DOCSLIB.ORG

The Genetic Architecture of Down Syndrome Phenotypes Revealed by High-Resolution Analysis of Human Segmental Trisomies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Genetic Architecture of Down Syndrome Phenotypes Revealed by High-Resolution Analysis of Human Segmental Trisomies The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies Jan O. Korbela,b,c,1, Tal Tirosh-Wagnerd,1, Alexander Eckehart Urbane,f,1, Xiao-Ning Chend, Maya Kasowskie, Li Daid, Fabian Grubertf, Chandra Erdmang, Michael C. Gaod, Ken Langeh,i, Eric M. Sobelh, Gillian M. Barlowd, Arthur S. Aylsworthj,k, Nancy J. Carpenterl, Robin Dawn Clarkm, Monika Y. Cohenn, Eric Dorano, Tzipora Falik-Zaccaip, Susan O. Lewinq, Ira T. Lotto, Barbara C. McGillivrayr, John B. Moeschlers, Mark J. Pettenatit, Siegfried M. Pueschelu, Kathleen W. Raoj,k,v, Lisa G. Shafferw, Mordechai Shohatx, Alexander J. Van Ripery, Dorothy Warburtonz,aa, Sherman Weissmanf, Mark B. Gersteina, Michael Snydera,e,2, and Julie R. Korenbergd,h,bb,2 Departments of aMolecular Biophysics and Biochemistry, eMolecular, Cellular, and Developmental Biology, and fGenetics, Yale University School of Medicine, New Haven, CT 06520; bEuropean Molecular Biology Laboratory, 69117 Heidelberg, Germany; cEuropean Molecular Biology Laboratory (EMBL) Outstation Hinxton, EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom; dMedical Genetics Institute, Cedars–Sinai Medical Center, Los Angeles, CA 90048; gDepartment of Statistics, Yale University, New Haven, CT 06520; Departments of hHuman Genetics, and iBiomathematics, University of California, Los Angeles, CA 90095; Departments of jPediatrics and kGenetics, University of North Carolina, Chapel Hill, NC 27599; lCenter for Genetic Testing, Tulsa, OK 74136; mDivision of Medical Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92354; nDepartment of Genetics, Kinderzentrum Munich, 81377 Munich, Germany; oDepartment of Pediatrics and Neurology, Irvine Medical Center, University of California, Orange, CA 92868; pInstitute of Human Genetics, Western Galilee Hospital, Nahariya 22100, Israel; qSection of Clinical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84132; rDepartment of Medical Genetics, Women’s Health Centre, University of British Columbia, Vancouver, BC, Canada V6H 3V5; sSection of Clinical Genetics, Department of Pediatrics, Dartmouth–Hitchcock Medical Center, Lebanon, NH 03756; tDepartment of Pediatrics, Section on Medical Genetics, Wake Forest University School of Medicine, Winston-Salem, NC 27157; uChild Development Center, Rhode Island Hospital, Providence RI 02902; vDepartment of Pathology, University of North Carolina, Chapel Hill, NC 27514; wSignature Genomic Laboratories, Spokane, WA 99207; xRecanati Institute for Medical Genetics, Rabin Medical Center, Tel Aviv University, Petah Tikva, 49100 Israel; yGenetics Department, Kaiser Permanente Medical Offices, Sacramento, CA 95815; zDepartment of Genetics and Development, Columbia University, New York, NY 10032; aaChildren’s Hospital of New York, New York, NY 10032; and bbDepartment of Pediatrics, Center for Integrated Neurosciences and Human Behavior, The Brain Institute, University of Utah, Salt Lake City, UT 84108 Edited by Joseph R. Ecker, The Salk Institute for Biological Studies, La Jolla, CA, and approved May 29, 2009 (received for review December 30, 2008) Down syndrome (DS), or trisomy 21, is a common disorder associated gene–disease links have often been based on indirect evidence from with several complex clinical phenotypes. Although several hypoth- cellular or animal models (6, 7). Moreover, current hypotheses eses have been put forward, it is unclear as to whether particular gene argue for the existence of a critical region, the DS consensus region loci on chromosome 21 (HSA21) are sufficient to cause DS and its (DSCR), responsible for most severe DS features (6, 8, 9), or associated features. Here we present a high-resolution genetic map presume the causative role of a small set of genes including DSCR1 of DS phenotypes based on an analysis of 30 subjects carrying rare and DYRK1A,orAPP, for these phenotypes (6, 7). segmental trisomies of various regions of HSA21. By using state-of- By using state-of-the-art genomics together with a large panel of the-art genomics technologies we mapped segmental trisomies at partially trisomic individuals, we present the highest resolution DS exon-level resolution and identified discrete regions of 1.8–16.3 Mb phenotype map to date and identify distinct genomic regions that likely to be involved in the development of 8 DS phenotypes, 4 of likely contribute to the manifestation of 8 DS features. Four of these which are congenital malformations, including acute megakaryocytic phenotypes have never been associated with a particular region of leukemia, transient myeloproliferative disorder, Hirschsprung dis- HSA21. The map also enables us to rule out the necessary GENETICS ease, duodenal stenosis, imperforate anus, severe mental retardation, contribution of other HSA21 regions, thus providing strong evi- DS-Alzheimer Disease, and DS-specific congenital heart disease dence against the existence of a single DSCR, and a lack of support (DSCHD). Our DS-phenotypic maps located DSCHD to a <2-Mb inter- for the necessary synergistic roles of DSCR1 and DYRK1A,orAPP, val. Furthermore, the map enabled us to present evidence against the as predominant contributors to many DS phenotypes. necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS—i.e., the Results and Discussion presence of a single DS consensus region and the sufficiency of DSCR1 To construct a high-resolution map of DS we assembled a panel and DYRK1A,orAPP, in causing several severe DS phenotypes. Our of 30 individuals with rare, segmental trisomies 21 whose clinical study demonstrates the value of combining advanced genomics with features are summarized in Table 1. Nine patients are described cohorts of rare patients for studying DS, a prototype for the role of for the first time, 16 were reassessed with respect to phenotype, copy-number variation in complex disease. ͉ ͉ ͉ copy number variants genomic structural variation human genome Author contributions: J.O.K., T.T.-W., A.E.U., S.W., M. Snyder, and J.R.K. designed research; congenital heart disease ͉ leukemia J.O.K., T.T.-W., A.E.U., X.-N.C., M.K., L.D., F.G., M.C.G., K.L., E.M.S., G.M.B., A.S.A., N.J.C., R.D.C., M.Y.C., E.D., T.F.-Z., S.O.L., I.T.L., B.C.M., J.B.M., M.J.P., S.M.P., K.W.R., L.G.S., M. Shohat, A.J.V.R., D.W., M.B.G., M. Snyder, and J.R.K. performed research; C.E., K.L., and or over two decades trisomy 21 has represented a prototype E.M.S. contributed new reagents/analytic tools; J.O.K., T.T.-W., A.E.U., M. Snyder, and J.R.K. Fdisorder for the study of human aneuploidy and copy-number analyzed data; and J.O.K., T.T.-W., A.E.U., M. Snyder, and J.R.K. wrote the paper. variation (1, 2), but the genes responsible for most Down syndrome The authors declare no conflict of interest. (DS) phenotypes are still unknown. The analysis of several over- This article is a PNAS Direct Submission. lapping segmental trisomies 21 has led to the suggestion that dosage Freely available online through the PNAS open access option. alteration through duplication of an extended region on chromo- 1J.O.K, T.T.