DOCSLIB.ORG

Peroxisomal D-Hydroxyacyl-Coa Dehydrogenase Deficiency: Resolution of the Enzyme Defect and Its Molecular Basis in Bifunctional Protein Deficiency

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Peroxisomal D-Hydroxyacyl-Coa Dehydrogenase Deficiency: Resolution of the Enzyme Defect and Its Molecular Basis in Bifunctional Protein Deficiency Proc. Natl. Acad. Sci. USA Vol. 95, pp. 2128–2133, March 1998 Biochemistry Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: Resolution of the enzyme defect and its molecular basis in bifunctional protein deficiency ELISABETH G. VAN GRUNSVEN*, EMANUEL VAN BERKEL*, LODEWIJK IJLST*, PETER VREKEN*, JOHANNIS B. C. DE KLERK†,JERZY ADAMSKI‡,HUGH LEMONDE§,PETER T. CLAYTON§,DEAN A. CUEBAS¶, \ AND RONALD J. A. WANDERS* ** *University of Amsterdam, Academic Medical Centre, Department of Clinical Chemistry, Laboratory of Genetic Metabolic Diseases, Amsterdam, The Netherlands; †Erasmus University, Sophia Children’s Hospital, Department of Paediatrics, Rotterdam, The Netherlands; ‡GSF-Forzungszentrum, Institut fu¨r Sa¨ugetiergenetik,Neuherberg, D-85764 Oberschleissheim, Germany; §Institute of Child Health, University of London, London WC1N 1EH, United Kingdom; \ ¶Southwest Missouri State University, Department of Chemistry, Springfield, MO 65804; and University of Amsterdam, Academic Medical Centre, Department of Paediatrics, Emma Children’s Hospital, Amsterdam, The Netherlands Edited by Christian de Duve, International Institute of Cellular and Molecular, Brussels, Belgium, and approved December 2, 1997 (received for review September 3, 1997) ABSTRACT Peroxisomes play an essential role in a num- the b-oxidation of fatty acids, the a-oxidation of phytanic acid, ber of different metabolic pathways, including the b-oxidation the synthesis of cholesterol and other isoprenoids, the detox- of a distinct set of fatty acids and fatty acid derivatives. The ification of glyoxylate, and the synthesis of docosahexaenoic importance of the peroxisomal b-oxidation system in humans acid (3, 4). is made apparent by the existence of a group of inherited One of the most important functions of peroxisomes is the diseases in which peroxisomal b-oxidation is impaired. This b-oxidation of fatty acids and fatty acid derivatives (4, 5). Fatty includes X-linked adrenoleukodystrophy and other disorders acid oxidation in peroxisomes differs from that in mitochon- with a defined defect. On the other hand, many patients have dria in many respects, although the overall b-oxidative mech- been described with a defect in peroxisomal b-oxidation of anisms are the same. In both organelles, fatty acid oxidation unknown etiology. Resolution of the defects in these patients proceeds via a sequence of four steps involving a,b- requires the elucidation of the enzymatic organization of the dehydrogenation, hydration, 3-hydroxyacyl-CoA dehydroge- peroxisomal b-oxidation system. Importantly, a new peroxi- nation, and, finally, thiolytic cleavage. An important difference somal b-oxidation enzyme was recently described called D- is that the two b-oxidation systems display different substrate bifunctional protein with enoyl-CoA hydratase and 3-hy- specificities. Indeed, the major dietary fatty acids including droxyacyl-CoA dehydrogenase activity primarily reacting with palmitate, oleate, and linoleate are oxidized in mitochondria, a-methyl fatty acids like pristanic acid and di- and trihy- whereas peroxisomes are involved in the b-oxidation of a range droxycholestanoic acid. In this patient we describe the first of minor fatty acids including very-long-chain fatty acids case of D-bifunctional protein deficiency as resolved by enzyme (notably C26:0), and 2-methyl branched-chain fatty acids like activity measurements and mutation analysis. The mutation pristanic acid. Furthermore, peroxisomes are the sole site of found (Gly16Ser) is in the dehydrogenase coding part of the di- and trihydroxycholestanoic acid (DHC and THC) b-oxi- gene in an important loop of the Rossman fold forming the dation. b-Oxidation of the latter two cholestanoic acids results 1 NAD -binding site. The results show that the newly identified in the formation of the primary bile acids chenodeoxycholic D-bifunctional protein plays an essential role in the peroxi- acid and cholic acid, respectively (4, 5). somal b-oxidation pathway that cannot be compensated for by Several peroxisomal disorders have been described in which the L-specific bifunctional protein. peroxisomal fatty acid b-oxidation is defective. These include X-linked adrenoleukodystrophy (6), the