DOCSLIB.ORG

Analysis of IFT74 As a Candidate Gene for Chromosome 9P-Linked ALS-FTD Parastoo Momeni National Institutes of Health

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Analysis of IFT74 As a Candidate Gene for Chromosome 9P-Linked ALS-FTD Parastoo Momeni National Institutes of Health Washington University School of Medicine Digital Commons@Becker Open Access Publications 2006 Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD Parastoo Momeni National Institutes of Health Jennifer Schymick National Institutes of Health Shushant Jain National Institutes of Health Mark R. Cookson National Institutes of Health Nigel J. Cairns Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Part of the Medicine and Health Sciences Commons Recommended Citation Momeni, Parastoo; Schymick, Jennifer; Jain, Shushant; Cookson, Mark R.; Cairns, Nigel J.; Greggio, Elisa; Greenway, Matthew J.; Berger, Stephen; Pickering-Brown, Stuart; Chiò, Adriano; Fung, Hon Chung; Holtzman, David M.; Huey, Edward D.; Wassermann, Eric M.; Adamson, Jennifer; Hutton, Michael L.; Rogaeva, Ekaterina; St George-Hyslop, Peter; Rothstein, Jeffrey D.; Hardiman, Orla; Grafman, Jordan; Singleton, Andrew; Hardy, John; and Traynor, Bryan J., ,"Analysis of IFT74 as a candidate gene for chromosome 9p- linked ALS-FTD." BMC Neurology.,. 44. (2006). https://digitalcommons.wustl.edu/open_access_pubs/170 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Parastoo Momeni, Jennifer Schymick, Shushant Jain, Mark R. Cookson, Nigel J. Cairns, Elisa Greggio, Matthew J. Greenway, Stephen Berger, Stuart Pickering-Brown, Adriano Chiò, Hon Chung Fung, David M. Holtzman, Edward D. Huey, Eric M. Wassermann, Jennifer Adamson, Michael L. Hutton, Ekaterina Rogaeva, Peter St George-Hyslop, Jeffrey D. Rothstein, Orla Hardiman, Jordan Grafman, Andrew Singleton, John Hardy, and Bryan J. Traynor This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/170 BMC Neurology BioMed Central Research article Open Access Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD Parastoo Momeni†1, Jennifer Schymick†1, Shushant Jain†1, Mark R Cookson1, Nigel J Cairns2,3, Elisa Greggio1, Matthew J Greenway4, Stephen Berger1, Stuart Pickering-Brown5, Adriano Chiò6, Hon Chung Fung1, David M Holtzman2, Edward D Huey7, Eric M Wassermann7, Jennifer Adamson8, Michael L Hutton8, Ekaterina Rogaeva9, Peter St George- Hyslop9, Jeffrey D Rothstein10, Orla Hardiman11, Jordan Grafman7, Andrew Singleton1, John Hardy*1 and Bryan J Traynor12 Address: 1Laboratory of Neurogenetics, National Institute of Aging, NIH, Bethesda, MD, USA, 2Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA, 3Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA, 4Department of Clinical Neurological Sciences Royal College of Surgeons in Ireland, Dublin, Ireland, 5Centre for Clinical Neurosciences, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital, Salford, UK, 6Department of Neuroscience, Via Cherasco 15, 10126 Turin, Italy, 7Cognitive Neuroscience Section, National Institute of Neurological Diseases and Stroke, Bethesda, MD 20892, USA, 8Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida, USA, 9Department of Medicine and Physiology, Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada, 10Department of Neurology and Neuroscience, Johns Hopkins University, Baltimore, Maryland, USA, 11Department of Neurology, Beaumont Hospital, Dublin 9, Ireland and 12SDGE, National Institute of Mental Health, Bethesda, Maryland, USA Email: Parastoo Momeni - [email protected]; Jennifer Schymick - [email protected]; Shushant Jain - [email protected]; Mark R Cookson - [email protected]; Nigel J Cairns - [email protected]; Elisa Greggio - [email protected]; Matthew J Greenway - [email protected]; Stephen Berger - [email protected]; Stuart Pickering-Brown - [email protected]; Adriano Chiò - [email protected]; Hon Chung Fung - [email protected]; David M Holtzman - [email protected]; Edward D Huey - [email protected]; Eric M Wassermann - [email protected]; Jennifer Adamson - [email protected]; Michael L Hutton - [email protected]; Ekaterina Rogaeva - [email protected]; Peter St George- Hyslop - [email protected]; Jeffrey D Rothstein - [email protected]; Orla Hardiman - [email protected]; Jordan Grafman - [email protected]; Andrew Singleton - [email protected]; John Hardy* - [email protected]; Bryan J Traynor - [email protected] * Corresponding author †Equal contributors Published: 13 December 2006 Received: 03 August 2006 Accepted: 13 December 2006 BMC Neurology 2006, 6:44 doi:10.1186/1471-2377-6-44 This article is available from: http://www.biomedcentral.com/1471-2377/6/44 © 2006 Momeni et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: A new locus for amyotrophic lateral sclerosis – frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p. Methods: