DOCSLIB.ORG

Determining the Causes of Recessive Retinal Dystrophy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Determining the Causes of Recessive Retinal Dystrophy Determining the causes of recessive retinal dystrophy By Mohammed El-Sayed Mohammed El-Asrag BSc (hons), MSc (hons) Genetics and Molecular Biology Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Medicine September 2016 The candidate confirms that the work submitted is his own, except where work which has formed part of jointly- authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated overleaf. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Mohammed El-Sayed Mohammed El-Asrag to be identified as author of this work has been asserted by his in accordance with the Copyright, Designs and Patents Act 1988. © 2016 The University of Leeds and Mohammed El-Sayed Mohammed El-Asrag Jointly authored publications statement Chapter 3 (first results chapter) of this thesis is entirely the work of the author and appears in: Watson CM*, El-Asrag ME*, Parry DA, Morgan JE, Logan CV, Carr IM, Sheridan E, Charlton R, Johnson CA, Taylor G, Toomes C, McKibbin M, Inglehearn CF and Ali M (2014). Mutation screening of retinal dystrophy patients by targeted capture from tagged pooled DNAs and next generation sequencing. PLoS One 9(8): e104281. *Equal first- authors. Shevach E, Ali M, Mizrahi-Meissonnier L, McKibbin M, El-Asrag ME, Watson CM, Inglehearn CF, Ben-Yosef T, Blumenfeld A, Jalas C, Banin E and Sharon D (2015). Association between missense mutations in the BBS2 gene and nonsyndromic retinitis pigmentosa. JAMA Ophthalmology 133(3): 312-318. Chapter 4 (second results chapter) of this thesis is entirely the work of the author and appears in: Ravesh Z, El-Asrag ME*, Weisschuh N, McKibbin M, Reuter P, Watson CM, Baumann B, Poulter JA, Sajid S, Panagiotou ES, O'Sullivan J, Abdelhamed Z, Bonin M, Soltanifar M, Black GC, Amin-ud Din M, Toomes C, Ansar M, Inglehearn CF, Wissinger B and Ali M (2015). Novel C8orf37 mutations cause retinitis pigmentosa in consanguineous families of Pakistani origin. Molecular Vision 21: 236-243. *Equal first-authors. iii Bedoni N*, Haer-Wigman L*, Vaclavik V, Tran HV, Farinelli P, Balzano S, Royer- Bertrand B, El-Asrag ME, Bonny O, Ikonomidis C, Litzistorf Y, Nikopoulos K, Yioti G, Stefaniotou M, McKibbin M, Ellingford J, Booth AP, Black G, Toomes C, Inglehearn CF, Hoyng CB, Bax N, Klaver CCW, Thiadens AA, Murisier F, Schorderet DF, Ali M, Cremers FPM, Andréasson S, Munier FL and Rivolta C (2016). Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility. Human Molecular Genetics doi:10.1093/hmg/ddw282. *Equal first-authors. Khan KN*, El-Asrag ME*, Ku CA, Holder GE, McKibbin M, Arno G, Poulter JA, Carss K, Bommireddy T, Bagheri S, NIHR BioResource-Rare Diseases, UK Inherited Retinal Disease Consortium, Bakall B, Scholl HP, Raymond FL, Toomes C, Inglehearn CF, Pennesi ME, Moore AT, Michaelides M, Ali M, and Webster AR (2016). Recessive mutations in MFSD8 are a cause of non-syndromic rod-cone dystrophy with severe macular involvement. Submitted to Investigative Ophthalmology and Visual Science. *Equal first-authors. Chapter 5 (third results chapter) of this thesis is entirely the work of the author and appears in: El-Asrag ME*, Sergouniotis PI*, McKibbin M, Plagnol V, Sheridan E, Waseem N, Abdelhamed Z, McKeefry D, Van Schil K, Poulter JA, Johnson CA, Carr IM, Leroy BP, De Baere E, Inglehearn CF, Webster AR, Toomes C and Ali M (2015). Biallelic mutations in the autophagy regulator DRAM2 cause retinal dystrophy with early macular involvement. American Journal of Human Genetics 96(6): 948-954. *Equal first- authors iv Sergouniotis PI*, McKibbin M*, Robson AG, Bolz HJ, De Baere E, Muller PL, Heller R, El-Asrag ME, Van Schil K, Plagnol V, Toomes C, Ali M, Holder GE, Charbel Issa P, Leroy BP, Inglehearn CF and Webster AR (2015). Disease expression in autosomal recessive retinal dystrophy associated with mutations in the DRAM2 gene. Investigative Ophthalmology and Visual Science 56(13): 8083-8090. *Equal first-authors Publication in preparation from this thesis El-Asrag ME, McKibbin M, Poulter JA, Abdelmottaleb DI, Black GC, Toomes C, Inglehearn CF and Ali M. Whole exome sequencing identifies LARGE as novel gene candidate for autosomal recessive retinal dystrophy. In preparation. Publications related to other work done during this study Al-Amri A, Saegh AA, Al-Mamari W, El-Asrag ME, Ivorra JL, Cardno AG, Inglehearn CF, Clapcote SJ and Ali M (2016). Homozygous single base deletion in TUSC3 causes intellectual disability with developmental delay in an Omani family. American