most common perox- Although peroxisomes were initially believed to play only a isomal disorder, as well as pseudo-neonatal adrenoleukodys- minor role in mammalian metabolism, it is now clear that they trophy due to straight-chain acyl-CoA oxidase deficiency (7), catalyze essential reactions in a number of different metabolic L-bifunctional protein deficiency (8), and pseudo-Zellweger pathways and thus play an indispensable role in intermediary syndrome due to a deficiency of 41-kDa peroxisomal thiolase metabolism. (9, 10). Apart from these disorders with a defined defect in The importance of peroxisomes in humans is made apparent peroxisomal b-oxidation, many patients have been described by the existence of a group of inherited diseases, the peroxi- with a defect in peroxisomal b-oxidation of unknown etiology somal disorders, caused by an impairment in one or more (see references 52–59 in ref. 1). peroxisomal functions. The cerebro-hepato-renal (Zellweger) One of the major reasons for the difficulty in resolving the syndrome is generally considered to be the prototype of this underlying defect in these patients has been our insufficient group of diseases. Patients with this disease lack morpholog- knowledge about the functional organization of the peroxiso- ically distinguishable peroxisomes leading to the loss of virtu- mal b-oxidation system. Recent studies, however, have shed ally all peroxisomal functions. Clinically, patients with Zell- new light on the enzymology of the peroxisomal system. weger syndrome show a large variety of severe abnormalities Indeed, it is now clear that multiple enzymes are present for often leading to early death (1, 2). each of the b-oxidation steps. The existence of multiple The metabolic pathways in which peroxisomes are involved acyl-CoA oxidases had already been established (see ref. 4 for include the biosynthesis of ether phospholipids and bile acids, This paper was submitted directly (Track II) to the Proceedings office. The publication costs of this article were defrayed in part by page charge Abbreviations: DHC, dihydroxycholestanoic acid; THC, trihydroxy- cholestanoic acid. payment. This article must therefore be hereby marked ‘‘advertisement’’ in **To whom reprint requests and correspondence should be addressed accordance with 18 U.S.C. §1734 solely to indicate this fact. at: University of Amsterdam, Academic Medical Centre, Depart- © 1998 by The National Academy of Sciences 0027-8424y98y952128-6$2.00y0 ment of Clinical Chemistry (Room F0-226), Meibergdreef 9, 1105 PNAS is available online at http:yywww.pnas.org. AZ, Amsterdam, The Netherlands. 2128 Downloaded by guest on September 30, 2021 Biochemistry: van Grunsven et al. Proc. Natl. Acad. Sci. USA 95 (1998) 2129 review). Recently, however, a new peroxisomal b-oxidation acid b-oxidation, DHAPAT-activity, catalase immunofluores- enzyme was discovered containing both enoyl-CoA hydratase cence, and very-long-chain fatty acids were measured as and 3-hydroxyacyl-CoA dehydrogenase activity (11–15), which described before (19). was first identified as a 17b-estradiol dehydrogenase (16, 17). Measurement of the Enoyl-CoA Hydratase and 3-Hydroxy- Structural analysis of this protein has revealed three functional acyl-CoA Dehydrogenase Components of D-Bifunctional Pro- domains. The N-terminal part (amino acids 1–323) contains tein. The combined activity of the enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activity, whereas the 3-hydroxyacyl-CoA dehydrogenase components of the D- central part (amino acids 324–596) harbors the 2-enoyl-CoA bifunctional protein were measured in a medium of the hydratase activity. The C-terminal part (amino acids 597–737) following composition: 50 mM TriszHCl (pH 8.5), 1 mM shows strong homology with sterol carrier protein and cata- NAD1, 150 mM KCl, 0.1 mM (24E)-3a,7a,12a-trihydroxy-5b- lyzes the in vitro transfer of 7-dehydrocholesterol and phos- cholest-24-enoyl-CoA (24-ene-THC-CoA; prepared as de- phatidylcholine between membranes (11). scribed in ref. 21), 5 mM pyruvate, and 18 unitsyml lactate In contrast to the well known L-bifunctional protein (18) that dehydrogenase. Reactions were allowed to proceed for 60 min converts trans-enoyl-CoA thioesters to their 3-keto forms via at 37°C by using a protein concentration of 150 mgyml. the L-hydroxy-stereoisomer, this new bifunctional enzyme Reactions were terminated by addition of 2 M HCl to a final catalyzes these same transformations via D-hydroxyacyl-CoAs, concentration of 0.18 M followed by neutralization to a pH of which has prompted Hashimoto and coworkers (14, 15) to about 5.0 by using 0.6 M Mes plus 2 M KOH. Resolution of the name it D-bifunctional enzyme. different CoA-esters was achieved essentially as described by An important finding is that the two bifunctional proteins the method of Xu and Cuebas (21). have different substrate specificities. The D-bifunctional pro- RNA Isolation and cDNA Synthesis. Total RNA was isolated tein catalyzes the formation of 3-ketoacyl-CoA intermediates either from cultured skin fibroblasts (stored at 280°C) or from from both straight-chain and 2-methyl-branched-chain fatty freshly prepared lymphocytes by using the acid guanidinium acids, whereas the L-specific bifunctional protein is incapable thiocyanate-phenol-chloroform extraction
Load more

Recommended publications
  • Shorthand Notation for Lipid Structures Derived from Mass Spectrometry
    special report Shorthand notation for lipid structures derived from mass spectrometry Gerhard Liebisch , 1, * Juan Antonio Vizcaíno , † Harald Köfeler , ** Martin Trötzmüller , ** William J. Griffi ths , †† Gerd Schmitz , * Friedrich Spener , § , ** and Michael J. O. Wakelam *** Institute of Clinical Chemistry and Laboratory Medicine,* University of Regensburg , Regensburg, Germany ; EMBL-European Bioinformatics Institute , † Hinxton, Cambridge, United Kingdom ; Institute of Molecular Biology and Biochemistry, § and Core Facility Mass Spectrometry,** Medical University of Graz , Graz, Austria ; Institute of Mass Spectrometry, †† College of Medicine, Swansea University , Singleton Park, Swansea, United Kingdom ; and Babraham Institute ,*** Babraham Research Campus, Cambridge, United Kingdom Abstract There is a need for a standardized, practical an- Nomenclature Committee (ILCNC) in 2005 (1 ) and up- notation for structures of lipid species derived from mass dated in 2009 (2 ). This system places lipids into eight cat- spectrometric approaches; i.e., for high-throughput data egories and is available online on the LIPID MAPS website obtained from instruments operating in either high- or low- (http://www.lipidmaps.org). The LIPID MAPS nomencla- Downloaded from resolution modes. This proposal is based on common, ture precisely describes lipid structures. offi cially accepted terms and builds upon the LIPID MAPS terminology. It aims to add defi ned levels of information The key technology for lipid species analysis is mass spec- below the LIPID MAPS nomenclature, as detailed chemical trometry (MS) ( 3, 4 ). Typically, MS analysis without inter- structures, including stereochemistry, are usually not auto- mediate chemical steps does not provide the structural matically provided by mass spectrometric analysis. To this details covered by the LIPID MAPS nomenclature, which www.jlr.org end, rules for lipid species annotation were developed that led mass spectrometrists to use a variety of different nota- refl ect the structural information derived from the analysis.
    [Show full text]
  • Newborn Screening for X-Linked Adrenoleukodystrophy: Information for Parents
    Newborn Screening for X-linked Adrenoleukodystrophy: Information for Parents Baby girl with ABCD1 gene mutation What is newborn screening? the symptoms of ALD during childhood. Rarely, some women who are carriers of ALD develop mild symptoms as adults. It Newborn screening involves laboratory testing on a small is important for your family to meet with a genetic counselor sample of blood collected from newborns’ heels. Every state to talk about the genetics of ALD and implications for other has a newborn screening program to identify infants with rare family members. disorders, which would not usually be detected at birth. Early diagnosis and treatment of these disorders often prevents Why do only boys have ALD? serious complications. Only boys have ALD because it is caused by a mutation in What is adrenoleukodystrophy (ALD)? a gene (ABCD1) on the X chromosome, called “X-linked inheritance.” Males only have one X chromosome so they have ALD is one of over 40 disorders included in newborn screening one ABCD1 gene. Males with a nonfunctioning ABCD1 gene in New York State. It is a rare genetic disorder. People with have ALD. Females have 2 X chromosomes, so they have two ALD are unable to breakdown a component of food called ABCD1 genes. Females with one ABCD1 gene mutation will very long chain fatty acids (VLCFA). If VLCFA are not broken be carriers. When a mother is a carrier of ALD, each son has a down, they build up in the body and cause symptoms. 50% chance of inheriting the disorder and each daughter has a 50% chance of being a carrier.