-W., and A.E.U. contributed equally to this work. some 21 (HSA21) is associated with DS features (2–5, 42). How- 2To whom correspondence may be addressed. E-mail: [email protected] or ever, humans with segmental trisomy 21 are rare, and thus human- [email protected]. based DS-phenotypic maps have been of low resolution, far beyond This article contains supporting information online at www.pnas.org/cgi/content/full/ the level of few or single genes, or even exons. Consequently, 0813248106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0813248106 PNAS ͉ July 21, 2009 ͉ vol. 106 ͉ no. 29 ͉ 12031–12036 Downloaded by guest on September 28, 2021 Table 1. Major clinical features of patients Feature JL JG GY IS MI WB JS KG GP KJ BS HOU WS MJF WA DS SOS SW MB ZSC JJS STO SOL JSB NA NO BA SM HAD PM DSCHD – – – – – – PDA† – – – AVSD*† ASD* – – AVSD§ – ϩ TOF*†‡ – TOF*†‡ MI† VSD* VSD*†‡ – ASD – AVSD PS† AVSD VSD*†‡ AMKL – – – – – – – – – – – ϩ –– ––– – – – – – – – –– –– –– TMD – – – – – – – – – – – – ϩ ––––––––ϩ –––––––– HSCR – – – – – – – – – – – – – – – – ϩ* ϩ* ϩ*– – – – – –– – DST – – – – – – ϩ*––– – ––– ––– –– – –– – ––– – IA –––––––––– – ––– ––– –––– ϩ*– – –– –– –– MR Ͻ30 P 59 Nor M M M M-P 85 70 52 ϩ 47 P M M 69 P M 42 P P 52 Numbers represent full scale IQ test. ϩ, phenotype present; –, phenotype not present; AVSD, atrioventricular septal defect; PDA, patent ductus arteriosus; ASD, atrial septal defect; TOF, tetralogy of Fallot; MI, mitral insufficiency; VSD, ventricular septal defect; PS, pulmonic stenosis; blank, no information available; P, profound MR; M, moderate MR. *Surgically repaired. †Determined by echocardiogram. ‡Determined by cardiac catheterization. §Determined by autopsy. molecular cytogenetics, and breakpoints, and 5 were previously phenotype) and expressivity (variation of the phenotype, such as published (2, 10). We note that the ability to parse DS genes to types of congenital heart disease) as is seen in full trisomy 21. phenotypes is determined by 3 factors: (i) phenotypic resolution, Specifically, we mapped HSA21 chromosomal rearrangements determined by the high-risk ratio of a given feature for DS versus across patients by successively and systematically applying several normal and by the number of affected individuals; (ii) molecular technologies
Load more

Recommended publications
  • Activation of ATM Depends on Chromatin Interactions Occurring Before Induction of DNA Damage
    LETTERS Activation of ATM depends on chromatin interactions occurring before induction of DNA damage Yong-Chul Kim1,6, Gabi Gerlitz1,6, Takashi Furusawa1, Frédéric Catez1,5, Andre Nussenzweig2, Kyu-Seon Oh3, Kenneth H. Kraemer3, Yosef Shiloh4 and Michael Bustin1,7 Efficient and correct responses to double-stranded breaks the KAP-1 protein9. The local and global changes in chromatin organiza- (DSB) in chromosomal DNA are crucial for maintaining genomic tion facilitate recruitment of damage-response proteins and remodelling stability and preventing chromosomal alterations that lead to factors, which further modify chromatin in the vicinity of the DSB and cancer1,2. The generation of DSB is associated with structural propagate the DNA damage response. Given the extensive changes in chro- changes in chromatin and the activation of the protein kinase matin structure associated with the DSB response, it could be expected ataxia-telangiectasia mutated (ATM), a key regulator of the that architectural chromatin-binding proteins, such as the high mobility signalling network of the cellular response to DSB3,4. The group (HMG) proteins, would be involved in this process10–12. interrelationship between DSB-induced changes in chromatin HMG is a superfamily of nuclear proteins that bind to chromatin architecture and the activation of ATM is unclear4. Here we show without any obvious specificity for a particular DNA sequence and affect that the nucleosome-binding protein HMGN1 modulates the the structure and activity of the chromatin fibre10,12,13. We have previ- interaction of ATM with chromatin both before and after DSB ously reported that HMGN1, an HMG protein that binds specifically to formation, thereby optimizing its activation.