We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus. Results: Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in Page 1 of 11 (page number not for citation purposes) BMC Neurology 2006, 6:44 http://www.biomedcentral.com/1471-2377/6/44 a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples. Conclusion: Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families. Background Methods Amyotrophic lateral sclerosis (ALS, Online Mendelian Subjects and samples Inheritance in Man (OMIM) 105400) is characterized by F476 was a four-generation, 15-member North American progressive motor neuron degeneration resulting in paral- ALS-FTD kindred. The proband (figure 2a, III-3) was a 58- ysis and death, usually from respiratory failure, within 3 year-old male with a seven year history of behavioral FTD to 5 years of symptom onset[1]. ALS is typically sporadic symptoms who subsequently developed ALS during the in nature. However, 5–10% of cases are familial, and the course of his illness. His younger brother (III-4) devel- identification of causal mutations has provided insight oped perseveration, lack of insight and dysregulation of into the disease processes that lead to neurodegeneration social and interpersonal conduct at the age of 52. He later [2-5]. Frontotemporal dementia (FTD, OMIM 600274) is developed motor weakness and remains alive three years a degenerative disorder of the frontal and anterior tempo- after disease onset. An older brother (III-1) began show- ral lobes [6] and is the second most common cause of ing poor judgment and inappropriate behavior at 50 years dementia accounting for approximately 20% of pre-senile of age. He died twelve years later with severe dementia. cases [7]. The syndrome is characterized clinically by ini- Marked frontal and anterior temporal lobe atrophy was tial behavioral and psychological disturbances, followed detected at post-mortem. Histology revealed the stereo- by cognitive decline eventually leading to dementia and typical features of frontotemporal lobar degenerations death within a median of seven years from symptom (FTLDs): neuronal loss, microvacuolation, and gliosis onset [8]. There is a family history of dementia in over (figure 3). The frontal lobe was the most severely affected 40% of FTD cases suggesting genetic components [8]. region with focal trancortical neuronal loss. Ubiquitin immunohistochemistry revealed neuronal cytoplasmic Clinical and pathological data indicate that ALS and FTD inclusions, sparse neuronal intranuclear inclusions, and can form a spectrum of disease [9]. Approximately 5% of dystrophic neurites identical to those seen in familial and ALS patients have clinically florid dementia (ALS-FTD) sporadic cases of FTLD with ubiquitin-positive, tau-nega- [10] and roughly half of patients with "classical" ALS have tive inclusions (FTLD-U). There were Bunina bodies in the subtle frontal and temporal lobe impairment [11]. Many motor neurons of the anterior horns of the cervical spinal sporadic and familial FTD cases similarly develop clinical cord, but there was no evidence of corticospinal tract symptoms of motor neuron
Load more

Recommended publications
  • Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice
    Loyola University Chicago Loyola eCommons Biology: Faculty Publications and Other Works Faculty Publications 2013 Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice Mihaela Palicev Gunter P. Wagner James P. Noonan Benedikt Hallgrimsson James M. Cheverud Loyola University Chicago, [email protected] Follow this and additional works at: https://ecommons.luc.edu/biology_facpubs Part of the Biology Commons Recommended Citation Palicev, M, GP Wagner, JP Noonan, B Hallgrimsson, and JM Cheverud. "Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice." Genome Biology and Evolution 5(10), 2013. This Article is brought to you for free and open access by the Faculty Publications at Loyola eCommons. It has been accepted for inclusion in Biology: Faculty Publications and Other Works by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. © Palicev et al., 2013. GBE Genomic Correlates of Relationship QTL Involved in Fore- versus Hind Limb Divergence in Mice Mihaela Pavlicev1,2,*, Gu¨ nter P. Wagner3, James P. Noonan4, Benedikt Hallgrı´msson5,and James M. Cheverud6 1Konrad Lorenz Institute for Evolution and Cognition Research, Altenberg, Austria 2Department of Pediatrics, Cincinnati Children‘s Hospital Medical Center, Cincinnati, Ohio 3Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University 4Department of Genetics, Yale University School of Medicine 5Department of Cell Biology and Anatomy, The McCaig Institute for Bone and Joint Health and the Alberta Children’s Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Canada 6Department of Anatomy and Neurobiology, Washington University *Corresponding author: E-mail: [email protected].