Journal of Medical Genetics Part A 170(7): 1826-1831. El-Asrag ME, McKibbin M, Mohamed MD, Toomes C, Inglehearn CF and Ali M. Next generation sequencing identifies novel loss of function mutations in NRL cause autosomal recessive retinitis pigmentosa. In preparation. v Acknowledgements First and above all, I praise God Almighty for providing me this opportunity, for without His blessings, guidance and assistance, this study would not have been possible. I also offer my immeasurable appreciation and deepest gratitude to Dr Manir Ali for his expert guidance, profound interest, support, assistance, valuable remarks and continuous encouragement. I also my grateful thanks to Prof. Chris Inglehearn for accepting me as a doctoral student at Leeds University, for his friendly advice, thoughtful guidance and for imparting his knowledge and bringing his expertise to this study. Also many thanks to Dr Carmel Toomes for her unfailing advice and constructive criticism; she did not spare any efforts in guiding me towards the best. Sincere appreciation also goes to my colleague Dr James Poulter for his valuable help and friendship throughout this study. I would also like to thank all my laboratory colleagues, past and present, in Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences (LIBACS) who in one way or another have contributed to the successful completion of this study, particularly Ahmed, Zakia, Kamron, Claire, Evi, Carla, Layal, Tom, Denisa, Emma, Ekram, Clare, Suba and Kasia. Many thanks also to Dr David Parry and Dr Ian Carr for their help with bioinformatics analysis and to Prof. Colin Johnson and Dr Jacquelyn Bond for their friendly advice. I would also like to thank Mr Martin McKibbin for providing the clinical data and images of the patients. I would also like to acknowledge the financial support that I received from the Egyptian Ministry of Higher Education. I would like to warmly thank my parents and my brother Ahmed for their spiritual support in all aspects of my life. To my dearest daughters, Maram and Maryam, as you grow older, I want you to know that just watching you smile makes me realize how beautiful my life is, and that I love you, and have done this for you. Hopefully, I have made you proud. Finally, my lovely wife, dear Dina, although I know that you did not want to be named, you put your own career on hold to come with me to the United Kingdom. Without your constant support and encouragement, I would never have finished this work. You became the bedrock of our family, and I know how difficult it was for you, so all I can say is: Thank you for everything and may Allah reward you for your generosity of spirit. vi Abstract Inherited retinal dystrophies (RDs) are a clinically heterogeneous group of eye diseases that result from mutations in more than 250 genes. Genetic diagnosis of these diseases has, until recently, been hampered by the lack of suitable technologies to perform high throughput screening. This thesis describes two different strategies for using next generation sequencing (NGS) in RD patients to find the pathogenic mutation(s) involved. In the first results chapter, a customised capture reagent (called Retinome) designed against the known retinal dystrophy genes (RetNet, June 2010) was used in NGS analysis of 20 RD families. The disease-causing mutations were identified in 12 of 20 cases (60%). These included previously reported mutations in ABCA4 (c.6088C>T, p.R2030*; c.5882G>A, p.G1961E), RDH12 (c.601T>C, p.C201R; c.506G>A, p.R169Q), PROM1 (c.1117C>T, p.R373C), GUCY2D (c.2512C>T, p.R838C), RPGRIP1 (c.3565C>T, p.R1189*), BBS2 (c.1895G>C, p.R632P) and SPATA7 (c.253C>T, p.R85*) and new mutations in CRB1 (c.2832_2842+23del), USH2A (c.12874A>G, p.N4292D), RP2 (c.884-1G>T) and ABCA4 (c.3328+1G>C). In eight cases the causative mutation could not be unambiguously identified. In the second results chapter, whole-exome NGS was performed on five RD families that had been pre-screened with the Retinome reagent. This identified mutations in three known RD genes, MFSD8 (c.1006G>C, p.E336Q; c.1394G>A, p.R465Q), C8orf37 (c.555G>A, p.W185*) and TTLL5 (c.1627G>A, p.E543K), and mutations in two potentially new RD genes, LARGE (c.2089G>T, p.V697L) and FDFT1 (c.930C>G, p.F310L). In the third results chapter, whole-exome NGS was performed, without pre- screening of known genes, in a family with atypical adult-onset RD with early macular involvement. NGS identified a mutation in a novel RD gene, DRAM2 (c.140delG, p.G47Vfs*3). Further DRAM2 screening in DNA panels identified a compound heterozygote case (c.494G>A, p.W165*; c.131G>A, p.S44N).
