DOCSLIB.ORG

Defective Protein Folding and Function in Metabolic Disorders

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Defective Protein Folding and Function in Metabolic Disorders DEFECTIVE PROTEIN FOLDING AND FUNCTION IN METABOLIC DISORDERS STUDIES ON THE MITOCHONDRIAL FLAVOENZYME ETF Bárbara Joana de Almeida Henriques Dissertation presented to obtain the PhD degree in Biochemistry at the Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa Supervisor Cláudio Emanuel Moreira Gomes Opponents Ronald J. A. Wanders & Carlos M. S. Farinha Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa Oeiras, October 2010 Second Edition, October 2010 ITQB - Protein Biochemistry Folding and Stability Laboratory Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa Av. da República (EAN), 2785-572 Oeiras, PORTUGAL http://www.itqb.unl.pt/pbfs ii FOREWORD This dissertation describes the work performed under the supervision of Prof. Cláudio M. Gomes, in the Protein Biochemistry Folding and Stability Laboratory, Instituto de Tecnologia Química e Biológica from October 2006 to June 2010. The studies here presented aim to contribute to a better understanding of human electron transfer flavoprotein (ETF) folding and stability, towards the elucidation of the molecular rationale of multiple acyl-CoA dehydrogenase deficiency (MADD). First, ETF disease causing missense mutations and the impact of three of those mutations on the protein folding and stability is overviewed. Subsequently, the role of flavinylation on a mutant variant resulting in a mild phenotype was addressed in order to gain a better understanding on the molecular rationale for riboflavin supplementation. Further, two polymorphic ETF variants were analyzed to explore their effects on the protein folding and function and to investigate possible implication in MADD. This thesis is organised in three parts. The first part is an introduction comprising two chapters: the first describing the state of knowledge on the protein folding problem and protein homeostasis, and the second presenting an overview on mitochondrial fatty acid β-oxidation (FAO) enzymes (particularly ETF) and on FAO associated disorders. In addition, a brief description on riboflavin as a therapeutic agent is also presented in the second chapter. The second part of the thesis is organized in three chapters describing the experimental results obtained. The third and last part consists of a general discussion integrating the described results. iii iv ACKNOWLEDGMENTS I would like to express my sincere gratitude to the following people without whom this work would not have been possible: My supervisor, Cláudio M. Gomes, for all the knowledge and dedication to the work developed in the lab. For his confidence in me and my work. And especially for his passion for science that always keep me motivated. Peter Bross, for receiving me at Aarhus University Hospital, and for scientific training in molecular biology techniques. I also thank him for all the enthusiastic scientific discussions. Rikke Olsen, from Aarhus University Hospital for her helpful discussions. Niels Gregersen and the entire group at Aarhus University Hospital for making my visit there a very pleasant journey. Mark Fisher, from the University of Kansas Medical Center (US), for sharing immobilized GroEL beads, and for his useful discussions. My present and past colleagues at the Protein Biochemistry, Folding and Stability Laboratory, for their precious support in the lab, helpful discussions, and amazing work environment. Hugo Botelho, for being so helpful, and especially for his patience and friendship. João Rodrigues, for his work in ETF and for all brainstorming, especially the ones on Kds. v Raquel Correia, for her friendship, and all the helpful discussion and advices on my work. It is fantastic to share science with you. Sonia Leal, for the support given during these 6 years, and all the good times we shared. Ana Paula for always having 5 minutes to listen to me, for her interest in science and for all the laughs in the difficult moments. All my friends that in someway helped me during these 4 years, especially to Sofia, Patricia, Vera, and Lígia, for always being there and for sharing with me the ups and downs of being a PhD student. My family for the support and love. Lipe, for his love, encouragement and for all the support given during this long walk. I could not have done