DOCSLIB.ORG

Phenotypic Variability in Familial Amyloid Polyneuropathy: TTR Modifiers in Caenorhabditis Elegans and D.ICBAS 2019 Human Models

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Phenotypic Variability in Familial Amyloid Polyneuropathy: TTR Modifiers in Caenorhabditis Elegans and D.ICBAS 2019 Human Models and Human Human and Caenorhabditis Elegans DOUTORAMENTO CIÊNCIAS BIOMÉDICAS Phenotypic Variability in Familial TTR modifiers Polyneuropathy: Amyloid in Models. FerreiraMiguel Alves D 2019 Miguel Alves Ferreira. Phenotypic Variability in Familial Amyloid Polyneuropathy: TTR modifiers in Caenorhabditis Elegans and D.ICBAS 2019 Human Models. Phenotypic Variability in Familial Amyloid Polyneuropathy: TTR modifiers in Caenorhabditis Elegans and Human Models. Miguel Alves Ferreira INSTITUTO DE CIÊNCIAS BIOMÉDICAS ABEL SALAZAR D 2019 PHENOTYPIC VARIABILITY IN FAMILIAL AMYLOID POLYNEUROPATHY: TTR MODIFIERS IN CAENORHABDITIS ELEGANS AND HUMAN MODELS. Doctoral program in Biomedical Sciences MIGUEL FERNANDO ALVES FERREIRA PHENOTYPIC VARIABILITY IN FAMILIAL AMYLOID POLYNEUROPATHY: TTR MODIFIERS IN CAENORHABDITIS ELEGANS AND HUMAN MODELS. Tese de Candidatura ao grau de Doutor em Ciências Biomédicas submetida ao Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto. Orientador – Prof. Doutora Carolina Luísa Cardoso Lemos Categoria – Professora Auxiliar Convidada Afiliação – Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto. Co-orientadora – Prof. Doutora Alda Maria Botelho Correia de Sousa Categoria – Professora Associada com Agregação Afiliação – Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto. Co-orientadora – Prof. Doutora Sandra Encalada Categoria – Assistant Professor Afiliação – The Scripps Research Institute (TSRI) Porto, 2019 Financial support This study was supported by Fundação para a Ciência e Tecnologia, FCT, (PTDC/SAU- GMG/100240/2008) and PEsT, co-supported by ERDF and COMPETE, and by Financiamento Plurianual de Unidades de Investigação and through a PhD grant (SFRH/BD/101352/2014) financed by Programa Operacional and União Europeia. "Sou incapaz de dar respostas às minhas interrogações, exatamente porque sou um homem de interrogações." Corino de Andrade ACKNOWLEDGMENTS/AGRADECIMENTOS "Se vi mais longe foi por estar de pé sobre ombros de gigantes." (Isaac Newton) Quero agradecer a todas as pessoas que cientificamente e/ou pessoalmente me ajudaram a ver mais longe. À Prof. Doutora Carolina Lemos, por desde sempre ter confiado em mim e apoiado todos aqueles momentos em que eu surgia com “Tive uma ideia! Acho que podíamos…”. Pela orientação, incentivo e por mostrar o quão prazeroso é trabalhar em equipa. Gratidão! À Prof. Doutora Alda Sousa, um agradecimento muito especial, por toda a dedicação, racionalidade e partilha de conhecimentos demonstrada ao longo destes anos. Pelos conselhos tão imparciais e assertivos, sempre na altura certa. Ao Professor Jorge Sequeiros, por me ter aceitado desde início no seu grupo e continuar a apoiar os meus projetos. Pelas sábias correções e questões pertinentes que tem feito aos meus trabalhos. To Professor Sandra Encalada, thank you for welcoming me in your great lab and for everything you taught me about C. elegans. Your advice and support were very helpful to complete part of my graduate work. To Professor Jeffery Kelly, for the valuable collaboration, and for many insightful discussions and suggestions about amyloidosis. I also immensely appreciated the very kind and warm welcome to San Diego. À Dra. Teresa Coelho, por ter proporcionado as colaborações e fornecido muito do material que ajudaram a que esta tese fosse possível. Obrigado pelas interessantes e motivadoras reuniões e por ter partilhado tanto do seu excecional conhecimento sobre a PAF. À Prof. Doutora Isabel Alonso, pela disponibilidade e apoio neste projeto e por me ter transmitido muitas das minhas bases científicas. À Doutora Diana Santos, pela constante disponibilidade e ajuda. Pelo companheirismo neste mundo da PAF em que tantas histórias hilariantes partilhámos. À Dra. Ana Azevedo, pela estima, dedicação e contributo neste trabalho. Aos meus colegas da UnIGENe, Conceição, João, Sara, Marlene, Mariana, Joana, Cátia e Andreia, por todos os conselhos, amizade, pela prontidão em ajudar, boa disposição, e essencialmente por criarem um bom ambiente no laboratório. Aos meus colegas do CGPP, Ana Brandão, Ana Margarida, Rita, Patrícia, Susana, Paulo, Milena, Andreia e Victor, pela colaboração e ajuda ao longo destes anos. To Encalada Lab: Diana, Phil, Romain, George, Kayal and Shirley for their excellent team spirit and for making me feeling comfortable. I would like to specially mention Erin and Nirvan for your tremendously help, support and friendship. À Doutora Cecília Monteiro, por toda a amizade, encorajamento e constante cuidado. To everyone in Petrascheck, Wiseman and Kelly laboratories, for their support and assistance. À equipa da Unidade Corino de Andrade – CHP, pela disponibilidade e auxílio na recolha dos dados/amostras. Um especial agradecimento à Marta e à Vanessa, pela boa disposição e recetividade aos meus pedidos. Aos doentes e familiares, que foram imprescindíveis neste projeto. Aos meus Amigos, que durante estes anos compreenderam as minhas ausências e pelos desabafos e pelas tantas conversas não-científicas que me ajudavam a “desligar”. À Bárbara e Família, pelas palavras de ânimo, carinho, cuidado constante e motivação. Bem hajam! Aos meus Pais, pelo amor, alegria e apoio incondicional em tudo o que faço. Grato pela educação que também permitiu que esta tese fosse possível. Agradeço também à Fundação para a Ciência e a Tecnologia (FCT) a atribuição da bolsa de doutoramento SFRH/BD/101352/2014 e à Amyloidosis Foundation e à Pfizer o apoio nos projetos. Agradeço ao Instituto