: Prof. dr. R.J.A. Wanders Co-promotor: Dr. H.R. Waterham Overige leden: Prof. dr. R.A.W. van Lier Prof. dr. C.J.F. van Noorden Prof. dr. A.J. Verhoeven Prof. dr. F.A. Wijburg Dr. F.M. Vaz Dr. J. Frenkel Faculteit der Geneeskunde The work described in this thesis was carried out at the laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, The Netherlands. The Research was financially supported by a grant of ZonMW, grant number 912-03-024. TABLe oF CoNTeNTS Abbreviations 6 Chapter 1 General introduction 9 Chapter 2 Detection of nonsterol isoprenoids by HPLC–MS/MS 31 Analytical Biochemistry (2008) 383: 18-24 Chapter 3 Inhibition of the isoprenoid biosynthesis pathway; 47 detection of intermediates by UPLC–MS/MS Biochimica et Biophysica Acta (2011) 1811: 227-233 Chapter 4 Compromised geranylgeranylation of RhoA and Rac1 in 61 mevalonate kinase deficiency Journal of Inherited Metabolic Disease (2010) 33: 625-632 Chapter 5 Fever induces ectopic activation of small GTPases in the 75 autoinflammatory disorder mevalonate kinase deficiency In preparation for submission Chapter 6 Generation and characterization of two mouse models for 89 mevalonate kinase deficiency General discussion and summary 107 Samenvatting voor iedereen 113 Dankwoord 119 ABBreviatioNS AGP a1-glycoprotein DMAPP dimethylallyl pyrophosphate DMEM Dulbecco’s Modified Eagles medium DMSO dimethylsulfoxide ER endoplasmic reticulum ES embryonic stem FCS fetal calf serum FMF familial Mediterranean fever FMVA 6-fluoromevalonate FPP farnesyl pyrophosphate FPPS farnesyl pyrophosphate synthase FTase farnesyltransferase FTI farnesyltransferase inhibitor GAP GTPase activating protein GDI guanine nucleotide dissociation inhibitor GEF guanine nucleotide exchange factor GGOH geranylgeraniol GGPP geranylgeranyl pyrophosphate GGTase geranylgeranyltransferase GGTI geranylgeranyltransferase inhibitor GPP geranyl pyrophosphate GST-PAK glutathione S-transferase p21-activated Ser/Thr kinase GST-RBD glutathione S-transferase Ras-binding domain HEPES 4-2-hydroxyethyl-1-piperazineethanesulfonic acid HIDS hyper-IgD and periodic fever syndrome HMG-CoA 3-hydroxy-3-methylglutaryl-CoA HPLC-MS/MS high performance liquid chromatography-tandem mass spectrometry IFN interferon IgD immunoglobulin D IL interleukin IPP isopentenyl pyrophosphate IPPI isopentenyl pyrophosphate isomerase IS internal standard LDL low density lipoprotein LOD limit of detection LOQ limit of quantification LPS lipopolysaccharide MA mevalonic aciduria MBP maltose-binding protein MDP muramyldipeptide MK mevalonate kinase MKD mevalonate kinase deficiency MPD mevalonate pyrophosphate decarboxylase MRM multiple reaction monitoring MVA mevalonate MVAL mevalonolactone MVAP 5-phosphomevalonate MVAPP 5-pyrophosphomevalonate MVK gene encoding MK PAGE polyacrylamide gel electrophoresis PAM pamidronate PBMC peripheral blood mononuclear cell PBS phosphate buffered saline PMK phosphomevalonate kinase SAA serum amyloid A SCAP SREBP cleavage-activating protein SDS sodium dodecyl sulfate SRE sterol regulatory element SREBP sterol regulatory element binding protein TNF tumor necrosis factor TRAPS TNF-receptor associated periodic syndrome UPLC-MS/MS ultra performance liquid chromatography-tandem mass spectrometry ZAA zaragozic acid A ZOL zoledronate Chapter 1 O O P P O O O- O- O- General introduction Chapter 1 ISoPreNoID BIoSyNTHeSIS pathwAy Introduction The isoprenoid biosynthesis pathway plays an important role in cellular metabolism. 1 It provides the cell with sterol and nonsterol isoprenoids which are incorporated into diverse classes of end products that participate in processes relating to cell growth, differentiation, glycosylation, isoprenylation and various signal transduction pathways [1;2]. Cholesterol is the major sterol end product of the pathway and is not only an important structural component of cellular membranes and myelin, but is also the precursor of oxysterols, steroid hormones and bile acids. Furthermore, cholesterol plays a crucial role in human embryogenesis and development [3]. In addition to the synthesis of sterol compounds, the isoprenoid biosynthesis pathway produces a variety of nonsterol isoprenoids. These include, among others: 1) ubiquinone-10 and the side chains of heme A, which are both involved in electron transport in the mitochondrial respiratory chain; 2) dolichol, a mediator of N-linked protein glycosylation; 