    [Show full text]
  • Peroxisome Biogenesis Disorders ⁎ Steven J
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1763 (2006) 1733–1748 www.elsevier.com/locate/bbamcr Review Peroxisome biogenesis disorders ⁎ Steven J. Steinberg a,b, , Gabriele Dodt c, Gerald V. Raymond a,b, Nancy E. Braverman d, Ann B. Moser a,b, Hugo W. Moser a,b a Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA b Kennedy Krieger Institute, Baltimore, MD, USA c Interfakultäres Institut für Biochemie, Eberhard Karls Universität, Tübingen, Germany d Department of Pediatrics and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Received 25 May 2006; received in revised form 5 September 2006; accepted 6 September 2006 Available online 14 September 2006 Abstract Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the peroxisome biogenesis disorders (PBD). PBD are divided into two types—Zellweger syndrome spectrum (ZSS) and rhizomelic chondrodysplasia punctata (RCDP). Biochemical studies performed in blood and urine are used to screen for the PBD. DNA testing is possible for all of the disorders, but is more challenging for the ZSS since 12 PEX genes are known to be associated with this spectrum of PBD. In contrast, PBD-RCDP is associated with defects in the PEX7 gene alone. Studies of the cellular and molecular defects in PBD patients have contributed significantly to our understanding of the role of each PEX gene in peroxisome assembly. © 2006 Elsevier B.V.
    [Show full text]
  • Inositol Triphosphate-Triggered Calcium Release Blocks Lipid Exchange at Endoplasmic Reticulum- Golgi Contact Sites
    ARTICLE https://doi.org/10.1038/s41467-021-22882-x OPEN Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum- Golgi contact sites Mouhannad Malek 1, Anna M. Wawrzyniak 1, Peter Koch1, Christian Lüchtenborg2, Manuel Hessenberger1, ✉ Timo Sachsenheimer2, Wonyul Jang 1, Britta Brügger 2 & Volker Haucke 1,3 fi 1234567890():,; Vesicular traf c and membrane contact sites between organelles enable the exchange of proteins, lipids, and metabolites. Recruitment of tethers to contact sites between the endo- plasmic reticulum (ER) and the plasma membrane is often triggered by calcium. Here we reveal a function for calcium in the repression of cholesterol export at membrane contact sites between the ER and the Golgi complex. We show that calcium efflux from ER stores induced by inositol-triphosphate [IP3] accumulation upon loss of the inositol 5-phosphatase INPP5A or receptor signaling triggers depletion of cholesterol and associated Gb3 from the cell surface, resulting in a blockade of clathrin-independent endocytosis (CIE) of Shiga toxin. This phenotype is caused by the calcium-induced dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing membrane contact sites. Our findings reveal a crucial function for INPP5A-mediated IP3 hydrolysis in the control of lipid exchange at membrane contact sites. 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany. 2 Heidelberg University Biochemistry Center (BZH), Heidelberg ✉ University, Heidelberg, Germany. 3 Faculty of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany. email: [email protected] NATURE COMMUNICATIONS | (2021) 12:2673 | https://doi.org/10.1038/s41467-021-22882-x | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-22882-x ellular membrane homeostasis and the exchange of Results material between compartments can occur by vesicular INPP5A is required for Gb3-mediated Shiga toxin cell entry.