    [Show full text]
  • The Mineralocorticoid Receptor Leads to Increased Expression of EGFR
    www.nature.com/scientificreports OPEN The mineralocorticoid receptor leads to increased expression of EGFR and T‑type calcium channels that support HL‑1 cell hypertrophy Katharina Stroedecke1,2, Sandra Meinel1,2, Fritz Markwardt1, Udo Kloeckner1, Nicole Straetz1, Katja Quarch1, Barbara Schreier1, Michael Kopf1, Michael Gekle1 & Claudia Grossmann1* The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important efector of the renin–angiotensin–aldosterone‑system and elicits pathophysiological efects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR‑mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identifed a SNP within the EGFR promoter that modulates MR‑induced EGFR expression. In RNA‑sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to diferential expression of cardiac ion channels, especially of the T‑type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone‑ and EGF‑responsiveness of CACNA1H expression was confrmed in HL‑1 cells by Western blot and by measuring peak current density of T‑type calcium channels. Aldosterone‑induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T‑type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL‑1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an efect on HL‑1 cell diameter, and the extent of this regulation seems to depend on the SNP‑216 (G/T) genotype.
    [Show full text]
  • Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
    Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A.
    [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]
  • Investigation of Copy Number Variations on Chromosome 21 Detected by Comparative Genomic Hybridization
    Li et al. Molecular Cytogenetics (2018) 11:42 https://doi.org/10.1186/s13039-018-0391-3 RESEARCH Open Access Investigation of copy number variations on chromosome 21 detected by comparative genomic hybridization (CGH) microarray in patients with congenital anomalies Wenfu Li, Xianfu Wang and Shibo Li* Abstract Background: The clinical features of Down syndrome vary among individuals, with those most common being congenital heart disease, intellectual disability, developmental abnormity and dysmorphic features. Complex combination of Down syndrome phenotype could be produced by partially copy number variations (CNVs) on chromosome 21 as well. By comparing individual with partial CNVs of chromosome 21 with other patients of known CNVs and clinical phenotypes, we hope to provide a better understanding of the genotype-phenotype correlation of chromosome 21. Methods: A total of 2768 pediatric patients sample collected at the Genetics Laboratory at Oklahoma University Health Science Center were screened using CGH Microarray for CNVs on chromosome 21. Results: We report comprehensive clinical and molecular descriptions of six patients with microduplication and seven patients with microdeletion on the long arm of chromosome 21. Patients with microduplication have varied clinical features including developmental delay, microcephaly, facial dysmorphic features, pulmonary stenosis, autism, preauricular skin tag, eye pterygium, speech delay and pain insensitivity. We found that patients with microdeletion presented with developmental delay, microcephaly, intrauterine fetal demise, epilepsia partialis continua, congenital coronary anomaly and seizures. Conclusion: Three patients from our study combine with four patients in public database suggests an association between 21q21.1 microduplication of CXADR gene and patients with developmental delay. One patient with 21q22.13 microdeletion of DYRK1A shows association with microcephaly and scoliosis.