3) isopentenyl tRNAs, involved in protein translation; 4) farnesyl and geranylgeranyl moieties, used for the prenylation of cellular proteins, which in most cases makes them membrane associated. Many isoprenylated proteins participate in important cellular functions, such as signal transduction, cell cycle control, cytoskeletal organization, intracellular vesicle traffic and inflammation [1;2]. Pathway intermediates and enzymes The first part of the isoprenoid biosynthesis pathway is also known as the mevalonate pathway and consists of a series of reactions in which acetyl-CoA is converted into farnesyl pyrophosphate (FPP) (Figure 1). The pathway starts with two acetyl-CoAs, which are converted into acetoacetyl-CoA by the enzyme acetoacetyl-CoA thiolase. 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) is then formed through the addition of a third acetyl-CoA by HMG-CoA synthase. The reduction of HMG-CoA is catalyzed by the rate-limiting enzyme of the pathway, HMG-CoA reductase, and yields mevalonate. Subsequently, mevalonate is phosphorylated twice, first by mevalonate kinase (MK) followed by phosphomevalonate kinase, which produces 5-phosphomevalonate and 5-pyrophosphomevalonate, respectively. Decarboxylation of this latter compound by mevalonate pyrophosphate decarboxylase yields isopentenyl pyrophosphate (IPP). This basic C5 isoprene unit is used for the synthesis of all isoprenoid end products including some tRNAs in which IPP is added to adenosine. After isomerization of IPP to dimethylallyl pyrophosphate (DMAPP) by the enzyme isopentenyl pyrophosphate isomerase, a head- to-tail condensation of IPP to DMAPP by farnesyl pyrophosphate synthase results in the formation of geranyl pyrophosphate (GPP). The same enzyme then adds another IPP to GPP, which forms FPP [1;4]. At the level of FPP, the pathway branches off into a sterol and nonsterol part of the isoprenoid biosynthesis pathway. The conversion of two FPP molecules into squalene is the first reaction exclusively committed to the synthesis of sterol end products. This reaction is catalyzed by squalene synthase and is followed by the condensation of squalene into lanosterol. To eventually generate C27 cholesterol from lanosterol, a series of at least 8 different enzyme reactions is required (Figure 2). This complex set of enzyme reactions include one methylation at C14 and two demethylations
Load more

Recommended publications
  • A Defective Response to Hedgehog Signaling in Disorders of Cholesterol Biosynthesis
    letter A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis Michael K. Cooper1,2,5, Christopher A. Wassif3, Patrycja A. Krakowiak3, Jussi Taipale1, Ruoyu Gong1, Richard I. Kelley4, Forbes D. Porter3 & Philip A. Beachy1 Published online 24 March 2003; doi:10.1038/ng1134 Smith–Lemli–Opitz syndrome (SLOS), desmosterolosis and lath- additional role for cholesterol in Hh signal response was sug- osterolosis are human syndromes caused by defects in the final gested by the observation that cyclopamine and jervine, terato- stages of cholesterol biosynthesis. Many of the developmental genic plant alkaloids that block Hh signaling, also inhibit malformations in these syndromes occur in tissues and struc- cholesterol transport and synthesis2,3. But cyclopamine has since tures whose embryonic patterning depends on signaling by the been shown to specifically inhibit Hh signaling by binding to a Hedgehog (Hh) family of secreted proteins. Here we report that pathway component4, and the doses of these alkaloids required response to the Hh signal is compromised in mutant cells from to inhibit Hh signaling are lower than those required to block mouse models of SLOS and lathosterolosis and in normal cells cholesterol transport (ref. 5 and M.K.C., unpublished data). pharmacologically depleted of sterols. We show that decreas- To determine how cholesterol may affect Hh signaling in embry- ing levels of cellular sterols correlate with diminishing respon- onic development, we exposed chick embryos to cyclodextrin, a http://www.nature.com/naturegenetics siveness to the Hh signal. This diminished response occurs at cyclic oligosaccharide that forms non-covalent complexes with sterol levels sufficient for normal autoprocessing of Hh protein, sterols6 and can be used to extract and deplete cholesterol from liv- which requires cholesterol as cofactor and covalent adduct.