    [Show full text]
  • Functions of Plasmalogen Lipids in Health and Disease☆
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1822 (2012) 1442–1452 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis Review Functions of plasmalogen lipids in health and disease☆ Nancy E. Braverman a,⁎, Ann B. Moser b a Department of Human Genetics and Pediatrics, McGill University-Montreal Childrens Hospital Research Institute, 4060 Ste-Catherine West, PT-406.2, Montreal, QC, Canada H3Z 2Z3 b Department of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins Hospital, Baltimore, MD, USA article info abstract Article history: Plasmalogens are a unique class of membrane glycerophospholipids containing a fatty alcohol with a vinyl- Received 30 January 2012 ether bond at the sn-1 position, and enriched in polyunsaturated fatty acids at the sn-2 position of the Received in revised form 21 April 2012 glycerol backbone. These two features provide novel properties to these compounds. Although plasmalogens Accepted 9 May 2012 represent up to 20% of the total phospholipid mass in humans their physiological roles have been challenging Available online 22 May 2012 to identify, and are likely to be particular to different tissues, metabolic processes and developmental stages. Their biosynthesis starts in peroxisomes, and defects at these steps cause the malformation syndrome, Keywords: Plasmalogen Rhizomelic Chondrodysplasia Punctata (RCDP). The RCDP phenotype predicts developmental roles for Rhizomelic Chondrodysplasia Punctata plasmalogens in bone, brain, lens, lung, kidney and heart. Recent studies have revealed secondary plasmalogen Alzheimer disease deficiencies associated with more common disorders and allow us to tease out additional pathways dependent Respiratory disease on plasmalogen functions.
    [Show full text]
  • Peroxisomal Disorders and Their Mouse Models Point to Essential Roles of Peroxisomes for Retinal Integrity
    International Journal of Molecular Sciences Review Peroxisomal Disorders and Their Mouse Models Point to Essential Roles of Peroxisomes for Retinal Integrity Yannick Das, Daniëlle Swinkels and Myriam Baes * Lab of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; [email protected] (Y.D.); [email protected] (D.S.) * Correspondence: [email protected] Abstract: Peroxisomes are multifunctional organelles, well known for their role in cellular lipid homeostasis. Their importance is highlighted by the life-threatening diseases caused by peroxisomal dysfunction. Importantly, most patients suffering from peroxisomal biogenesis disorders, even those with a milder disease course, present with a number of ocular symptoms, including retinopathy. Patients with a selective defect in either peroxisomal α- or β-oxidation or ether lipid synthesis also suffer from vision problems. In this review, we thoroughly discuss the ophthalmological pathology in peroxisomal disorder patients and, where possible, the corresponding animal models, with a special emphasis on the retina. In addition, we attempt to link the observed retinal phenotype to the underlying biochemical alterations. It appears that the retinal pathology is highly variable and the lack of histopathological descriptions in patients hampers the translation of the findings in the mouse models. Furthermore, it becomes clear that there are still large gaps in the current knowledge on the contribution of the different metabolic disturbances to the retinopathy, but branched chain fatty acid accumulation and impaired retinal PUFA homeostasis are likely important factors. Citation: Das, Y.; Swinkels, D.; Baes, Keywords: peroxisome; Zellweger; metabolism; fatty acid; retina M. Peroxisomal Disorders and Their Mouse Models Point to Essential Roles of Peroxisomes for Retinal Integrity.
    [Show full text]
  • Lipid Class and Phospholipid Species Composition Associated with Life History Variation In
    Lipid class and phospholipid species composition associated with life history variation in north temperate and neotropical birds DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Elisabeth Ann Calhoon Graduate Program in Evolution, Ecology and Organismal Biology The Ohio State University 2016 Dissertation Committee: Professor Joseph B. Williams, Advisor Professor David L. Stetson Professor David L. Denlinger Copyright by Elisabeth Ann Calhoon 2016 Abstract Life-history traits are often linked, generating a spectrum where organisms that have long lifespans usually have low metabolic rates and low reproductive effort, whereas organisms with short lifespans usually have high metabolic rates and high reproductive effort. Physiological mechanisms likely underlie these variations in life history. As such, a recent focus in the field of physiological ecology has been connecting life-history traits to physiological attributes. An emerging study system for research on these connections is tropical and temperate bird species. Temperate bird species tend have low annual survival, high metabolic rates, and high reproductive effort, whereas tropical birds tend to have high annual survival, low metabolic rates, and low reproductive effort. Also emerging as a tool in physiological ecology, primary cell culture allows researchers to take samples from individuals in minimally invasive ways and compare cells grown under the same environmental and nutritive conditions. In this dissertation, I first ascertained what kinds of differences there are between cultured fibroblast cells and their progenitor cells extracted from individual organisms. Fibroblasts are likely to change in culture due to differences in the environment around them and because the cells switch from a mostly quiescent state to an actively proliferating state.