this without you, thanks! This thesis is dedicated to a wonderful woman, my grandmother Maria, without whom I would not be the person I am today. Fundação para a Ciência e Tecnologia is acknowledged for financial support, by awarding a PhD Grant SFRH/BD/29200/2006 This wok has been funded through a research grant PTDC/SAU- GMG/70033/2006 to Cláudio M. Gomes. vi THESIS PUBLICATIONS 1. Henriques, B. J., Rodrigues, J. V., Olsen, R. K., Bross, P., Gomes C. M. "Role of flavinylation in a mild variant of multiple acyl-CoA dehydrogenation deficiency: A molecular rationale for the effects of riboflavin supplementation" J. Biol. Chem. 2009, 284 (7): 4222-4229 2. Henriques, B. J., Bross, P., Gomes C. M. "Mutational hotspots in electron transfer flavoprotein underlie defective folding and function in multiple acyl-CoA dehydrogenase deficiency" BBA - Molecular Basis of Disease 2010, 1802 (11):1070-1077 3. Henriques, B. J., Olsen, R. K., Bross, P., Gomes C. M. "Emerging Roles for Riboflavin in Functional Rescue of Mitochondrial Oxidation Flavoenzymes" Current Medicinal Chemistry 2010 (in press) 4. Henriques, B. J., Fisher M., Bross P., Gomes, C.M. "A polymorphic position in electron transfer flavoprotein modulates kinetic stability as evidenced by thermal stress" FEBS Letters 2010 (in press) Other publications not included in this thesis 5. Henriques, B. J., Saraiva, L. M., Gomes, C. M., "Combined spectroscopic and calorimetric characterisation of rubredoxin reversible thermal transition" J. Biol. Inorg. Chem. 2006, 11:73-81 6. Henriques, B. J., Saraiva, L. M., Gomes, C. M., "Probing the mechanism of rubredoxin thermal unfolding in the absence of salt bridges by temperature jump experiments" Bioch. Bioph. Res. Comm. 2005, 333: 839-844 vii viii DISSERTATION ABSTRACT The work presented in this dissertation concerns the study of the electron transfer flavoprotein (ETF), a protein involved in mitochondrial β-oxidation whose deficiency is associated to multiple acyl-CoA dehydrogenase deficiency (MADD). The thesis will focus on establishing the functional, cellular and molecular consequences of the genetic variability in ETF, and in particular it aims to clarify the basis for the effect of heat stress on disease progression. Moreover, the beneficial effects of vitamin B2 supplementation will be addressed. MADD, which is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolisms, results from deficiencies in any of the following genes: ETFA, ETFB or ETFDH. ETFA and ETFB genes encode for the α and β subunits of ETF, whereas ETFDH encodes for electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO). ETF is a key enzyme in a series of mitochondrial metabolic pathways, mediating electron transfer from at least 12 dehydrogenases to the membrane-bound ETF-QO, thus funneling reducing power to the respiratory chain for subsequent ATP production. The clinical features of patients with MADD are heterogeneous and fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (Type II), and a late- onset form (Type III). This variety of effects presumably depends on the location and nature of the intragenic lesion. Although over 55 distinct genotypes have been identified on MADD patients, with approximately one third corresponding to missense mutations in ETF, only a limited number of genotypes have been characterised. The available data is, in fact, highly suggestive of a direct correlation between the genotype and clinical ix phenotype. Accordingly, while null mutations result in severe phenotypes, missense mutations in the above mentioned genes result in proteins with a lower enzymatic activity leading to cellular functional deficiency and thus milder phenotypes. In these cases, the amino acid alterations are likely to cause conformational changes in the expressed gene products which account for disease. This effect is mostly evident in late-onset MADD patients, in which the disease is often intermittent and only becomes evident during periods of illness or catabolic stress. Even so, the molecular genetic basis and functional characterisation of MADD genotypes remains elusive, thus a detailed in vitro investigation will contribute to a better functional understanding of the clinical heterogeneity in MADD. An extensive in silico analysis was carried out on 18 disease associated missense mutations found in ETF. The analysis revealed that known mutations fall essentially in two groups: 