    [Show full text]
  • Proteomics Provides Insights Into the Inhibition of Chinese Hamster V79
    www.nature.com/scientificreports OPEN Proteomics provides insights into the inhibition of Chinese hamster V79 cell proliferation in the deep underground environment Jifeng Liu1,2, Tengfei Ma1,2, Mingzhong Gao3, Yilin Liu4, Jun Liu1, Shichao Wang2, Yike Xie2, Ling Wang2, Juan Cheng2, Shixi Liu1*, Jian Zou1,2*, Jiang Wu2, Weimin Li2 & Heping Xie2,3,5 As resources in the shallow depths of the earth exhausted, people will spend extended periods of time in the deep underground space. However, little is known about the deep underground environment afecting the health of organisms. Hence, we established both deep underground laboratory (DUGL) and above ground laboratory (AGL) to investigate the efect of environmental factors on organisms. Six environmental parameters were monitored in the DUGL and AGL. Growth curves were recorded and tandem mass tag (TMT) proteomics analysis were performed to explore the proliferative ability and diferentially abundant proteins (DAPs) in V79 cells (a cell line widely used in biological study in DUGLs) cultured in the DUGL and AGL. Parallel Reaction Monitoring was conducted to verify the TMT results. γ ray dose rate showed the most detectable diference between the two laboratories, whereby γ ray dose rate was signifcantly lower in the DUGL compared to the AGL. V79 cell proliferation was slower in the DUGL. Quantitative proteomics detected 980 DAPs (absolute fold change ≥ 1.2, p < 0.05) between V79 cells cultured in the DUGL and AGL. Of these, 576 proteins were up-regulated and 404 proteins were down-regulated in V79 cells cultured in the DUGL. KEGG pathway analysis revealed that seven pathways (e.g.
    [Show full text]
  • Uncoupling Intraflagellar Transport and Primary Cilia Formation Demonstrates Deep Integration of IFT in Hedgehog Signaling
    bioRxiv preprint doi: https://doi.org/10.1101/226324; this version posted November 28, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Uncoupling Intraflagellar Transport and Primary Cilia Formation Demonstrates Deep Integration of IFT in Hedgehog Signaling Thibaut Eguether1, 2, Fabrice P Cordelieres3, Gregory J Pazour1, 4 1Program in Molecular Medicine University of Massachusetts Medical School Biotech II, Suite 213 373 Plantation Street Worcester, MA 01605, USA [email protected] 2Current address Université Pierre et Marie Curie U1157 INSERM / UMR 7203 ENS CNRS UPMC Faculté de Médecine Pierre et Marie Curie Etage 6 porte 606 27 rue de Chaligny 75012 Paris, France [email protected] 3Université de Bordeaux UMS 3420 CNRS-Université de Bordeaux-US4 INSERM, Bordeaux Imaging Center Pôle d’imagerie photonique Bordeaux F-33000, France [email protected] 4Corresponding Author Running Title: Uncoupling IFT and ciliogenesis Key words: Primary cilia, Intraflagellar Transport, IFT, Hedgehog Signaling Abbreviations: MEFs, mouse embryonic fibroblasts; SAG, smoothen agonist; IFT intraflagellar transport; FKBP, FK506 Binding Protein 12; FRB, FKBP12-rapamycin binding bioRxiv preprint doi: https://doi.org/10.1101/226324; this version posted November 28, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The vertebrate hedgehog pathway is organized in primary cilia and hedgehog components relocate into or out of cilia during signaling. Defects in intraflagellar transport (IFT) typically disrupt ciliary assembly and attenuate hedgehog signaling.
