Phd Thesis Tjaard Pijning
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Hemoglobin Variants: Biochemical Properties and Clinical Correlates
Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Hemoglobin Variants: Biochemical Properties and Clinical Correlates Christopher S. Thom1,2, Claire F. Dickson3, David A. Gell3, and Mitchell J. Weiss2 1Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 2Hematology Department, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 3Menzies Research Institute, University of Tasmania, Hobart, Australia Correspondence: [email protected] Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochem- ical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on he- moglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochem- istry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples. lobin gene mutations affecting hemoglobin stitutions, antitermination mutations, and al- G(Hb), the major blood oxygen (O2) carrier, tered posttranslational processing (Table 1). are common, affecting an estimated 7% of the Naturally occurring Hb mutations cause a world’s population (Weatherall and Clegg 2001; range of biochemical abnormalities, some of Kohne 2011). These mutations are broadly sub- which produce clinically significant symptoms. -
Hemoglobinopathies: Clinical & Hematologic Features And
Hemoglobinopathies: Clinical & Hematologic Features and Molecular Basis Abdullah Kutlar, MD Professor of Medicine Director, Sickle Cell Center Georgia Health Sciences University Types of Normal Human Hemoglobins ADULT FETAL Hb A ( 2 2) 96-98% 15-20% Hb A2 ( 2 2) 2.5-3.5% undetectable Hb F ( 2 2) < 1.0% 80-85% Embryonic Hbs: Hb Gower-1 ( 2 2) Hb Gower-2 ( 2 2) Hb Portland-1( 2 2) Hemoglobinopathies . Qualitative – Hb Variants (missense mutations) Hb S, C, E, others . Quantitative – Thalassemias Decrease or absence of production of one or more globin chains Functional Properties of Hemoglobin Variants . Increased O2 affinity . Decreased O2 affinity . Unstable variants . Methemoglobinemia Clinical Outcomes of Substitutions at Particular Sites on the Hb Molecule . On the surface: Sickle Hb . Near the Heme Pocket: Hemolytic anemia (Heinz bodies) Methemoglobinemia (cyanosis) . Interchain contacts: 1 1 contact: unstable Hbs 1 2 contact: High O2 affinity: erythrocytosis Low O2 affinity: anemia Clinically Significant Hb Variants . Altered physical/chemical properties: Hb S (deoxyhemoglobin S polymerization): sickle syndromes Hb C (crystallization): hemolytic anemia; microcytosis . Unstable Hb Variants: Congenital Heinz body hemolytic anemia (N=141) . Variants with altered Oxygen affinity High affinity variants: erythrocytosis (N=93) Low affinity variants: anemia, cyanosis (N=65) . M-Hemoglobins Methemoglobinemia, cyanosis (N=9) . Variants causing a thalassemic phenotype (N=51) -thalassemia Hb Lepore ( ) fusion Aberrant RNA processing (Hb E, Hb Knossos, Hb Malay) Hyperunstable globins (Hb Geneva, Hb Westdale, etc.) -thalassemia Chain termination mutants (Hb Constant Spring) Hyperunstable variants (Hb Quong Sze) Modified and updated from Bunn & Forget: Hemoglobin: Molecular, Genetic, and Clinical Aspects. WB Saunders, 1986. -
Genetic Modifiers at the Crossroads of Personalised Medicine for Haemoglobinopathies
Journal of Clinical Medicine Article Genetic Modifiers at the Crossroads of Personalised Medicine for Haemoglobinopathies Coralea Stephanou, Stella Tamana , Anna Minaidou, Panayiota Papasavva, , , Marina Kleanthous * y and Petros Kountouris * y Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus; [email protected] (C.S.); [email protected] (S.T.); [email protected] (A.M.); [email protected] (P.P.) * Correspondence: [email protected] (M.K.); [email protected] (P.K.); Tel.:+357-2239-2652 (M.K.); +357-2239-2623 (P.K.) Equal contribution; Joint last authorship. y Received: 20 September 2019; Accepted: 5 November 2019; Published: 9 November 2019 Abstract: Haemoglobinopathies are common monogenic