    [Show full text]
  • Table S1. Disease Classification and Disease-Reaction Association
    Table S1. Disease classification and disease-reaction association Disorder class Associated reactions cross Disease Ref[Goh check et al.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2010/0210567 A1 Bevec (43) Pub
    US 2010O2.10567A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0210567 A1 Bevec (43) Pub. Date: Aug. 19, 2010 (54) USE OF ATUFTSINASATHERAPEUTIC Publication Classification AGENT (51) Int. Cl. A638/07 (2006.01) (76) Inventor: Dorian Bevec, Germering (DE) C07K 5/103 (2006.01) A6IP35/00 (2006.01) Correspondence Address: A6IPL/I6 (2006.01) WINSTEAD PC A6IP3L/20 (2006.01) i. 2O1 US (52) U.S. Cl. ........................................... 514/18: 530/330 9 (US) (57) ABSTRACT (21) Appl. No.: 12/677,311 The present invention is directed to the use of the peptide compound Thr-Lys-Pro-Arg-OH as a therapeutic agent for (22) PCT Filed: Sep. 9, 2008 the prophylaxis and/or treatment of cancer, autoimmune dis eases, fibrotic diseases, inflammatory diseases, neurodegen (86). PCT No.: PCT/EP2008/007470 erative diseases, infectious diseases, lung diseases, heart and vascular diseases and metabolic diseases. Moreover the S371 (c)(1), present invention relates to pharmaceutical compositions (2), (4) Date: Mar. 10, 2010 preferably inform of a lyophilisate or liquid buffersolution or artificial mother milk formulation or mother milk substitute (30) Foreign Application Priority Data containing the peptide Thr-Lys-Pro-Arg-OH optionally together with at least one pharmaceutically acceptable car Sep. 11, 2007 (EP) .................................. O7017754.8 rier, cryoprotectant, lyoprotectant, excipient and/or diluent. US 2010/0210567 A1 Aug. 19, 2010 USE OF ATUFTSNASATHERAPEUTIC ment of Hepatitis BVirus infection, diseases caused by Hepa AGENT titis B Virus infection, acute hepatitis, chronic hepatitis, full minant liver failure, liver cirrhosis, cancer associated with Hepatitis B Virus infection. 0001. The present invention is directed to the use of the Cancer, Tumors, Proliferative Diseases, Malignancies and peptide compound Thr-Lys-Pro-Arg-OH (Tuftsin) as a thera their Metastases peutic agent for the prophylaxis and/or treatment of cancer, 0008.