de Ciências Biomédicas de Abel Salazar (ICBAS); ao Instituto de Biologia Molecular e Celular (IBMC) - Instituto de Investigação e Inovação em Saúde (i3S) e ao The Scripps Research Institute por terem proporcionado as condições essenciais ao desenvolvimento desta tese. TABLE OF CONTENTS Publications .................................................................................................................................. I Abbreviations .............................................................................................................................. II Abstract ..................................................................................................................................... VI Sumário ................................................................................................................................... VIII INTRODUCTION ......................................................................................................................... 1 Transthyretin familial amyloid polyneuropathy (TTR-FAP) ....................................................... 5 History of FAP: Major Milestones ......................................................................................... 5 Genetic Scenario .................................................................................................................. 6 Epidemiology ........................................................................................................................ 8 Transthyretin Biochemistry ................................................................................................... 9 Transthyretin Aggregation .................................................................................................. 10 TTR Partners ...................................................................................................................... 11 Symptomatology ................................................................................................................ 13 Age-at-onset (AO) .............................................................................................................. 15 Genetic Modifiers ............................................................................................................... 17 Origin ................................................................................................................................. 19 Misdiagnosed/ Mimicking neuropathies .............................................................................. 19 Treatment ........................................................................................................................... 19 Animal Models .................................................................................................................... 22 MAIN OBJECTIVES .................................................................................................................. 25 Specific Objectives ................................................................................................................ 27 GENERAL METHODS .............................................................................................................. 29 RESULTS.................................................................................................................................. 35 Article 1: Beyond TTR Val30Met: potential regulatory variants associated with age-at-onset in familial amyloid polyneuropathy ............................................................................................. 38 Article 2: A trans-acting factor may modify age-at-onset in familial amyloid polyneuropathy ATTRV30M in Portugal .......................................................................................................... 56 Article 3: Large anticipation of genetic TTR Familial Amyloid Polyneuropathy Val30Met: MYH11 gene as a putative modulator .................................................................................... 80 Article 4: Cellular
Load more

Recommended publications
  • Supplemental Material Table of Contents
    Supplemental material Table of Contents Detailed Materials and Methods ......................................................................................................... 2 Perioperative period ........................................................................................................................... 2 Ethical aspects ................................................................................................................................... 4 Evaluation of heart failure ................................................................................................................. 4 Sample preparation for ANP mRNA expression .................................................................................. 5 Sample preparation for validative qRT-PCR (Postn, Myh7, Gpx3, Tgm2) ............................................ 6 Tissue fibrosis .................................................................................................................................... 7 Ventricular remodeling and histological tissue preservation ................................................................ 8 Evaluation of the histological preservation of cardiac tissue ................................................................ 9 Sample preparation and quantitative label-free proteomics analyses .................................................. 10 Statistical methods ........................................................................................................................... 12 References ........................................................................................................................................