disorders with diverse clinical manifestations, partly attributed to the influence of modifier genes. Recent years have seen enormous growth in the amount of genetic data, instigating the need for ranking methods to identify candidate genes with strong modifying effects. Here, we present the first evidence-based gene ranking metric (IthaScore) for haemoglobinopathy-specific phenotypes by utilising curated data in the IthaGenes database. IthaScore successfully reflects current knowledge for well-established disease modifiers, while it can be dynamically updated with emerging evidence. Protein–protein interaction (PPI) network analysis and functional enrichment analysis were employed to identify new potential disease modifiers and to evaluate the biological profiles of selected phenotypes. The most relevant gene ontology (GO) and pathway gene annotations for (a) haemoglobin (Hb) F levels/Hb F response to hydroxyurea included urea cycle, arginine metabolism and vascular endothelial growth factor receptor (VEGFR) signalling, (b) response to iron chelators included xenobiotic metabolism and glucuronidation, and (c) stroke included cytokine signalling and inflammatory reactions. -
Pathological Conditions Involving Extracellular Hemoglobin
Pathological Conditions Involving Extracellular Hemoglobin: Molecular Mechanisms, Clinical Significance, and Novel Therapeutic Opportunities for alpha(1)-Microglobulin Gram, Magnus; Allhorn, Maria; Bülow, Leif; Hansson, Stefan; Ley, David; Olsson, Martin L; Schmidtchen, Artur; Åkerström, Bo Published in: Antioxidants & Redox Signaling DOI: 10.1089/ars.2011.4282 2012 Link to publication Citation for published version (APA): Gram, M., Allhorn, M., Bülow, L., Hansson, S., Ley, D., Olsson, M. L., Schmidtchen, A., & Åkerström, B. (2012). Pathological Conditions Involving Extracellular Hemoglobin: Molecular Mechanisms, Clinical Significance, and Novel Therapeutic Opportunities for alpha(1)-Microglobulin. Antioxidants & Redox Signaling, 17(5), 813-846. https://doi.org/10.1089/ars.2011.4282 Total number of authors: 8 General rights Unless other specific re-use rights are stated the following general rights apply: Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Read more about Creative commons licenses: https://creativecommons.org/licenses/ Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. -
The Crystal Structure of Novel Chondroitin Lyase ODV-E66, A
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 587 (2013) 3943–3948 journal homepage: www.FEBSLetters.org The crystal structure of novel chondroitin lyase ODV-E66, a baculovirus envelope protein ⇑ Yoshirou Kawaguchi a, Nobuo Sugiura b, Koji Kimata c, Makoto Kimura a,d, Yoshimitsu Kakuta a,d, a Laboratory of Structural Biology, Graduate School of System Life Sciences, Kyushu University, 6-10-1 Hakozaki, Fukuoka 812-8581, Japan b Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan c Research Complex for the Medicine Frontiers, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan d Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Fukuoka 812-8581, Japan article info abstract Article history: Chondroitin lyases have been known as pathogenic bacterial enzymes that degrade chondroitin. Received 5 August 2013 Recently, baculovirus envelope protein ODV-E66 was identified as the first reported viral chondroi- Revised 1 October 2013 tin lyase. ODV-E66 has low sequence identity with bacterial lyases at <12%, and unique characteris- Accepted 15 October 2013 tics reflecting the life cycle of baculovirus. To understand ODV-E66’s structural basis, the crystal Available online 26 October 2013 structure was determined and it was found that the structural fold resembled that of polysaccharide Edited by Christian Griesinger lyase 8 proteins and that the catalytic residues were also conserved. This structure enabled discus- sion of the unique substrate specificity and the stability of ODV-E66 as well as the host specificity of baculovirus. -