Load more

Recommended publications
  • PRODUCT SPECIFICATION Prest Antigen GJB5
    PrEST Antigen GJB5 Product Datasheet PrEST Antigen PRODUCT SPECIFICATION Product Name PrEST Antigen GJB5 Product Number APrEST78107 Gene Description gap junction protein, beta 5, 31.1kDa Alternative Gene CX31.1 Names Corresponding Anti-GJB5 (HPA038146) Antibodies Description Recombinant protein fragment of Human GJB5 Amino Acid Sequence Recombinant Protein Epitope Signature Tag (PrEST) antigen sequence: KRCHECLAARKAQAMCTGHHPHGTTSSCKQDDLLSGDLIFLGSDSHPPLL PDRPRDHVKK Fusion Tag N-terminal His6ABP (ABP = Albumin Binding Protein derived from Streptococcal Protein G) Expression Host E. coli Purification IMAC purification Predicted MW 24 kDa including tags Usage Suitable as control in WB and preadsorption assays using indicated corresponding antibodies. Purity >80% by SDS-PAGE and Coomassie blue staining Buffer PBS and 1M Urea, pH 7.4. Unit Size 100 µl Concentration Lot dependent Storage Upon delivery store at -20°C. Avoid repeated freeze/thaw cycles. Notes Gently mix before use. Optimal concentrations and conditions for each application should be determined by the user. Product of Sweden. For research use only. Not intended for pharmaceutical development, diagnostic, therapeutic or any in vivo use. No products from Atlas Antibodies may be resold, modified for resale or used to manufacture commercial products without prior written approval from Atlas Antibodies AB. Warranty: The products supplied by Atlas Antibodies are warranted to meet stated product specifications and to conform to label descriptions when used and stored properly. Unless otherwise stated, this warranty is limited to one year from date of sales for products used, handled and stored according to Atlas Antibodies AB's instructions. Atlas Antibodies AB's sole liability is limited to replacement of the product or refund of the purchase price.