1) mutations affecting protein folding and assembly; 2) mutations impairing catalytic activity and interactions with partner dehydrogenases. We have focused our studies on three of these mutations, ETFβ Cys42Arg, Asp128Asn and Arg191Cys, which typify different clinical phenotypes. This part of the investigation involved the study of expressed ETF variants, aiming at evaluating the impact of mutagenesis on ETF intrinsic conformational stability, enzymatic activity, protein assembly and interaction with functionally relevant enzymes. The ETFβ-Cys42Arg mutation, a severe MADD mutation, affects directly the AMP binding site and the intersubunit contacts impairing protein folding. In vivo assays following the recombinant expression of the protein
Load more

Recommended publications
  • Identification of Isobutyryl-Coa Dehydrogenase and Its Deficiency
    Molecular Genetics and Metabolism 77 (2002) 68–79 www.academicpress.com Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans Tien V. Nguyen,a Brage S. Andresen,b,c Thomas J. Corydon,b Sandro Ghisla,d Nasser Abd-El Razik,d Al-Walid A. Mohsen,a Stephen D. Cederbaum,e Diane S. Roe,f Charles R. Roe,f Nicolas J. Lench,g and Jerry Vockleya,* a Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA b Institute for Human Genetics, Aarhus University, Aarhus, Denmark c Research Unit for Molecular Medicine, Skejby Sygehus and Aarhus University, Aarhus, Denmark d Faculty of Biology, University of Konstanz, Konstanz, Germany e Department of Pediatrics, UCLA Medical Center, Los Angeles, CA, USA f Institute of Metabolic Disease, Baylor University, Dallas, TX, USA g Molecular Medicine Unit, University of Leeds, St. JamesÕ University Hospital, Leeds, UK Received 19 July 2002; received in revised form 31 July 2002; accepted 1 August 2002 Abstract The acyl-CoA dehydrogenases (ACDs) are a family of related enzymes that catalyze the a,b-dehydrogenation of acyl-CoA esters. Two homologues active in branched chain amino acid metabolism have previously been identified. We have used expression in Escherichia coli to produce a previously uncharacterized ACD-like sequence (ACAD8) and define its substrate specificity. Purified À1 À1 recombinant enzyme had a kcat=Km of 0.8, 0.23, and 0.04 (lM s ) with isobutyryl-CoA, (S) 2-methylbutyryl-CoA, and n-propionyl- CoA, respectively, as substrates. Thus, this enzyme is an isobutyryl-CoA dehydrogenase. A single patient has previously been described whose fibroblasts exhibit a specific deficit in the oxidation of valine.
    [Show full text]
  • Establishment and Characterisation of a New Breast Cancer Xenograft Obtained from a Woman Carrying a Germline BRCA2 Mutation
    British Journal of Cancer (2010) 103, 1192 – 1200 & 2010 Cancer Research UK All rights reserved 0007 – 0920/10 www.bjcancer.com Establishment and characterisation of a new breast cancer xenograft obtained from a woman carrying a germline BRCA2 mutation 1 ´ 2 1 1 1 2 2,3 L de Plater , A Lauge , C Guyader , M-F Poupon , F Assayag , P de Cremoux , A Vincent-Salomon , 2,3,4 2 5 6 6 6 1,7 D Stoppa-Lyonnet , B Sigal-Zafrani , J-J Fontaine , R Brough , CJ Lord , A Ashworth , P Cottu , 1,7 *,1 D Decaudin and E Marangoni 1 Preclinical Investigation Unit, Institut Curie – Translational Research Department, Hoˆpital St Louis, Quadrilate`re historique, Porte 13, 1, Ave Claude 2 3 4 Vellefaux, Paris 75010, France; Department of Tumor Biology, Institut Curie, Paris, France; INSERM U830, Institut Curie, Paris, France; University Paris Translational Therapeutics 5 6 Descartes, Paris, France; National Veterinary School of Maisons Alfort, Maisons-Alfort, France; Gene Function Laboratory, The Breakthrough Breast 7 Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK; Department of Medical Oncology, Institut Curie, Paris, France BACKGROUND: The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient’s tumour features. The aim of this study was to establish and characterise a new human breast carcinoma xenograft obtained from a woman carrying a germline BRCA2 mutation. METHODS: A transplantable xenograft was obtained by grafting a breast cancer sample into nude mice.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2016/0002733 A1 Chu (43) Pub