    [Show full text]
  • Cdk15 Igfals Lingo4 Gjb3 Tpbg Lrrc38 Serpinf1 Apod Trp73 Lama4 Chrnd Col9a1col11a1col5a2 Fgl2 Pitx2 Col2a1 Col3a1 Lamb3 Col24a1
    Bnc2 Wdr72 Ptchd1 Abtb2 Spag5 Zfp385a Trim17 Ier2 Il1rapl1 Tpd52l1 Fam20a Car8 Syt5 Plxnc1 Sema3e Ndrg4 Snph St6galnac5 Mcpt2 B3galt2 Sphkap Arhgap24 Prss34 Lhfpl2 Ermap Rnf165 Shroom1 Grm4 Mobp Dock2 Tmem9b Slc35d3 Otud7b Serpinb3a Sh3d19 Syt6 Zan Trim67 Clec18a Mcoln1 Tob1 Slc45a2 Pcdhb9 Pcdh17 Plscr1 Gpr143 Cela1 Frem1 Sema3f Lgi2 Igsf9 Fjx1 Cpne4 Adgb Depdc7 Gzmm C1qtnf5 Capn11 Sema3c H2-T22 Unc5c Sytl4 Galnt5 Sytl2 Arhgap11a Pcdha1 Cdh20 Slc35f2 Trim29 B3gnt5 Dock5 Trim9 Padi4 Pcdh19 Abi2 Cldn11 Slitrk1 Fam13a Nrgn Cpa4 Clmp Il1rap Trpm1 Fat4 Nexn Pmel Mmp15 Fat3 H2-M5 Prss38 Wdr41 Prtg Mlana Mettl22 Tnrc6b Cdh6 Sema3b Ptgfrn Cldn1 Cntn4 Bcl2a1b Capn6 Capn5 Pcdhb19 Tcf15 Bmf Rgs8 Tecrl Tyrp1 Rhot1 Rnf123 Cldn6 Adam9 Hlx Rilpl1 Disp1 Atcay Vwc2 Fat2 Srpx2 Cldn3 Unc13c Creb3l1 Rab39b Robo3 Gpnmb Bves Orai2 Slc22a2 Prss8 Cdh10 Scg3 Adam33 Nyx Dchs1 Chmp4c Syt9 Ap1m2 Megf10 Cthrc1 Penk Igsf9b Akap2 Ltbp3 Dnmbp Tff2 Pnoc Vldlr Cpa3 Snx18 Capn3 Btla Htr1b Gm17231 Pcdh9Rab27a Grm8 Cnih2 Scube2 Id2 Reep1 Cpeb3 Mmp16 Slc18b1 Snx33 Clcn5 Cckbr Pkp2 Drp2 Mapk8ip1 Lrrc3b Cxcl14 Zfhx3 Esrp1 Prx Dock3 Sec14l1 Prokr1 Pstpip2 Usp2 Cpvl Syn2 Ntn1 Ptger1 Rxfp3 Tyr Snap91 Htr1d Mtnr1a Gadd45g Mlph Drd4 Foxc2 Cldn4 Birc7 Cdh17 Twist2 Scnn1b Abcc4 Pkp1 Dlk2 Rab3b Amph Mreg Il33 Slit2 Hpse Micu1 Creb3l2 Dsp Lifr S1pr5 Krt15 Svep1 Ahnak Kcnh1 Sphk1 Vwce Clcf1 Ptch2 Pmp22 Sfrp1 Sema6a Lfng Hs3st5 Efcab1 Tlr5 Muc5acKalrn Vwa2 Fzd8 Lpar6 Bmp5 Slc16a9 Cacng4 Arvcf Igfbp2 Mrvi1 Dusp15 Krt5 Atp13a5 Dsg1a Kcnj14 Edn3Memo1 Ngef Prickle2 Cma1 Alx4 Bmp3 Blnk GastAgtr2
    [Show full text]
  • HMGB1 in Health and Disease R
    Donald and Barbara Zucker School of Medicine Journal Articles Academic Works 2014 HMGB1 in health and disease R. Kang R. C. Chen Q. H. Zhang W. Hou S. Wu See next page for additional authors Follow this and additional works at: https://academicworks.medicine.hofstra.edu/articles Part of the Emergency Medicine Commons Recommended Citation Kang R, Chen R, Zhang Q, Hou W, Wu S, Fan X, Yan Z, Sun X, Wang H, Tang D, . HMGB1 in health and disease. 2014 Jan 01; 40():Article 533 [ p.]. Available from: https://academicworks.medicine.hofstra.edu/articles/533. Free full text article. This Article is brought to you for free and open access by Donald and Barbara Zucker School of Medicine Academic Works. It has been accepted for inclusion in Journal Articles by an authorized administrator of Donald and Barbara Zucker School of Medicine Academic Works. Authors R. Kang, R. C. Chen, Q. H. Zhang, W. Hou, S. Wu, X. G. Fan, Z. W. Yan, X. F. Sun, H. C. Wang, D. L. Tang, and +8 additional authors This article is available at Donald and Barbara Zucker School of Medicine Academic Works: https://academicworks.medicine.hofstra.edu/articles/533 NIH Public Access Author Manuscript Mol Aspects Med. Author manuscript; available in PMC 2015 December 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Mol Aspects Med. 2014 December ; 0: 1–116. doi:10.1016/j.mam.2014.05.001. HMGB1 in Health and Disease Rui Kang1,*, Ruochan Chen1, Qiuhong Zhang1, Wen Hou1, Sha Wu1, Lizhi Cao2, Jin Huang3, Yan Yu2, Xue-gong Fan4, Zhengwen Yan1,5, Xiaofang Sun6, Haichao Wang7, Qingde Wang1, Allan Tsung1, Timothy R.