PEST RISK ANALYSIS for Platynota Stultana Walsingham, 1884
REINO DE ESPAÑA MINISTERIO DE AGRICULTURA, ALIMENTACION Y MEDIO AMBIENTE Dirección General de Sanidad de la Producción Agraria Subdirección General de Sanidad e Higiene Vegetal y Forestal PEST RISK ANALYSIS FOR Platynota stultana Walsingham, 1884 Source: University of California May 2016 Express Pest Risk Analysis for Platynota stultana May 2016 Express Pest Risk Analysis for Platynota stultana Walsingham, 1884 This PRA follows the EPPO Standard PM 5/5(1) Decision support Scheme for an Express Pest Risk Analysis Summary of the Express Pest Risk Analysis for: “Platynota stultana” PRA area: The European Union Describe the endangered area: The pest has the potential for establishment in greenhouses and other protected conditions in all the PRA area, but with low likelihood as far as current phytosanitary management measures against other Lepidoptera are applied. Outdoors likelihood of establishment is higher in the Mediterranean basin and Portugal. Main conclusions Overall assessment of risk: Likelihood of: Rating of risk Uncertainty Comments Consignments originating outside the European Union in countries where P.stultana occurs (México or the USA) High – For Plants for planting (cuttings, life plants and floriculture products, plants for planting not yet planted) with or without soil attached in consignments originating outside the European Union in countries where P.stultana occurs (México or the USA) Worst case: [Dianthus caryophyllus L. (carnation)] High – For fresh fruits of Grapes (the pest can be carried not only internally in fruit -
(12) United States Patent (10) Patent No.: US 7,569,386 B2 Deangelis (45) Date of Patent: Aug
US007569386B2 (12) United States Patent (10) Patent No.: US 7,569,386 B2 DeAngelis (45) Date of Patent: Aug. 4, 2009 (54) CHONDROITINSYNTHASE GENE AND Terminal Position of Chondroitin Sulfate’ Nakanishi et al. The Jour METHODS OF MAKING AND USING SAME nal of Biological Chemistry 1981, 256 (11) 5443-5449). “Differences in the Effects of pH on the Hydrolytic and (75) Inventor: Paul L. DeAngelis, Edmond, OK (US) Transgalactosylic Reactions of Beta-Galactosidase (Escherichia coli), Huber et al., Can. J. Biochem. Cell Biol. 61: 198-206 (1983). (73) Assignee: The Board of Regents of the University “Binding and Reactivity at the 'Glucose' Site of Galactosyl-Beta Galactosidase (Escherichia coli), Huber et al., Arch Biochem of Oklahoma, Norman, OK (US) Biophys. 234: 151-160 (1984). (*) Notice: Subject to any disclaimer, the term of this “Effect of Replacing Uridine 33 in Yeast tRNAPhe on the Reaction patent is extended or adjusted under 35 With Ribosomes”. Dix et al., J. Biol. Chem., 261(22): 101 12-8 (1986). U.S.C. 154(b) by 656 days. "Structure and Serological Characteristics of the Capsular K4 Anti gen of Escherichia coli O5:K4:H4, A Fructose-Containing Polysac (21) Appl. No.: 11/042,530 charide With a Chondroitin Backbone', Rodriguez et al., Eur, J. Biochem., 177:117-124 (1988). (22) Filed: Jan. 24, 2005 “The Carboxy-Terminal Domain of the LexA Repressor Oligomerises Essentially as the Entire Protein'. Schnarret al., FEBS (65) Prior Publication Data Lett. 234:56-60 (1988). US 2005/O164984 A1 Jul. 28, 2005 "A Cryptic Fimbrial Gene in Serratia Marcescens”. Moriya et al., J. -
Research Article Association Between HBA Locus Copy Number Gains And