    [Show full text]
  • Clinical and Prognostic Significance of MYH11 in Lung Cancer
    ONCOLOGY LETTERS 19: 3899-3906, 2020 Clinical and prognostic significance ofMYH11 in lung cancer MENG-JUN NIE1,2, XIAO-TING PAN1,2, HE-YUN TAO1,2, MENG-JUN XU1,2, SHEN-LIN LIU1, WEI SUN1, JIAN WU1 and XI ZOU1 1Oncology Department, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029; 2No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China Received May 14, 2019; Accepted February 21, 2020 DOI: 10.3892/ol.2020.11478 Abstract. Myosin heavy chain 11 (MYH11), encoded by 5-year survival rate is estimated to approximately 18% (2). the MYH11 gene, is a protein that participates in muscle Therefore, novel targets for drug treatment and prognosis of contraction through the hydrolysis of adenosine triphosphate. lung cancer are needed. Although previous studies have demonstrated that MYH11 Myosin heavy chain 11 (MYH11), which is encoded by gene expression levels are downregulated in several types of the MYH11 gene, is a smooth muscle myosin belonging to the cancer, its expression levels have rarely been investigated in myosin heavy chain family (3). MYH11 is a contractile protein lung cancer. The present study aimed to explore the clinical that slides past actin filaments to induce muscle contraction significance and prognostic value of MYH11 expression levels via adenosine triphosphate hydrolysis (4,5). Previous findings in lung cancer and to further study the underlying molecular have shown that in aortic tissue, destruction of MYH11 can mechanisms of the function of this gene. The Oncomine lead to vascular smooth muscle cell loss, disorganization database showed that the MYH11 expression levels were and hyperplasia, which is one of the mechanisms leading to decreased in lung cancer compared with those noted in the thoracic aortic aneurysms and dissections (6,7).
    [Show full text]
  • Communication Pathways in Human Nonmuscle Myosin-2C 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Authors: 25 Krishna Chinthalapudia,B,C,1, Sarah M
    1 Mechanistic Insights into the Active Site and Allosteric 2 Communication Pathways in Human Nonmuscle Myosin-2C 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Authors: 25 Krishna Chinthalapudia,b,c,1, Sarah M. Heisslera,d,1, Matthias Prellera,e, James R. Sellersd,2, and 26 Dietmar J. Mansteina,b,2 27 28 Author Affiliations 29 aInstitute for Biophysical Chemistry, OE4350 Hannover Medical School, 30625 Hannover, 30 Germany. 31 bDivision for Structural Biochemistry, OE8830, Hannover Medical School, 30625 Hannover, 32 Germany. 33 cCell Adhesion Laboratory, Department of Integrative Structural and Computational Biology, The 34 Scripps Research Institute, Jupiter, Florida 33458, USA. 35 dLaboratory of Molecular Physiology, NHLBI, National Institutes of Health, Bethesda, Maryland 36 20892, USA. 37 eCentre for Structural Systems Biology (CSSB), German Electron Synchrotron (DESY), 22607 38 Hamburg, Germany. 39 1K.C. and S.M.H. contributed equally to this work 40 2To whom correspondence may be addressed: E-mail: [email protected] or 41 [email protected] 42 43 1 44 Abstract 45 Despite a generic, highly conserved motor domain, ATP turnover kinetics and their activation by 46 F-actin vary greatly between myosin-2 isoforms. Here, we present a 2.25 Å crystal pre- 47 powerstroke state (ADPVO4) structure of the human nonmuscle myosin-2C motor domain, one 48 of the slowest myosins characterized. In combination with integrated mutagenesis, ensemble- 49 solution kinetics, and molecular dynamics simulation approaches, the structure reveals an 50 allosteric communication pathway that connects the distal end of the motor domain with the 51 active site.