    [Show full text]
  • V45n4a03.Pdf
    Montoya JC/et al/Colombia Médica - Vol. 45 Nº4 2014 (Oct-Dec) Colombia Médica colombiamedica.univalle.edu.co Original Article Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain Expresión diferencial global de genes localizados en la Región Crítica del Síndrome de Down en el cerebro humano normal Julio Cesar Montoya1,3, Dianora Fajardo2, Angela Peña2 , Adalberto Sánchez1, Martha C Domínguez1,2, José María Satizábal1, Felipe García-Vallejo1,2 1 Department of Physiological Sciences, School of Basic Sciences, Faculty of Health, Universidad del Valle. 2 Laboratory of Molecular Biology and Pathogenesis LABIOMOL. Universidad del Valle, Cali, Colombia. 3 Faculty of Basic Sciences, Universidad Autónoma de Occidente, Cali, Colombia. Montoya JC , Fajardo D, Peña A , Sánchez A, Domínguez MC, Satizábal JM, García-Vallejo F.. Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain. Colomb Med. 2014; 45(4): 154-61. © 2014 Universidad del Valle. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Article history Abstract Resumen Background: The information of gene expression obtained from Introducción: La información de la expresión de genes consignada Received: 2 July 2014 Revised: 10 November 2014 databases, have made possible the extraction and analysis of data en bases de datos, ha permitido extraer y analizar información acerca Accepted: 19 December 2014 related with several molecular processes involving not only in procesos moleculares implicados tanto en la homeostasis cerebral y su brain homeostasis but its disruption in some neuropathologies; alteración en algunas neuropatologías.
    [Show full text]
  • Repositório Da Universidade De Lisboa
    UNIVERSIDADE DE LISBOA FACULDADE DE CIÊNCIAS DEPARTAMENTO DE BIOLOGIA ANIMAL TOWARDS THE IDENTIFICATION OF BIOMARKERS FOR CYSTIC FIBROSIS BY PROTEOMICS NUNO MIGUEL ANTUNES GARCIA CHARRO DOUTORAMENTO EM BIOLOGIA ESPECIALIDADE BIOLOGIA MOLECULAR 2011 ii iii iv UNIVERSIDADE DE LISBOA FACULDADE DE CIÊNCIAS DEPARTAMENTO DE BIOLOGIA ANIMAL TOWARDS THE IDENTIFICATION OF BIOMARKERS FOR CYSTIC FIBROSIS BY PROTEOMICS Tese orientada pela Doutora Deborah Penque e Professora Doutora Ana Maria Viegas Gonçalves Crespo NUNO MIGUEL ANTUNES GARCIA CHARRO DOUTORAMENTO EM BIOLOGIA (BIOLOGIA MOLECULAR) 2011 v The research described in this thesis was conducted at Laboratório de Proteómica, Departamento de Genética, Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA, I.P.), Lisbon, Portugal; Clinical Proteomics Facility, University of Pittsburgh Medical Centre, Pennsylvania, USA; and Laboratory of Proteomics and Analytical Technologies, National Cancer Institute at Frederick, Maryland, USA. Work partially supported by Fundação para a Ciência e a Tecnologia (FCT), Fundo Europeu para o Desenvolvimento (FEDER) (POCI/SAU-MMO/56163/2004), FCT/Poly-Annual Funding Program and FEDER/Saúde XXI Program (Portugal). Nuno Charro is a recipient of FCT doctoral fellowship (SFRH/BD/27906/2006). vi Agradecimentos/Acknowledgements “Nothing is hidden that will not be made known; Nothing is secret that will not come to light” Desde muito pequeno, a minha vontade em querer saber mais e porquê foi sempre presença constante. Ao iniciar e no decorrer da minha (ainda) curta na investigação científica, as perguntas foram mudando, o método também e várias pessoas contribuíram para o crescimento e desenvolvimento da minha personalidade científica e pessoal. Espero não me esquecer de ninguém e, se o fizer, não é intencional; apenas falibilidade.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Renal Physiology