    [Show full text]
  • Steroidal Triterpenes of Cholesterol Synthesis
    Molecules 2013, 18, 4002-4017; doi:10.3390/molecules18044002 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Steroidal Triterpenes of Cholesterol Synthesis Jure Ačimovič and Damjana Rozman * Centre for Functional Genomics and Bio-Chips, Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Zaloška 4, Ljubljana SI-1000, Slovenia; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +386-1-543-7591; Fax: +386-1-543-7588. Received: 18 February 2013; in revised form: 19 March 2013 / Accepted: 27 March 2013 / Published: 4 April 2013 Abstract: Cholesterol synthesis is a ubiquitous and housekeeping metabolic pathway that leads to cholesterol, an essential structural component of mammalian cell membranes, required for proper membrane permeability and fluidity. The last part of the pathway involves steroidal triterpenes with cholestane ring structures. It starts by conversion of acyclic squalene into lanosterol, the first sterol intermediate of the pathway, followed by production of 20 structurally very similar steroidal triterpene molecules in over 11 complex enzyme reactions. Due to the structural similarities of sterol intermediates and the broad substrate specificity of the enzymes involved (especially sterol-Δ24-reductase; DHCR24) the exact sequence of the reactions between lanosterol and cholesterol remains undefined. This article reviews all hitherto known structures of post-squalene steroidal triterpenes of cholesterol synthesis, their biological roles and the enzymes responsible for their synthesis. Furthermore, it summarises kinetic parameters of enzymes (Vmax and Km) and sterol intermediate concentrations from various tissues. Due to the complexity of the post-squalene cholesterol synthesis pathway, future studies will require a comprehensive meta-analysis of the pathway to elucidate the exact reaction sequence in different tissues, physiological or disease conditions.
    [Show full text]
  • GC-MS As a Tool for Reliable Non-Invasive Prenatal Diagnosis of Smith-Lemli-Opitz Syndrome but Essential Also for Other Cholesterolopathies Verification
    Ginekologia Polska 2020, vol. 91, no. 5, 287–293 Copyright © 2020 Via Medica REVIEW PAPER / OBSTETRICS ISSN 0017–0011 DOI: 10.5603/GP.2020.0049 GC-MS as a tool for reliable non-invasive prenatal diagnosis of Smith-Lemli-Opitz syndrome but essential also for other cholesterolopathies verification Aleksandra Jezela-Stanek1 , Anna Siejka2 , Ewa M. Kowalska2 , Violetta Hosiawa3 , Malgorzata Krajewska-Walasek1,4 1Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland 2Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children’s Memorial Health Institute, Warsaw, Poland 3Department of Gynecologic Oncology, Jagiellonian University Medical College, Cracow, Poland 4Department of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland ABSTRACT Rare multiple congenital malformations/developmental disorders are challenging in clinical diagnosis. The introduction of next-generation sequencing (NGS) has revolutionized this diagnostic by offering multigene panels or whole-exome sequencing. However, if there is no possibility to perform NGS or if we are facing prenatal ultrasound results, clinical diag- nostics is even more difficult. For a selected group of congenital metabolic disorders, resulting from defects in cholesterol biosynthesis (called cholesterolopathies), application of gas chromatography-mass spectrometry (GS-MS) may provide or orientate diagnostics. The most common of these is Smith-Lemli-Opitz syndrome (SLOS), but in this publication, we also want to introduce other cholesterolopathies and draw attention to the possibility of non-invasive prenatal diagnosis of SLOS. Key words: prenatal diagnosis; GC-MS; prenatal ultrasound; Smith-Lemli-Opitz; cholesterol biosynthesis Ginekologia Polska 2020; 91, 5: 287–293 INTRODUCTION skin, as well as in the central nervous system [1].
    [Show full text]
  • Smith–Lemli–Opitz Syndrome: Pathogenesis, Diagnosis and Management
    European Journal of Human Genetics (2008) 16, 535–541 & 2008 Nature Publishing Group All rights reserved 1018-4813/08 $30.00 www.nature.com/ejhg PRACTICAL GENETICS In association with Smith–Lemli–Opitz syndrome: pathogenesis, diagnosis and management Smith–Lemli–Opitz syndrome (SLOS) is a malformation syndrome due to a deficiency of 7-dehydrocholesterol reductase (DHCR7). DHCR7 primarily catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. In SLOS, this results in decreased cholesterol and increased 7DHC levels, both during embryonic development and after birth. The malformations found in SLOS may result from decreased cholesterol, increased 7DHC or a combination of these two factors. This review discusses the clinical aspects and diagnosis of SLOS, therapeutic interventions and the current understanding of pathophysiological processes involved in SLOS. In brief 5. A clinical diagnosis of SLOS is confirmed by finding elevated 7DHC in blood or tissues. A normal choles- 1. Smith–Lemli–Opitz syndrome (SLOS) is an autosomal terol level does not exclude SLOS. recessive, multiple malformation syndrome due to an 6. The incidence of SLOS is on the order of 1/20 000–1/ inborn error of cholesterol synthesis. 70 000. SLOS is more common in individuals of 2. The SLOS phenotypic spectrum is very broad, ranging European heritage. Carrier frequencies of specific from a mild disorder with behavioral and learning mutations vary widely depending on ethnic back- problems to a lethal malformation syndrome. ground, and for Caucasians, they are in the 1–2% 3. Syndactyly of the second and third toes is the most range. common physical finding in SLOS patients.