    [Show full text]
  • Cardiogenetics Testing Reference Guide December 2018
    Cardiogenetics Testing reference guide December 2018 Why Choose Ambry More than 1 in 200 people have an inherited cardiovascular condition. Ambry’s mission is to provide the most advanced genetic testing information available to help you identity those at-risk and determine the best treatment options. If we know a patient has a disease-causing genetic change, not only does it mean better disease management, it also indicates that we can test others in the family and provide them with potentially life-saving information. Diseases and Testing Options cardiomyopathies arrhythmias Hypertrophic Cardiomyopathy (HCMNext) Catecholaminergic Polymorphic Ventricular Dilated Cardiomyopathy (DCMNext) Tachycardia (CPVTNext) Arrhythmogenic Right Ventricular Long QT Syndrome, Short QT Syndrome, Cardiomyopathy (ARVCNext) Brugada Syndrome (LongQTNext, RhythmNext) Cardiomyopathies (CMNext, CardioNext) Arrhythmias (RhythmNext, CardioNext) other cardio conditions Transthyretin Amyloidosis (TTR) familial hypercholesterolemia Noonan Syndrome (NoonanNext) and lipid disorders Hereditary Hemorrhagic Telangiectasia Familial Hypercholesterolemia (FHNext) (HHTNext) Sitosterolemia (Sitosterolemia Panel) Comprehensive Lipid Menu thoracic aortic aneurysms (CustomNext-Cardio) and dissections Familial Chylomicronemia Syndrome (FCSNext) Thoracic Aneurysms and Dissections, aortopathies (TAADNext) Marfan Syndrome (TAADNext) Ehlers-Danlos Syndrome (TAADNext) Targeted Panels Gene Comparison ALL PANELS HAVE A TURNAROUND TIME OF 2-3 WEEKS arrhythmias CPVTNext CPVTNext CASQ2,
    [Show full text]
  • Microrna Regulatory Pathways in the Control of the Actin–Myosin Cytoskeleton
    cells Review MicroRNA Regulatory Pathways in the Control of the Actin–Myosin Cytoskeleton , , Karen Uray * y , Evelin Major and Beata Lontay * y Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; [email protected] * Correspondence: [email protected] (K.U.); [email protected] (B.L.); Tel.: +36-52-412345 (K.U. & B.L.) The authors contributed equally to the manuscript. y Received: 11 June 2020; Accepted: 7 July 2020; Published: 9 July 2020 Abstract: MicroRNAs (miRNAs) are key modulators of post-transcriptional gene regulation in a plethora of processes, including actin–myosin cytoskeleton dynamics. Recent evidence points to the widespread effects of miRNAs on actin–myosin cytoskeleton dynamics, either directly on the expression of actin and myosin genes or indirectly on the diverse signaling cascades modulating cytoskeletal arrangement. Furthermore, studies from various human models indicate that miRNAs contribute to the development of various human disorders. The potentially huge impact of miRNA-based mechanisms on cytoskeletal elements is just starting to be recognized. In this review, we summarize recent knowledge about the importance of microRNA modulation of the actin–myosin cytoskeleton affecting physiological processes, including cardiovascular function, hematopoiesis, podocyte physiology, and osteogenesis. Keywords: miRNA; actin; myosin; actin–myosin complex; Rho kinase; cancer; smooth muscle; hematopoiesis; stress fiber; gene expression; cardiovascular system; striated muscle; muscle cell differentiation; therapy 1. Introduction Actin–myosin interactions are the primary source of force generation in mammalian cells. Actin forms a cytoskeletal network and the myosin motor proteins pull actin filaments to produce contractile force. All eukaryotic cells contain an actin–myosin network inferring contractile properties to these cells.