INTERNATIONAL JOURNAL OF MEDICAL BIOCHEMISTRY DOI: 10.14744/ijmb.2021.65477 Int J Med Biochem 2021;4(2):91-6 Research Article Association between HBA locus copy number gains and pathogenic HBB gene variants Guven Toksoy1, Nergis Akay2, Agharza Aghayev1, Volkan Karaman1, Sahin Avci1, Tugba Kalayci1, Umut Altunoglu1, Zeynep Karakas2, Zehra Oya Uyguner1 1Department of Medical Genetics, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey 2Department of Pediatric Hematology-Oncology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey Abstract Objectives: Alpha (α) and beta (β) thalassemia are the most prevalent genetic hematological disorders. The co-occur- rence of silent β-thalassemia with excess α-globin gene copies is associated with the thalassemia intermedia pheno- type. This study was an investigation of the α-globulin gene dosage and sequence variations in thalassemia patients. Methods: Multiplex ligation-dependent probe amplification and Sanger sequencing were used to identify the hemo- globin subunit alpha 1 (HBA1) and HBA2 gene alterations in 32 patients. Deletion, duplication, and other findings were analyzed in the index cases and family members. Results: Four of the 32 cases (12.5%) were found to have gross duplications. Two cases demonstrated α-globin triplica- tion, and 2 had a quadruplicated HBA1/2 genes. Affected family members revealed genotype-phenotype correlation. In 1 patient, it was observed that quadruplicated HBA genes co-occurrence with hemoglobin subunit beta (HBB) mu- tation was inherited from his mother. Notably, the mother did not demonstrate any thalassemia phenotype. Further investigation showed that the mother was carrying a single copy HBA gene deletion in the trans allele that explained her clinical condition. -
(12) Patent Application Publication (10) Pub. No.: US 2003/0104601 A1 Deangelis (43) Pub
US 20030104601A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0104601 A1 DeAngelis (43) Pub. Date: Jun. 5, 2003 (54) CHONDROITINSYNTHASE GENE AND Publication Classification METHODS OF MAKING AND USING SAME (51) Int. Cl." ............................ C12P 21/02; C12N 1/21; (76) Inventor: Paul L. DeAngelis, Edmond, OK (US) C07H 21/04; CO8B 37/00; C12N 9/24; C12N 15/74; Correspondence Address: C12O 1/68 DUNLAP, CODDING & ROGERS PC. (52) U.S. Cl. ..................... 435/200; 435/69.1; 435/320.1; PO BOX 16370 435/252.3; 536/23.2; 536/54; OKLAHOMA CITY, OK 73114 (US) 435/6 (21) Appl. No.: 09/842,484 (57) ABSTRACT (22) Filed: Apr. 25, 2001 Related U.S. Application Data The present invention relates to a chondroitin Synthase gene and methods of making and using Same. In more particular, (63) Continuation-in-part of application No. 09/283,402, but not by way of limitation, the present invention relates to filed on Apr. 1, 1999, now abandoned, and which is a a chondroitin Synthase gene from Pasteurella multocida and continuation-in-part of application No. 09/437.277, methods of isolating and using Same. Additionally, the filed on Nov. 10, 1999, now Pat. No. 6,444447. present invention relates to the use of unsulfated chondroitin and its preparation, as well as conversion into modified (60) Provisional application No. 60/199,538, filed on Apr. versions Such as dermatan Sulfate and chondroitin Sulfate 25, 2000. polymers. Patent Application Publication Jun. 5, 2003. Sheet 5 of 10 US 2003/0104601 A1 Std CS V HAS 2. -
X-Ray Fluorescence Analysis Method Röntgenfluoreszenz-Analyseverfahren Procédé D’Analyse Par Rayons X Fluorescents
(19) & (11) EP 2 084 519 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: G01N 23/223 (2006.01) G01T 1/36 (2006.01) 01.08.2012 Bulletin 2012/31 C12Q 1/00 (2006.01) (21) Application number: 07874491.9 (86) International application number: PCT/US2007/021888 (22) Date of filing: 10.10.2007 (87) International publication number: WO 2008/127291 (23.10.2008 Gazette 2008/43) (54) X-RAY FLUORESCENCE ANALYSIS METHOD RÖNTGENFLUORESZENZ-ANALYSEVERFAHREN PROCÉDÉ D’ANALYSE PAR RAYONS X FLUORESCENTS (84) Designated Contracting States: • BURRELL, Anthony, K. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Los Alamos, NM 87544 (US) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR (74) Representative: Albrecht, Thomas Kraus & Weisert (30) Priority: 10.10.2006 US 850594 P Patent- und Rechtsanwälte Thomas-Wimmer-Ring 15 (43) Date of publication of application: 80539 München (DE) 05.08.2009 Bulletin 2009/32 (56) References cited: (60) Divisional application: JP-A- 2001 289 802 US-A1- 2003 027 129 12164870.3 US-A1- 2003 027 129 US-A1- 2004 004 183 US-A1- 2004 017 884 US-A1- 2004 017 884 (73) Proprietors: US-A1- 2004 093 526 US-A1- 2004 235 059 • Los Alamos National Security, LLC US-A1- 2004 235 059 US-A1- 2005 011 818 Los Alamos, NM 87545 (US) US-A1- 2005 011 818 US-B1- 6 329 209 • Caldera Pharmaceuticals, INC. US-B2- 6 719 147 Los Alamos, NM 87544 (US) • GOLDIN E M ET AL: "Quantitation of antibody (72) Inventors: binding to cell surface antigens by X-ray • BIRNBAUM, Eva, R. -