    Renal Physiology Distal Convoluted Tubule | Arohan R. Subramanya*†‡ and David H. Ellison§ ¶ Abstract The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a critical role in sodium, potassium, and divalent cation homeostasis. Recent genetic and physiologic studies have greatly expanded our understanding of how the distal convoluted tubule regulates these processes at the molecular level. This article provides an update on the distal convoluted tubule, highlighting concepts and pathophysiology relevant to clinical Departments of *Medicine and †Cell practice. Biology, University of Clin J Am Soc Nephrol 9: 2147–2163, 2014. doi: 10.2215/CJN.05920613 Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ‡Veterans Affairs Introduction structure to glucocorticoids, such as cortisol, and both Pittsburgh Healthcare The distal convoluted tubule (DCT) is the portion aldosterone and cortisol bind to the mineralocorticoid System, Pittsburgh, of the nephron that is immediately downstream of receptor with nearly equal affinity (3). Although min- Pennsylvania; the macula densa. Although the DCT is the shortest eralocorticoid receptors are expressed throughout the Departments of §Medicine and | segment of the nephron, spanning only about 5 mm entire DCT, the DCT2 is sensitive to the actions of Physiology and in length in humans (1), it plays a critical role in a va- aldosterone, because it expresses an enzyme called Pharmacology, riety of homeostatic processes, including sodium chlo- 11-b hydroxysteroid dehydrogenase 2 (11-bHSD2). Oregon Health and ride reabsorption, potassium secretion, and calcium 11-bHSD2 metabolizes cortisol to the inactive metab- Science University, Portland, Oregon; and and magnesium handling.
    [Show full text]
  • Concerted Action of KCNJ15/Kir4.2 and Intracellular Polyamines in Sensing Physiological Electric Fields for Galvanotaxis
    Concerted action of KCNJ15/Kir4.2 and intracellular polyamines in sensing physiological electric fields for galvanotaxis Ken-ichi Nakajima1, Min Zhao1,2 1Department of Dermatology, 2Department of Ophthalmology, School of Medicine, University of California Davis Correspondence to: Min Zhao; Email: [email protected] Keywords: inwardly rectifying K+ channel, polyamine, galvanotaxis, cell migration, electric field Autocommentary to: Nakajima K, Zhu K, Sun YH, Hegyi B, Zeng Q, Murphy CJ, Small JV, Chen-Izu Y, Izumiya Y, Penninger JM, Zhao M. KCNJ15/Kir4.2 couples with polyamines to sense weak extracellular electric fields in galvanotaxis. Nat Commun. 2015;6:8532. doi: 10.1038/ncomms9532. PubMed PMID: 26449415; PMCID: PMC4603535 Many motile cells, including epithelial cells, keratinocytes, leukocytes and cancer cells, can sense extracellular weak electric fields (EFs), and migrate directionally, a phenomenon termed electrotaxis/galvanotaxis (1). Direct current EFs have been detected at wounds, tissue lesions and during development in many organisms, including human. The molecular mechanisms by which cell senses extracellular EFs, however, remain largely unknown (1). "Taxis" is the directional movement of a cell (or a free-moving organism) in response to environmental stimuli, and plays fundamental roles at both cellular and tissue levels (2). Many types of taxis have been identified, and some of them are well characterized (2). For example, directional migration of cells toward or away from a soluble chemical compound is known as chemotaxis, and many receptors that are necessary for sensing the chemical compound and transduce its signals to intracellular downstream pathways have been identified and well characterized (3). Previous research demonstrated that galvanotaxis shares some similar signaling pathways with chemotaxis (4).
    [Show full text]