    [Show full text]
  • Download CGT Exome V2.0
    CGT Exome version 2.
    [Show full text]
  • WES Gene Package Multiple Congenital Anomalie.Xlsx
    Whole Exome Sequencing Gene package Multiple congenital anomalie, version 7, 18‐2‐2019 Technical information DNA was enriched using Agilent SureSelect Clinical Research Exome V2 capture and paired‐end sequenced on the Illumina platform (outsourced). The aim is to obtain 8.1 Giga base pairs per exome with a mapped fraction of 0.99. The average coverage of the exome is ~50x. Duplicate reads are excluded. Data are demultiplexed with bcl2fastq Conversion Software from Illumina. Reads are mapped to the genome using the BWA‐MEM algorithm (reference: http://bio‐bwa.sourceforge.net/). Variant detection is performed by the Genome Analysis Toolkit HaplotypeCaller (reference: http://www.broadinstitute.org/gatk/). The detected variants are filtered and annotated with Cartagenia software and classified with Alamut Visual. It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all types of sequence changes). HGNC approved Phenotype description including OMIM phenotype ID(s) OMIM median depth % covered % covered % covered gene symbol gene ID >10x >20x >30x A4GALT [Blood group, P1Pk system, P(2) phenotype], 111400[Blood group, P1Pk system, p phenotype], 111400NOR po 607922 141 100 100 99 AAAS Achalasia‐addisonianism‐alacrimia syndrome, 231550 605378 88 100 100 100 AAGAB Keratoderma, palmoplantar, punctate type IA, 148600
    [Show full text]
  • Smith-Lemli-Opitz Syndrome
    NLM Citation: Nowaczyk MJM, Wassif CA. Smith-Lemli-Opitz Syndrome. 1998 Nov 13 [Updated 2020 Jan 30]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/ Smith-Lemli-Opitz Syndrome Synonym: SLOS Malgorzata JM Nowaczyk, MD, MFA, FRCPC, FCCMG, FACMG1 and Christopher A Wassif, PhD2 Created: November 13, 1998; Updated: January 30, 2020. Summary Clinical characteristics Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple-anomaly / cognitive impairment syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol (7- DHC) reductase. It is characterized by prenatal and postnatal growth restriction, microcephaly, moderate-to- severe intellectual disability, and multiple major and minor malformations. The malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. The clinical spectrum is wide; individuals with normal development and only minor malformations have been described. Diagnosis/testing The diagnosis of SLOS is established in a proband with suggestive clinical features and elevated 7- dehydrocholesterol level and/or by identification of biallelic pathogenic variants in DHCR7 by molecular genetic testing. Although serum concentration of cholesterol is usually low, it may be in the normal range in approximately 10% of affected individuals, making it an unreliable test for screening and diagnosis. Management Treatment of manifestations: While no long-term dietary studies on cholesterol supplementation have been conducted in a randomized fashion, cholesterol supplementation may result in clinical improvement. Early intervention and physical/occupational/speech therapies are indicated for identified disabilities.