    [Show full text]
  • Functional Characterization of Novel Mutations in GNPAT and AGPS, Causing Rhizomelic Chondrodysplasia Punctata (RCDP) Types 2 and 3
    RESEARCH ARTICLE OFFICIAL JOURNAL Functional Characterization of Novel Mutations in GNPAT and AGPS, Causing Rhizomelic Chondrodysplasia Punctata www.hgvs.org (RCDP) Types 2 and 3 Brandon Itzkovitz,1† Sarn Jiralerspong,1† Graeme Nimmo,1 Melissa Loscalzo,2 Dafne D. G. Horovitz,3 Ann Snowden,4 Ann Moser,4 Steve Steinberg,4,5 and Nancy Braverman1,6∗ 1Montreal Children’s Hospital Research Institute, Montreal, Quebec, Canada; 2Division of Genetics, Department of Pediatrics, University of South Florida, Tampa, Florida; 3Centro de Genetica Medica, Instituto Fernandes Figueira—FIOCRUZ, Rio de Janeiro, Brazil; 4Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland; 5Department of Neurology, Johns Hopkins University, Baltimore, Maryland; 6Department of Human Genetics and Pediatrics, McGill University, Montreal, Quebec, Canada Communicated by Iain McIntosh Received 12 May 2011; accepted revised manuscript 13 September 2011. Published online 3 October 2011 in Wiley Online Library (www.wiley.com/humanmutation).DOI: 10.1002/humu.21623 Introduction ABSTRACT: Rhizomelic chondrodysplasia punctata Rhizomelic chondrodysplasia punctata (RCDP) is a rare disorder (RCDP) is a disorder of peroxisome metabolism result- of ether phospholipid, or plasmalogen, biosynthesis. Patients are ing from a deficiency of plasmalogens, a specialized class suspected clinically by proximal shortening of long bones or rhi- of membrane phospholipids. Classically, patients have a zomelia, bilateral congenital cataracts, dysmorphic facial features, skeletal dysplasia and profound mental retardation, al- and severe growth and developmental delays. Skeletal x-rays show though milder phenotypes are increasingly being iden- punctate epiphyseal calcifications, metaphyseal dysplasia, and ver- tified. It is commonly caused by defects in the peroxi- tebral coronal clefts. Various abnormalities on brain magnetic reso- some transporter, PEX7 (RCDP1), and less frequently nance imaging (MRI) were reported [Bams-Mengerink et al., 2006].
    [Show full text]
  • X Linked Adrenoleukodystrophy: Clinical Presentation, Diagnosis, and Therapy
    4 Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:4–14 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from REVIEW X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy Björn M van Geel, Johanna Assies, RonaldJAWanders, Peter G Barth Abstract that has its onset in adulthood, was first X linked adrenoleukodystrophy (X-ALD) reported in 1976.4 Now, at least six diVerent is an inherited disorder of peroxisomal phenotypes are recognised.5 Not only men are metabolism, biochemically characterised aVected: in the early 1980s it was shown that by accumulation of saturated very long female carriers are at risk for developing chain fatty acids. Accumulation of these neurological deficits as well.6 fatty acids is associated with cerebral In 1976 the accumulation of saturated very demyelination, peripheral nerve abnor- long chain fatty acids (VLCFAs) in brain lipids malities, and adrenocortical and testicu- and adrenal cortex of patients with X-ALD was lar insuYciency. The lowest estimated reported.78 In 1980 raised concentrations of birth incidence is one per 100 000. At least VLCFAs were shown in cultured skin 9 10 six phenotypes can be distinguished, of fibroblasts and in 1981 in plasma, thus Department of which the two most frequent are child- providing a reliable biochemical diagnostic Neurology, Academic hood cerebral ALD and adrenomyelo- test. In 1984 a defect in peroxisomal metabo- Medical Center, 11 neuropathy. The X-ALD gene has been lism was suggested, and shortly thereafter the University of defective enzyme activity in peroxisomal Amsterdam, PO Box identified, but thus far no relation between â-oxidation of VLCFAs was discovered.12 13 In 22700, 1100 DE genotype and phenotype has been found.