    US 2016.0002733A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0002733 A1 Chu (43) Pub. Date: Jan. 7, 2016 (54) ASSESSING RISK FORENCEPHALOPATHY Related U.S. Application Data INDUCED BYS-FLUOROURACL, OR (60) Provisional application No. 61/772,949, filed on Mar. CAPECTABINE 5, 2013. Publication Classification (71) Applicant: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNOR (51) Int. C. UNIVERSITY, Palo Alto, CA (US) CI2O I/68 (2006.01) (52) U.S. C. (72) Inventor: Gilbert Chu, Stanford, CA (US) CPC ........ CI2O I/6886 (2013.01); C12O 2600/156 (2013.01); C12O 2600/106 (2013.01); C12O (21) Appl. No.: 14/769,961 2600/142 (2013.01) (22) PCT Fled: Feb. 26, 2014 (57) ABSTRACT Methods and systems are provided for determining Suscepti (86) PCT NO.: PCT/US14/18739 bility to 5-fluorouracil (5-FU) or capecitabine toxicity. Meth ods are provided for treating a human Subject based on a S371 (c)(1), determined susceptibility to 5-fluorouracil (5-FU) or capecit (2) Date: Aug. 24, 2015 abine toxicity. Patent Application Publication Jan. 7, 2016 Sheet 1 of 17 US 2016/0002733 A1 Figure 1A urea cycle pyrimidine synthesis -- - - - - - - - - - - - Glin / WPA H al-NAGS NH 3. NH3CPSIDcarbamoyl-P Glu->NAG->|CPS Ca rbamyl-Asp: carbamoyl-P OHO : P. Orotate ornithine citruline s --AlORNT - Y - - - OMPwY Ornithine citruline UDP am UMP as UTP RR urea { UDP in OSuccinat A. 5-FUTP arginine 8 gypsuccina e CUMP i. cycleRECTS-5-FdUMP4-5-FU dTMP Figure IB /a-ketoglutarate pyruvate Asp PD PC 4-acetyl-CoA Glu oxaloacetate malate isocitrate Krebs cycle NH3 fumarate a-ketoglutarate Glu succinate succinyl-CoA methylmalonyl-CoA r a fatty acid proponyi-UOE.
    [Show full text]
  • Development of a Newborn Screening Follow-Up Algorithm for The
    article February 2007 ⅐ Vol. 9 ⅐ No. 2 Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency Devin Oglesbee, PhD1, Miao He, PhD4, Nilanjana Majumder4, Jerry Vockley, MD, PhD4, Ayesha Ahmad, MD5, Brad Angle, MD6, Barbara Burton, MD6, Joel Charrow, MD6, Regina Ensenauer, MD1,7, Can H. Ficicioglu, MD, PhD8, Laura Davis Keppen, MD9, Deborah Marsden, MD10, Silvia Tortorelli, MD, PhD1,2, Si Houn Hahn, MD, PhD1,2,3, and Dietrich Matern, MD1,2,3 Purpose: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenase– deficient patients through newborn screening due to an elevation of C4-acylcarnitine in dried blood spots. Because C4-acylcarnitine represents both isobutyryl- and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C4-acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions. Methods: Fibroblast cultures were established from infants with C4-acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydro- genase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase– and short-chain acyl-CoA dehydrogenase–deficient pa- tients.
    [Show full text]
  • Immune Deficiency in Jacobsen Syndrome: Molecular And
    G C A T T A C G G C A T genes Case Report Immune Deficiency in Jacobsen Syndrome: Molecular and Phenotypic Characterization Raquel Rodríguez-López 1,*, Fátima Gimeno-Ferrer 1, Elena Montesinos 2, Irene Ferrer-Bolufer 1, Carola Guzmán Luján 1, David Albuquerque 1, Carolina Monzó Cataluña 1, Virginia Ballesteros 2 and Monserrat Aleu Pérez-Gramunt 2 1 Laboratory of Molecular Genetics, Clinical Analysis Service, Consorcio Hospital General de Valencia, 46014 Valencia, Spain; [email protected] (F.G.-F.); [email protected] (I.F.-B.); [email protected] (C.G.L.); [email protected] (D.A.); [email protected] (C.M.C.) 2 Department of Pediatric, Consorcio Hospital General de Valencia, 46014 Valencia, Spain; [email protected] (E.M.); [email protected] (V.B.); [email protected] (M.A.P.-G.) * Correspondence: [email protected]; Tel.: +34-963-131-800; Fax: +34-963-131-979 Abstract: Jacobsen syndrome or JBS (OMIM #147791) is a contiguous gene syndrome caused by a deletion affecting the terminal q region of chromosome 11. The phenotype of patients with JBS is a specific syndromic phenotype predominately associated with hematological alterations. Complete and partial JBS are differentiated depending on which functional and causal genes are haploinsufficient in the patient. We describe the case of a 6-year-old Bulgarian boy in which it was possible to identify all of the major signs and symptoms listed by the Online Mendelian Inheritance Citation: Rodríguez-López, R.; in Man (OMIM) catalog using the Human Phenotype Ontology (HPO). Extensive blood and marrow Gimeno-Ferrer, F.; Montesinos, E.; tests revealed the existence of thrombocytopenia and leucopenia, specifically due to low levels Ferrer-Bolufer, I.; Luján, C.G.; of T and B cells and low levels of IgM.