    [Show full text]
  • Bioinformatic Analysis Reveals the Importance of Epithelial-Mesenchymal Transition in the Development of Endometriosis
    www.nature.com/scientificreports OPEN Bioinformatic analysis reveals the importance of epithelial- mesenchymal transition in the development of endometriosis Meihong Chen1,6, Yilu Zhou2,3,6, Hong Xu4, Charlotte Hill2, Rob M. Ewing2,3, Deming He1, Xiaoling Zhang1 ✉ & Yihua Wang2,3,5 ✉ Background: Endometriosis is a frequently occurring disease in women, which seriously afects their quality of life. However, its etiology and pathogenesis are still unclear. Methods: To identify key genes/ pathways involved in the pathogenesis of endometriosis, we recruited 3 raw microarray datasets (GSE11691, GSE7305, and GSE12768) from Gene Expression Omnibus database (GEO), which contain endometriosis tissues and normal endometrial tissues. We then performed in-depth bioinformatic analysis to determine diferentially expressed genes (DEGs), followed by gene ontology (GO), Hallmark pathway enrichment and protein-protein interaction (PPI) network analysis. The fndings were further validated by immunohistochemistry (IHC) staining in endometrial tissues from endometriosis or control patients. Results: We identifed 186 DEGs, of which 118 were up-regulated and 68 were down-regulated. The most enriched DEGs in GO functional analysis were mainly associated with cell adhesion, infammatory response, and extracellular exosome. We found that epithelial-mesenchymal transition (EMT) ranked frst in the Hallmark pathway enrichment. EMT may potentially be induced by infammatory cytokines such as CXCL12. IHC confrmed the down-regulation of E-cadherin (CDH1) and up-regulation of CXCL12 in endometriosis tissues. Conclusions: Utilizing bioinformatics and patient samples, we provide evidence of EMT in endometriosis. Elucidating the role of EMT will improve the understanding of the molecular mechanisms involved in the development of endometriosis. Endometriosis is a frequently occurring gynaecological disease characterised by chronic pelvic pain, dysmenor- rhea and infertility1.
    [Show full text]
  • Geneseq®: Cardio
    LabCorp GeneSeq®: Cardio Helping you provide better patient care Testing for more than 100 genetic causes of familial cardiac disease. Treatment That May Help Clinical Utility Familial cardiac diseases are associated with up to 80% • Establish/confirm a diagnosis of familial cardiac disease. of cases of sudden cardiac death in young patients.1 • Identify the need for regular cardiac screening, lifestyle Identification of individuals with pathogenic mutations in changes, or pharmacological or surgical intervention to genes associated with cardiac disease may allow timely prevent the progression of cardiac disease and secondary initiation of screening and treatment that may help prevent complications. myocardial infarction, stroke, and sudden cardiac death. • Identify first-degree relatives of the proband who have inherited a disease-causing genetic variant and may be GeneSeq: Cardio at risk for myocardial infarction, stroke, or sudden cardiac death. can be a useful prognostic tool in the presence of a positive • Facilitate appropriate genetic counseling for probands family history and symptoms of cardiomyopathy, arrhythmia, and their first-degree relatives. aortopathy, Noonan syndrome, RASopathies, congenital heart disease, early-onset coronary artery disease, or familial hypercholesterolemia. Sample Requirements • 10 mL whole blood or 30 mL if ordering multiple tests. Six indications for testing, available separately or in combination Test No. Test Name Genes Included In the Profile 451422 GeneSeq®: Cardio - Familial Cardiomyopathy Profile
    [Show full text]
  • Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated with Downregulation of LMOD1, SYNPO2, PDLIM7, PLN and SYNM