    [Show full text]
  • Amplification of Glyceronephosphate O-Acyltransferase and Recruitment of USP30 Stabilize DRP1 to Promote Hepatocarcinogenesis
    Author Manuscript Published OnlineFirst on August 24, 2018; DOI: 10.1158/0008-5472.CAN-18-0340 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Amplification of glyceronephosphate O-acyltransferase and recruitment of USP30 stabilize DRP1 to promote hepatocarcinogenesis Li Gu #, 1, 2, Yahui Zhu #, 1, 2, Xi Lin 1, 2, Yajun Li 1, 2, Kasa Cui 1, 2, Edward V. Prochownik 3, Youjun Li 1, 2,* 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China 2 Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China 3Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, The Department of Microbiology and Molecular Genetics and The Hillman Cancer Center of UPMC The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224, USA #These authors contributed equally. Running title: GNPAT and USP30-mediated DRP1 stabilization in HCC. *Correspondence to: Youjun Li, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China; Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China. Tel.: (86-27) 6875-2050; Fax: (86-27) 6875-2560; E-mail: [email protected] Conflict of interest: The authors declare no conflicts of interest. Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 24, 2018; DOI: 10.1158/0008-5472.CAN-18-0340
    [Show full text]
  • Change in Brain Plasmalogen Composition by Exposure to Prenatal Undernutrition Leads to Behavioral Impairment of Rats
    Research Articles: Behavioral/Cognitive Change in brain plasmalogen composition by exposure to prenatal undernutrition leads to behavioral impairment of rats https://doi.org/10.1523/JNEUROSCI.2721-18.2019 Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.2721-18.2019 Received: 21 October 2018 Revised: 28 July 2019 Accepted: 31 July 2019 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2019 the authors 1 Change in brain plasmalogen composition by exposure to prenatal 2 undernutrition leads to behavioral impairment of rats 3 4 Abbreviated title: Ethanolamine plasmalogen and behavior 5 6 Kodai Hino1, Shunya Kaneko1, Toshiya Harasawa1, Tomoko Kimura1, Shiro Takei2, 7 Masakazu Shinohara3,4, Fumiyoshi Yamazaki5, Shin-ya Morita6, Shumpei Sato5, 8 Yoshihito Kubo1, Tadaaki Kono1, Mitsutoshi Setou5,7,8, Mina Yoshioka1, Junya Fujino1, 9 Hiroyuki Sugihara9, Hideto Kojima10, Naoto Yamada11, Jun Udagawa1 10 11 1Division of Anatomy and Cell Biology, Department of Anatomy, Shiga University of 12 Medical Science, Otsu 520-2192, Japan 13 2Department of Environmental Biology, College of Bioscience and Biotechnology, 14 Chubu University, Kasugai, 487-8501, Japan 15 3Division of Epidemiology, Kobe University Graduate School
    [Show full text]
  • Inherited Peroxisomal Disorders Involving the Nervous System
    Arch Dis Child: first published as 10.1136/adc.63.7.767 on 1 July 1988. Downloaded from Archives of Disease in Childhood, i988, 63, 767-770 Annotations Inherited peroxisomal disorders involving the nervous system For genetic reasons peroxisomes may be absent or defective. Because of the great importance of the lack one or more of their enzymes. The result may peroxisomal enzymes involved in the I oxidation of be subtle and long delayed, but is often catastrophic VLCFA and the use of measurements of VLCFA in and immediately recognisable as a serious disorder diagnosis, this group is itself subdivided. Group 3A at birth. The trouble for the clinician is that it is includes those conditions in which VLCFA oxidation often not possible to make a diagnosis unless the is impaired and thus VLCFA accumulates, and right tests are thought of: these tests are not part of group 3B those in which the single enzyme defect is routine 'metabolic screens.' It is first necessary to of another sort. frame the question 'could this be a peroxisomopathy?' The object of this annotation is to help with when GENERALISED PEROXISOMAL DISORDERS (GROUP 1) and how to answer this question. The now classical example is the cerebro-hepato- renal syndrome of Zellweger. l 2The typical neonate Peroxisomes is more dysmorphic than a baby with Down's syndrome with high forehead and huge fontanelle Peroxisomes are subcellular organelles with a single with metopic extension. Inactivity is even greater membrane which occur in every cell apart from the than in the Prader-Willi syndrome and hypotonia mature erythrocyte.
    [Show full text]