    [Show full text]
  • Long-Term Outcome of Isobutyryl-Coa Dehydrogenase Deficiency
    Molecular Genetics and Metabolism Reports 10 (2017) 28–30 Contents lists available at ScienceDirect Molecular Genetics and Metabolism Reports journal homepage: www.elsevier.com/locate/ymgmr Case Report Long-term outcome of isobutyryl-CoA dehydrogenase deficiency diagnosed following an episode of ketotic hypoglycaemia S. Santra a,⁎,A.Macdonaldb, M.A. Preece c,R.K.Olsend,B.S.Andresend,e a Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, United Kingdom b Department of Dietetics, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, United Kingdom c Department of Newborn Screening and Biochemical Genetics, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, United Kingdom d Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark e The Villum Center for Bioanalytical Sciences and Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark article info abstract Article history: Isobutyryl-CoA Dehydrogenase Deficiency (IBDD) is an inherited disorder of valine metabolism caused by muta- Received 11 September 2016 tions in ACAD8. Most reported patients have been diagnosed through newborn screening programmes due to el- Received in revised form 23 November 2016 evated C4-carnitine levels and appear clinically asymptomatic. One reported non-screened patient had dilated Accepted 23 November 2016 cardiomyopathy and anaemia at the age
    [Show full text]
  • ACAD8 Gene Acyl-Coa Dehydrogenase Family Member 8
    ACAD8 gene acyl-CoA dehydrogenase family member 8 Normal Function The ACAD8 gene provides instructions for making an enzyme called isobutyryl-CoA dehydrogenase (IBD). This enzyme is found in mitochondria, the energy-producing centers inside cells. The IBD enzyme is involved in breaking down proteins from food. Specifically, this enzyme is responsible for the third step in the breakdown of a protein building block (amino acid) called valine. The IBD enzyme converts a molecule called isobutyryl-CoA into a molecule called methylacrylyl-CoA. Other enzymes further break down methylacrylyl-CoA into molecules that cells can use for energy. Health Conditions Related to Genetic Changes Isobutyryl-CoA dehydrogenase deficiency At least 19 mutations in the ACAD8 gene have been found to cause isobutyryl-CoA dehydrogenase (IBD) deficiency. Some of these mutations reduce the activity of the IBD enzyme, while other mutations prevent the gene from producing any functional enzyme. As a result, valine is not broken down properly. An inability to process valine may lead to reduced energy production and the features of IBD deficiency. Other Names for This Gene • ACAD-8 • ACAD8_HUMAN • Activator-recruited cofactor 42 kDa component • acyl-CoA dehydrogenase family, member 8 • acyl-coenzyme A dehydrogenase 8 • ARC42 • FLJ22590 Additional Information & Resources Tests Listed in the Genetic Testing Registry Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 1 • Tests of ACAD8 (https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=27034[geneid]) Scientific
    [Show full text]
  • 014150 01 FST NBS Handbook of Metabolic
    Isobutyryl-CoA Dehydrogenase Deficiency Informatics Training for Scientists Background Isobutyryl-CoA Dehydrogenase (IBD) is an enzyme involved in the metabolism of Valine, a branched-chain amino acid. Deficiency of IBD was recently described and only a few patients have been identified. The gene for IBD (ACAD8), located on chromosome 9, has been cloned and mutations have been identified in several patients. Clinical The clinical features of IBD deficiency are poorly defined and may have a highly variable presentation. The first patient described with this disease had failure to thrive and developed dilated cardiomyopathy associated with anemia at 11 months of age. Plasma carnitine levels were profoundly decreased. Several other patients have been identified by newborn screening and appear “asymptomatic”. Long-term clinical follow-up, however, is lacking and the true clinical spectrum of the disease is yet to be determined. Testing Newborns can be screened for IBD deficiency using tandem mass spectrometry analysis of a dried blood spot. The finding of elevated 4-carbon acylcarnitine (C4) indicates either IBD deficiency or short-chain acyl-CoA dehydrogenase deficiency. C4-acylcarnitine may also be seen in Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), but this is usually accompanied by other acylcarnitine metabolites. To differentiate and make a diagnosis of IBD deficiency, further testing with urine organic acid analysis is required. Urine from a patient suspected of IBD deficiency may reveal an elevation of isobutyryl-glycine or be normal, whereas patients with Short-Chain Acyl-CoA Dehydrogenase deficiency (SCAD) excrete ethylmalonic acid. Plasma free carnitine levels may be low. Identification of mutations in the ACAD8 gene should permit genetic counseling and prenatal diagnosis.