    Markers of smooth muscle cells Perisic et al. Phenotypic modulation of smooth muscle cells in atherosclerosis is associated with downregulation of LMOD1, SYNPO2, PDLIM7, PLN and SYNM Matic Perisic L1, Rykaczewska U1, Razuvaev A1, Sabater-Lleal M2, Lengquist M1, Miller CL3, Ericsson I1, Röhl S1, Kronqvist M1, Aldi S1, Magné J2, Paloschi V2, Vesterlund M4, Li Y2, Jin H2, Gonzalez Diez M2, Roy J1, Baldassarre D5,6, Veglia F6, Humphries SE7, de Faire U8,9, Tremoli E5,6, on behalf of the IMPROVE study group, Odeberg J10, Vukojević V11, Lehtiö J4, Maegdefessel L2, Ehrenborg E2, Paulsson- Berne G2, Hansson GK2, Lindeman JHN12, Eriksson P2, Quertermous T3, Hamsten A2, Hedin U1 1Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden, 2Department of Medicine, Karolinska Institutet, Sweden, 3Division of Vascular Surgery, Stanford University, USA, 4Science for Life Laboratory, Sweden, 5Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy, 6Centro Cardiologico Monzino, IRCCS, Milan, Italy, 7British Heart Foundation Laboratories, University College of London, Department of Medicine, Rayne Building, London, United Kingdom, 8Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, 9Department of Cardiology, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden, 10Science for Life Laboratory, Department of Proteomics, Sweden, 11Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Sweden,
    [Show full text]
  • Engineered Type 1 Regulatory T Cells Designed for Clinical Use Kill Primary
    ARTICLE Acute Myeloid Leukemia Engineered type 1 regulatory T cells designed Ferrata Storti Foundation for clinical use kill primary pediatric acute myeloid leukemia cells Brandon Cieniewicz,1* Molly Javier Uyeda,1,2* Ping (Pauline) Chen,1 Ece Canan Sayitoglu,1 Jeffrey Mao-Hwa Liu,1 Grazia Andolfi,3 Katharine Greenthal,1 Alice Bertaina,1,4 Silvia Gregori,3 Rosa Bacchetta,1,4 Norman James Lacayo,1 Alma-Martina Cepika1,4# and Maria Grazia Roncarolo1,2,4# Haematologica 2021 Volume 106(10):2588-2597 1Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 2Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 3San Raffaele Telethon Institute for Gene Therapy, Milan, Italy and 4Center for Definitive and Curative Medicine, Stanford School of Medicine, Stanford, CA, USA *BC and MJU contributed equally as co-first authors #AMC and MGR contributed equally as co-senior authors ABSTRACT ype 1 regulatory (Tr1) T cells induced by enforced expression of interleukin-10 (LV-10) are being developed as a novel treatment for Tchemotherapy-resistant myeloid leukemias. In vivo, LV-10 cells do not cause graft-versus-host disease while mediating graft-versus-leukemia effect against adult acute myeloid leukemia (AML). Since pediatric AML (pAML) and adult AML are different on a genetic and epigenetic level, we investigate herein whether LV-10 cells also efficiently kill pAML cells. We show that the majority of primary pAML are killed by LV-10 cells, with different levels of sensitivity to killing. Transcriptionally, pAML sensitive to LV-10 killing expressed a myeloid maturation signature.
    [Show full text]
  • Gene- and Tissue-Level Interactions in Normal Gastrointestinal Development and Hirschsprung Disease
    Gene- and tissue-level interactions in normal gastrointestinal development and Hirschsprung disease Sumantra Chatterjeea,b,1, Priyanka Nandakumara,1, Dallas R. Auera,b, Stacey B. Gabrielc, and Aravinda Chakravartia,b,2 aCenter for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; bCenter for Human Genetics and Genomics, New York University School of Medicine, New York, NY 10016; and cGenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142 Contributed by Aravinda Chakravarti, November 1, 2019 (sent for review May 21, 2019; reviewed by William J. Pavan and Tatjana Sauka-Spengler) The development of the gut from endodermal tissue to an organ between the longitudinal and circular muscles, and the sub- with multiple distinct structures and functions occurs over a mucosal (Meissner’s) plexus, between the circular muscle and prolonged time during embryonic days E10.5–E14.5 in the mouse. the submucosal layer. The myenteric and submucoal plexuses During this process, one major event is innervation of the gut by provide motor innervation to both muscular layers of the gut, enteric neural crest cells (ENCCs) to establish the enteric nervous and secretomotor innervation of the mucosa nearest the lumen system (ENS). To understand the molecular processes underpinning of the gut, respectively (6). gut and ENS development, we generated RNA-sequencing profiles The many stages of gut development require numerous initiat- from wild-type mouse guts at E10.5, E12.5, and E14.5 from both ing signaling events activating transcription factors (TFs) targeting sexes. We also generated these profiles from homozygous Ret null diverse genes and pathways varying across development (7, 8).