    [Show full text]
  • Mutations in the Human SC4MOL Gene Encoding a Methyl Sterol Oxidase Cause Psoriasiform Dermatitis, Microcephaly, and Developmental Delay
    Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay Miao He, … , Michael E. Zwick, Jerry Vockley J Clin Invest. 2011;121(3):976-984. https://doi.org/10.1172/JCI42650. Research Article Development Defects in cholesterol synthesis result in a wide variety of symptoms, from neonatal lethality to the relatively mild dysmorphic features and developmental delay found in individuals with Smith-Lemli-Opitz syndrome. We report here the identification of mutations in sterol-C4-methyl oxidase–like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay. This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4- methylsterols in the cholesterol synthesis pathway. C4-Methylsterols are meiosis-activating sterols (MASs). They exist at high concentrations in the testis and ovary and play roles in meiosis activation. In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood. SMO deficiency also substantially altered immunocyte phenotype and in vitro function. MASs serve as ligands for liver X receptors α and β (LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity. Deficiency of SMO represents a biochemical defect in the cholesterol synthesis pathway, the clinical spectrum of which remains to be defined. Find the latest version: https://jci.me/42650/pdf Research article Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay Miao He,1,2 Lisa E.
    [Show full text]
  • 30 Inborn Errors of Cholesterol Biosynthesis Dorothea Haas, Richard I
    30 Inborn Errors of Cholesterol Biosynthesis Dorothea Haas, Richard I. Kelley 30.1 Introduction Defects of cholesterol biosynthesis comprise a heterogeneous group of disor- ders, most of which have only recently been described. With the exception of cholesterol supplementation in Smith-Lemli-Opitz syndrome, no therapeutic regimens have yet been proven effective. Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) are due to defects in mevalonate kinase, an enzyme located proximally in the pathway of cholesterol biosynthesis. Patients affected with these disorders present with recurrent febrile attacks and, in the case of classic MVA,often have malformations, neurological symptoms, and psychomotor retardation (Hoff- mann et al. 1993). Long-term administration of coenzyme Q10 together with vitamin C and E to treat an intrinsic deficiency in the synthesis of coenzyme Q10 and to treat a possible increased sensitivity to reactive oxygen species seems to stabilize the clinical course and improve somatic and psychomotor development (Haas et al. 2001; Prietsch et al. 2003). Dietary supplementation of cholesterol may reduce frequency and severity of febrile attacks in some mildly affected patients, but has further compromised more severely affected patients, similar to the apparent adverse effect of lovastatin in some patients (Hoffmann et al. 1993). In two patients (siblings) followed closely, intervention with corticosteroids was highly beneficial during clinical crises, with resolution ofthecriseswithin24h. The severity of attacks can also be reduced with the leukotriene receptor inhibitors montelukast and zafirlukast (R. I. Kelley, unpub- lished observations). Despite the apparent adverse effect of lovastatin in classic MVA, a recently completed study has shown a beneficial effect of simvastatin in HIDS (Simon et al.
    [Show full text]
  • REVIEW Neuroprotective Effects of the Alzheimer's Disease-Related Gene Seladin-1
    251 REVIEW Neuroprotective effects of the Alzheimer’s disease-related gene seladin-1 Alessandro Peri and Mario Serio Endocrine Unit, Department of Clinical Physiopathology, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy (Correspondence should be addressed to A Peri; Email: [email protected]fi.it) Abstract The endocrine and the nervous system are closely correlated throughout life, starting from the embryo and until the late stages of life. Alzheimer’s disease (AD) is the most common neurodegenerative disease associated with ageing. Unfortunately, an effective way to prevent or to cure this disease does not exist, so far. There is evidence that estrogens exert neuroprotective properties, although their efficacy against AD is still a matter of debate. In 2000 a new neuroprotective gene, i.e. seladin-1 (for SELective AD INdicator-1) was identified and found to be down regulated in AD vulnerable brain regions. Seladin-1 inhibits the activation of caspase-3, a key modulator of apoptosis. This protein has also enzymatic activity. In fact, it has been demonstrated that the seladin-1 gene encodes 3-b-hydroxysterol D-24-reductase, which catalyzes the synthesis of cholesterol from desmosterol. In recent years, it has been demonstrated that an appropriate amount of membrane cholesterol determines the generation of a barrier against toxic insults and prevents the production of b-amyloid, the histopathological hallmark of AD. This review will summarize the studies that have been focused on the characterization of the biological properties of seladin-1 since its first identification.
    [Show full text]