    [Show full text]
  • Molecular Classification of Renal Tumors by Gene Expression Profiling
    Journal of Molecular Diagnostics, Vol. 7, No. 2, May 2005 Copyright © American Society for Investigative Pathology and the Association for Molecular Pathology Molecular Classification of Renal Tumors by Gene Expression Profiling Audrey N. Schuetz,* Qiqin Yin-Goen,*† Renal cell carcinoma (RCC) is the most common malig- Mahul B. Amin,*‡§ Carlos S. Moreno,*‡ nancy of the adult kidney, comprising 3% of all human 1 Cynthia Cohen,* Christopher D. Hornsby,* cancers. Localized tumors can be detected by abdom- 2 Wen Li Yang,*† John A. Petros,*†‡§ inal imaging and cured by surgery. However, 25 to 40% of cases present with extrarenal growth or metastases,3 Muta M. Issa,†§ John G. Pattaras,§ § § and one-third of apparently localized lesions develop Kenneth Ogan, Fray F. Marshall, and metastases during the postoperative course.4,5 Ad- † Andrew N. Young* vanced RCC responds poorly to systemic therapy and From the Departments of Pathology and Laboratory Medicine* has a 5-year survival rate of less than 10%.6,7 and Urology,§ and the Winship Cancer Institute,‡ Emory Important predictors of outcome for RCC include tumor University School of Medicine, Atlanta; and the Atlanta Veterans stage, Fuhrman nuclear grade, histopathological classi- 3,8–10 Affairs Medical Center,† Decatur, Georgia fication, and perioperative thrombocytosis. The cur- rent renal tumor classification system is based on mor- phology, as well as underlying genetic differences.3,11,12 More than 90% of clinically significant lesions can be diagnosed as one of the common subtypes of renal ep- Renal tumor classification is important because his- ithelial tumor: clear cell (conventional) RCC, papillary topathological subtypes are associated with distinct RCC, chromophobe RCC, and renal oncocytoma.
    [Show full text]
  • Drug Database for Inborn Errors of Metabolism
    Abdelhakim et al. Orphanet Journal of Rare Diseases (2020) 15:146 https://doi.org/10.1186/s13023-020-01428-2 RESEARCH Open Access DDIEM: drug database for inborn errors of metabolism Marwa Abdelhakim1,2, Eunice McMurray3, Ali Raza Syed1,2, Senay Kafkas1,2, Allan Anthony Kamau1,PaulN Schofield3 and Robert Hoehndorf1,2* Abstract Background: Inborn errors of metabolism (IEM) represent a subclass of rare inherited diseases caused by a wide range of defects in metabolic enzymes or their regulation. Of over a thousand characterized IEMs, only about half are understood at the molecular level, and overall the development of treatment and management strategies has proved challenging. An overview of the changing landscape of therapeutic approaches is helpful in assessing strategic patterns in the approach to therapy, but the information is scattered throughout the literature and public data resources. Results: We gathered data on therapeutic strategies for 300 diseases into the Drug Database for Inborn Errors of Metabolism (DDIEM). Therapeutic approaches, including both successful and ineffective treatments, were manually classified by their mechanisms of action using a new ontology. Conclusions: We present a manually curated, ontologically formalized knowledgebase of drugs, therapeutic procedures, and mitigated phenotypes. DDIEM is freely available through a web interface and for download at http://ddiem.phenomebrowser.net. Keywords: Inborn errors of metabolism, Orphan disease, Ontology, Drug effect, Drug repositioning, Therapeutic procedure Background Europe, and elsewhere to coordinate international infras- Rare hereditary diseases together make up a significant tructure, research and development, and delivery of new component of overall morbidity and mortality around the therapeutics [2]. While much effort has gone into mobiliz- world.