    [Show full text]
  • The Landscape of Genomic Imprinting Across Diverse Adult Human Tissues
    Downloaded from genome.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Research The landscape of genomic imprinting across diverse adult human tissues Yael Baran,1 Meena Subramaniam,2 Anne Biton,2 Taru Tukiainen,3,4 Emily K. Tsang,5,6 Manuel A. Rivas,7 Matti Pirinen,8 Maria Gutierrez-Arcelus,9 Kevin S. Smith,5,10 Kim R. Kukurba,5,10 Rui Zhang,10 Celeste Eng,2 Dara G. Torgerson,2 Cydney Urbanek,11 the GTEx Consortium, Jin Billy Li,10 Jose R. Rodriguez-Santana,12 Esteban G. Burchard,2,13 Max A. Seibold,11,14,15 Daniel G. MacArthur,3,4,16 Stephen B. Montgomery,5,10 Noah A. Zaitlen,2,19 and Tuuli Lappalainen17,18,19 1The Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv 69978, Israel; 2Department of Medicine, University of California San Francisco, San Francisco, California 94158, USA; 3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; 4Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA; 5Department of Pathology, Stanford University, Stanford, California 94305, USA; 6Biomedical Informatics Program, Stanford University, Stanford, California 94305, USA; 7Wellcome Trust Center for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7BN, United Kingdom; 8Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; 9Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland;
    [Show full text]
  • Investigation of Modifier Genes Within Copy Number Variations in Rett Syndrome
    See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/51147767 Investigation of modifier genes within copy number variations in Rett syndrome ARTICLE in JOURNAL OF HUMAN GENETICS · MAY 2011 Impact Factor: 2.53 · DOI: 10.1038/jhg.2011.50 · Source: PubMed CITATIONS DOWNLOADS VIEWS 6 89 134 15 AUTHORS, INCLUDING: Dag H Yasui Maria Antonietta Mencarelli University of California, Davis Azienda Ospedaliera Universitaria Senese 30 PUBLICATIONS 1,674 CITATIONS 58 PUBLICATIONS 962 CITATIONS SEE PROFILE SEE PROFILE Francesca Mari Janine M Lasalle Università degli Studi di Siena University of California, Davis 81 PUBLICATIONS 1,658 CITATIONS 98 PUBLICATIONS 3,525 CITATIONS SEE PROFILE SEE PROFILE Available from: Janine M Lasalle Retrieved on: 22 July 2015 Europe PMC Funders Group Author Manuscript J Hum Genet. Author manuscript; available in PMC 2012 January 01. Published in final edited form as: J Hum Genet. 2011 July ; 56(7): 508–515. doi:10.1038/jhg.2011.50. Europe PMC Funders Author Manuscripts Investigation of modifier genes within copy number variations in Rett syndrome Rosangela Artuso1,*, Filomena Tiziana Papa1,*, Elisa Grillo1, Mafalda Mucciolo1, Dag H. Yasui2, Keith W. Dunaway2, Vittoria Disciglio1, Maria Antonietta Mencarelli1, Marzia Pollazzon1, Michele Zappella3, Giuseppe Hayek4, Francesca Mari1, Alessandra Renieri1, Janine M. LaSalle2, and Francesca Ariani1 1 Medical Genetics Section, Biotechnology Department, University of Siena, Italy 2 Medical Microbiology and Immunology, Genome Center, School of Medicine, University of California, Davis, CA, USA 3 Child Neuropsychiatry, Versilia Hospital, Viareggio, Italy 4 Infantile Neuropsychiatry, Siena General Hospital, Italy Abstract MECP2 mutations are responsible for two different phenotypes in females, classical Rett syndrome and the milder Zappella variant (Z-RTT).
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Cells Expression and Function of CD300 in NK
    Expression and Function of CD300 in NK Cells Dikla Lankry, Hrvoje Simic, Yair Klieger, Francesca Levi-Schaffer, Stipan Jonjic and Ofer Mandelboim This information is current as of September 26, 2021. J Immunol 2010; 185:2877-2886; Prepublished online 23 July 2010; doi: 10.4049/jimmunol.0903347 http://www.jimmunol.org/content/185/5/2877 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/07/23/jimmunol.090334 Material 7.DC1 References This article cites 44 articles, 13 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/185/5/2877.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Expression and Function of CD300 in NK Cells Dikla Lankry,* Hrvoje Simic,† Yair Klieger,* Francesca Levi-Schaffer,‡ Stipan Jonjic,† and Ofer Mandelboim* The killing activity of NK cells is regulated by signals derived from inhibitory and activating NK cell receptors, including the CD300 family of proteins.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • Cellular and Molecular Signatures in the Disease Tissue of Early
    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
    [Show full text]
  • Análise Integrativa De Perfis Transcricionais De Pacientes Com
    UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DE RIBEIRÃO PRETO PROGRAMA DE PÓS-GRADUAÇÃO EM GENÉTICA ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Ribeirão Preto – 2012 ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Tese apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo para obtenção do título de Doutor em Ciências. Área de Concentração: Genética Orientador: Prof. Dr. Eduardo Antonio Donadi Co-orientador: Prof. Dr. Geraldo A. S. Passos Ribeirão Preto – 2012 AUTORIZO A REPRODUÇÃO E DIVULGAÇÃO TOTAL OU PARCIAL DESTE TRABALHO, POR QUALQUER MEIO CONVENCIONAL OU ELETRÔNICO, PARA FINS DE ESTUDO E PESQUISA, DESDE QUE CITADA A FONTE. FICHA CATALOGRÁFICA Evangelista, Adriane Feijó Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. Ribeirão Preto, 2012 192p. Tese de Doutorado apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Área de Concentração: Genética. Orientador: Donadi, Eduardo Antonio Co-orientador: Passos, Geraldo A. 1. Expressão gênica – microarrays 2. Análise bioinformática por module maps 3. Diabetes mellitus tipo 1 4. Diabetes mellitus tipo 2 5. Diabetes mellitus gestacional FOLHA DE APROVAÇÃO ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas.