    [Show full text]
  • Conformational Distributions of Isolated Myosin Motor Domains
    RESEARCH ARTICLE Conformational distributions of isolated myosin motor domains encode their mechanochemical properties Justin R Porter1, Artur Meller1, Maxwell I Zimmerman1, Michael J Greenberg1, Gregory R Bowman1,2* 1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine in St. Louis, St. Louis, United States; 2Center for the Science and Engineering of Living Systems, Washington University in St. Louis, St. Louis, United States Abstract Myosin motor domains perform an extraordinary diversity of biological functions despite sharing a common mechanochemical cycle. Motors are adapted to their function, in part, by tuning the thermodynamics and kinetics of steps in this cycle. However, it remains unclear how sequence encodes these differences, since biochemically distinct motors often have nearly indistinguishable crystal structures. We hypothesized that sequences produce distinct biochemical phenotypes by modulating the relative probabilities of an ensemble of conformations primed for different functional roles. To test this hypothesis, we modeled the distribution of conformations for 12 myosin motor domains by building Markov state models (MSMs) from an unprecedented two milliseconds of all-atom, explicit-solvent molecular dynamics simulations. Comparing motors reveals shifts in the balance between nucleotide-favorable and nucleotide-unfavorable P-loop conformations that predict experimentally measured duty ratios and ADP release rates better than sequence or individual structures. This result demonstrates the power of an ensemble perspective for interrogating sequence-function relationships. *For correspondence: [email protected] Competing interests: The authors declare that no Introduction competing interests exist. Myosin motors (Figure 1A) perform an extraordinary diversity of biological functions despite sharing Funding: See page 17 a common mechanochemical cycle.
    [Show full text]
  • Non‐Coding Variants in MYH11, FZD3, and SORCS3 Are Associated
    Received: 2 March 2020 Revised: 17 July 2020 Accepted: 3 August 2020 DOI: 10.1002/alz.12181 FEATURED ARTICLE Non-coding variants in MYH11, FZD3,andSORCS3 are associated with dementia in women Elizabeth E. Blue1 Timothy A. Thornton2 Charles Kooperberg3 Simin Liu4,5,6 Jean Wactawski-Wende7 JoAnn Manson8 Lew Kuller9 Kathleen Hayden10 Alexander P.Reiner3,11 1 Division of Medical Genetics, University of Washington, Seattle, Washington, USA 2 Department of Biostatistics, University of Washington, Seattle, Washington, USA 3 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA 4 Department of Epidemiology, Brown University, Providence, Rhode Island, USA 5 Department of Surgery, Brown University, Providence, Rhode Island, USA 6 Department of Medicine, Brown University, Providence, Rhode Island, USA 7 Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York, USA 8 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA 9 Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA 10 Department of Social Science and Health Policy, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA 11 Department of Epidemiology, University of Washington, Seattle, Washington, USA Correspondence Elizabeth E. Blue, Division of Medical Genet- Abstract ics, University of Washington, BOX 357220, Seattle WA 98195-7720. Introduction: Recent studies suggest that both sex-specific genetic risk factors and Email: [email protected] those shared between dementia and stroke are involved in dementia pathogenesis. Methods: We performed both single-variant and gene-based genome-wide associa- tion studies of >11,000 whole genome sequences from the Women’s Health Initiative cohort to discover loci associated with dementia, with adjustment for age, ethnicity, stroke, and venous thromboembolism status.
    [Show full text]