    [Show full text]
  • Association Study of Cholesterol-Related Genes in Alzheimer’S Disease
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by RERO DOC Digital Library Neurogenetics (2007) 8:179–188 DOI 10.1007/s10048-007-0087-z ORIGINAL ARTICLE Association study of cholesterol-related genes in Alzheimer’s disease M. Axel Wollmer & Kristel Sleegers & Martin Ingelsson & Cezary Zekanowski & Nathalie Brouwers & Aleksandra Maruszak & Fabienne Brunner & Kim-Dung Huynh & Lena Kilander & Rose-Marie Brundin & Marie Hedlund & Vilmantas Giedraitis & Anna Glaser & Sebastiaan Engelborghs & Peter P. De Deyn & Elisabeth Kapaki & Magdalini Tsolaki & Makrina Daniilidou & Dimitra Molyva & George P. Paraskevas & Dietmar R. Thal & Maria Barcikowska & Jacek Kuznicki & Lars Lannfelt & Christine Van Broeckhoven & Roger M. Nitsch & Christoph Hock & Andreas Papassotiropoulos Received: 28 December 2006 /Accepted: 12 March 2007 / Published online: 27 March 2007 # Springer-Verlag 2007 Abstract Alzheimer’s disease (AD) is a genetically com- To identify further AD susceptibility genes, we have plex disorder, and several genes related to cholesterol screened genes that map to chromosomal regions with high metabolism have been reported to contribute to AD risk. logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European Electronic supplementary material The online version of this article screening sample of 115 sporadic AD patients and 191 (doi:10.1007/s10048-007-0087-z) contains supplementary material, healthy control subjects, we analyzed single nucleotide which is available to authorized users. * : : : : : M. A. Wollmer: ( ) F. Brunner K.-D. Huynh R. M. Nitsch S. Engelborghs P. P. De Deyn C. Hock A. Papassotiropoulos Laboratory of Neurochemistry and Behavior, Division of Psychiatry Research, University of Zürich, Institute Born-Bunge, University of Antwerp, August Forel Str.
    [Show full text]
  • The Proteome of Prostate Cancer Bone Metastasis Reveals
    Published OnlineFirst July 24, 2018; DOI: 10.1158/1078-0432.CCR-18-1229 Biology of Human Tumors Clinical Cancer Research The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications Diego Iglesias-Gato1,2, Elin Thysell3, Stefka Tyanova4, Sead Crnalic5, Alberto Santos6, Thiago S. Lima1,2, Tamar Geiger7,Jurgen€ Cox4, Anders Widmark8, Anders Bergh3, Matthias Mann4,6, Amilcar Flores-Morales1,2, and Pernilla Wikstrom€ 3 Abstract Purpose: Bone is the most predominant site of distant fatty acid b-oxidation; and reduced levels of proteins were metastasis in prostate cancer, and patients have limited ther- related to cell adhesion and carbohydrate metabolism. Within apeutic options at this stage. bone metastases, we identified two phenotypic subgroups: Experimental Design: We performed a system-wide BM1, expressing higher levels of AR canonical targets, and quantitative proteomic analysis of bone metastatic prostate mitochondrial and Golgi apparatus resident proteins; and tumors from 22 patients operated to relieve spinal cord BM2, with increased expression of proliferation and DNA compression. At the time of surgery, most patients had repair–related proteins. The two subgroups, validated by the relapsed after androgen-deprivation therapy, while 5 were inverse correlation between MCM3 and prostate specific anti- previously untreated. An extended cohort of prostate cancer gen immunoreactivity, were related to disease prognosis, bone metastases (n ¼ 65) was used for immunohistochem- suggesting that this molecular heterogeneity should be con- ical validation. sidered when developing personalized therapies. Results: On average, 5,067 proteins were identified Conclusions: This work is the first system-wide quantitative and quantified per tumor. Compared with primary tumors characterization of the proteome of prostate cancer bone (n ¼ 26), bone metastases were more heterogeneous and metastases and a valuable resource for understanding the showed increased levels of proteins involved in cell-cycle etiology of prostate cancer progression.
    [Show full text]