    [Show full text]
  • Molecular Effects of Isoflavone Supplementation Human Intervention Studies and Quantitative Models for Risk Assessment
    Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis committee Promotors Prof. Dr Pieter van ‘t Veer Professor of Nutritional Epidemiology Wageningen University Prof. Dr Evert G. Schouten Emeritus Professor of Epidemiology and Prevention Wageningen University Co-promotors Dr Anouk Geelen Assistant professor, Division of Human Nutrition Wageningen University Dr Lydia A. Afman Assistant professor, Division of Human Nutrition Wageningen University Other members Prof. Dr Jaap Keijer, Wageningen University Dr Hubert P.J.M. Noteborn, Netherlands Food en Consumer Product Safety Authority Prof. Dr Yvonne T. van der Schouw, UMC Utrecht Dr Wendy L. Hall, King’s College London This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 20 June 2014 at 13.30 p.m. in the Aula. Vera van der Velpen Molecular effects of isoflavone supplementation: Human intervention studies and quantitative models for risk assessment 154 pages PhD thesis, Wageningen University, Wageningen, NL (2014) With references, with summaries in Dutch and English ISBN: 978-94-6173-952-0 ABSTRact Background: Risk assessment can potentially be improved by closely linked experiments in the disciplines of epidemiology and toxicology.
    [Show full text]
  • Null Mutation of the Fascin2 Gene by TALEN Leading to Progressive Hearing Loss and Retinal Degeneration in C57BL/6J Mice
    G3: Genes|Genomes|Genetics Early Online, published on August 6, 2018 as doi:10.1534/g3.118.200405 Null mutation of the Fascin2 gene by TALEN leading to progressive hearing loss and retinal degeneration in C57BL/6J mice Xiang Liu1,3,§, Mengmeng Zhao1,2,§, Yi Xie1,2, §, Ping Li1, Oumei Wang1 , Bingxin Zhou1,2, Linlin Yang1,4, Yao Nie1, Lin Cheng1, Xicheng Song1,5, Changzhu Jin1,3,**, Fengchan Han1,2,* 1Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai264003, Shandong, P. R. China 2Department of Biochemistry and Molecular Biology, Binzhou Medical University, 346 Guanhai Road, Yantai264003, Shandong, P. R. China 3Department of Human Anatomy and Histology and Embryology, Binzhou Medical University, 346 Guanhai Road, Yantai264003, Shandong, P. R. China 4Department of Otorhinolaryngology-Head and Neck Surgery, Yuhuangding Hospital, 20 East Yuhuangding Road, Yantai 264000, Shandong, P.R .China § These authors contribute equally *The First Corresponding Author: [email protected] **The Second Corresponding Author: [email protected] Key Laboratory for Genetic Hearing Disorders in Shandong, Department of Biochemistry and Molecular Biology, Binzhou Medical University, 346 Guanhai Road, Yantai264003, Shandong, P. R. China © The Author(s) 2013. Published by the Genetics Society of America. Abstract Fascin2 (FSCN2) is an actin cross-linking protein that is mainly localized in retinas and in the stereocilia of hair cells. Earlier studies showed that a deletion mutation in human FASCIN2 (FSCN2) gene could cause autosomal dominant retinitis pigmentosa. Recent studies have indicated that a missense mutation in mouse Fscn2 gene (R109H) can contribute to the early onset of hearing loss in DBA/2J mice.
    [Show full text]
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement.
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]