SVM and a Novel POOL Method Coupled with THEMATICS For
SVM and a Novel POOL Method Coupled with THEMATICS for Protein Active Site Prediction A DISSERTATION SUBMITTED TO THE COLLEGE OF COMPUTER AND INFORMATION SCIENCE OF NORTHEASTERN UNIVERSITY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY By Wenxu Tong April 2008 ©Wenxu Tong, 2008 ALL RIGHTS RESERVED Acknowledgements I have a lot of people to thank. I am mostly indebted to my advisor Dr. Ron Williams. He generously allowed me to work on a problem with the idea he developed decades ago and guided me through the research to turn it from just a mere idea into a useful system to solve important problems. Without his kindness, wisdom and persistence, there would be no this dissertation. Another person I am so fortunate to meet and work with is Dr. Mary Jo Ondrechen, my co-advisor. It was her who developed the THEMATICS method, which this dissertation works on. Her guidance and help during my research is critical for me. I am grateful to all the committee members for reading and commenting my dissertation. Especially, I am thankful to Dr. Jay Aslam, who provided a lot of advice for my research, and Dr. Bob Futrelle, who brought me into the field and provided much help in my writing of this dissertation. I also thank Dr. Budil for the time he spent serving as my committee member, especially during all the difficulties and inconvenience he happened to experience unfortunately during the time. I am so fortunate to work in the THEMATICS group with Dr. Leo Murga, Dr. -
The Normal Structure and Regulation of Human Globin Gene Clusters
CHAPTER 3 The Normal Structure and Regulation of Human Globin Gene Clusters Bernard G. Forget and Ross C. Hardison The genes encoding the different globin chains of hemoglobin are members of an ancient gene family. In this chapter we will review the structural features of the globin genes, with particular attention to the sequences needed for proper regulation of gene expression. Some of these have been well- conserved during mammalian evolution and therefore are likely to provide a common function in many mammals. Others are only found in higher primates, and may play roles in lineage-specific regulation. We will first describe the structural characteristics of the human globin genes and then provide a comparative analysis of the genomic contexts, regulatory regions and evolutionary conservation of features present in the globin gene clusters. NUMBER AND CHROMOSOMAL LOCALIZATION OF HUMAN GLOBIN GENES Hemoglobin is a heterotetramer that contains two polypeptide subunits related to the α-globin gene subfamily (referred to here as α-like globins) and two polypeptide subunits related to the β-globin gene subfamily (β-like globins). Globin polypeptides bind heme, which in turn allows the hemoglobin in erythrocytes to bind oxygen reversibly and transport it from the lungs to respiring tissues. In humans, as in all vertebrate species studied, different α-like and β-like globin chains are synthesized at Chapter 3 The Normal Structure and Regulation of the Globin Gene Clusters progressive stages of development to produce hemoglobins characteristic of primitive (embryonic) and definitive (fetal and adult) erythroid cells (Figure 3.1). Before precise knowledge of globin gene organization was gained by gene mapping and molecular cloning, a general picture of the number and arrangement of the human globin genes emerged from the genetic analysis of normal and abnormal hemoglobins and their pattern of inheritance.