    [Show full text]
  • Variation in Protein Coding Genes Identifies Information
    bioRxiv preprint doi: https://doi.org/10.1101/679456; this version posted June 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Animal complexity and information flow 1 1 2 3 4 5 Variation in protein coding genes identifies information flow as a contributor to 6 animal complexity 7 8 Jack Dean, Daniela Lopes Cardoso and Colin Sharpe* 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Institute of Biological and Biomedical Sciences 25 School of Biological Science 26 University of Portsmouth, 27 Portsmouth, UK 28 PO16 7YH 29 30 * Author for correspondence 31 [email protected] 32 33 Orcid numbers: 34 DLC: 0000-0003-2683-1745 35 CS: 0000-0002-5022-0840 36 37 38 39 40 41 42 43 44 45 46 47 48 49 Abstract bioRxiv preprint doi: https://doi.org/10.1101/679456; this version posted June 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Animal complexity and information flow 2 1 Across the metazoans there is a trend towards greater organismal complexity. How 2 complexity is generated, however, is uncertain. Since C.elegans and humans have 3 approximately the same number of genes, the explanation will depend on how genes are 4 used, rather than their absolute number.
    [Show full text]
  • Blood-Based Molecular Biomarker Signatures in Alzheimer's
    bioRxiv preprint doi: https://doi.org/10.1101/481879; this version posted December 31, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Article Blood-based molecular biomarker signatures in Alzheimer’s disease: insights from systems biomedicine perspective Tania Islam 1,#, Md. Rezanur Rahman 2,#,*, Md. Shahjaman3, Toyfiquz Zaman2, Md. Rezaul Karim2, Julian M.W. Quinn4, R.M. Damian Holsinger5,6, and Mohammad Ali Moni 6,* 1Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia, Bangladesh; [email protected](T.I.). 2 Department of Biochemistry and Biotechnology, School of Biomedical Science, Khwaja Yunus Ali University, Sirajgonj, Bangladesh; [email protected](M.R.R.). 3 Department of Statistics, Begum Rokeya University, Rangpur, Bangladesh; [email protected] (M.S.). 4 Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia;[email protected](J.W.W.Q.). 5 Laboratory of Molecular Neuroscience and Dementia, Brain and Mind Centre, The University of Sydney, Camperdown, NSW, Australia; [email protected] (R.M.D.H.). 6 Discipline of Biomedical Science, School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia; [email protected] (M.A.M.). #These two authors have made an equal contribution and hold joint first authorship for this work. * Correspondence: [email protected] (M.R.R.) or [email protected] (M.A.M.). Abstract: Background and objectives: Alzheimer’s disease (AD) is the progressive neurodegenerative disease characterized by dementia, but no peripheral biomarkers available yet that can detect the AD.
    [Show full text]
  • High Diagnostic Yield in Skeletal Ciliopathies Using Massively Parallel Genome Sequencing, Structural Variant Screening and RNA Analyses
    Journal of Human Genetics (2021) 66:995–1008 https://doi.org/10.1038/s10038-021-00925-x ARTICLE High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses 1 1 2,3 4 1 Anna Hammarsjö ● Maria Pettersson ● David Chitayat ● Atsuhiko Handa ● Britt-Marie Anderlid ● 5 6 7 8 9 Marco Bartocci ● Donald Basel ● Dominyka Batkovskyte ● Ana Beleza-Meireles ● Peter Conner ● 10 11 12,13 7,14 15 Jesper Eisfeldt ● Katta M. Girisha ● Brian Hon-Yin Chung ● Eva Horemuzova ● Hironobu Hyodo ● 16 1 17 18,19 20 Liene Korņejeva ● Kristina Lagerstedt-Robinson ● Angela E. Lin ● Måns Magnusson ● Shahida Moosa ● 11 10 21 15 18,22 Shalini S. Nayak ● Daniel Nilsson ● Hirofumi Ohashi ● Naoko Ohashi-Fukuda ● Henrik Stranneheim ● 1 23 24 19,22 1 7,25 Fulya Taylan ● Rasa Traberg ● Ulrika Voss ● Valtteri Wirta ● Ann Nordgren ● Gen Nishimura ● 1 1 Anna Lindstrand ● Giedre Grigelioniene Received: 4 December 2020 / Revised: 31 March 2021 / Accepted: 31 March 2021 / Published online: 20 April 2021 © The Author(s) 2021. This article is published with open access Abstract Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including 1234567890();,: 1234567890();,: bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes.
    [Show full text]
  • Characterization of Genetic Aberrations in a Single Case of Metastatic Thymic Adenocarcinoma Yeonghun Lee1, Sehhoon Park2, Se-Hoon Lee2,3* and Hyunju Lee1*
    Lee et al. BMC Cancer (2017) 17:330 DOI 10.1186/s12885-017-3282-9 RESEARCH ARTICLE Open Access Characterization of genetic aberrations in a single case of metastatic thymic adenocarcinoma Yeonghun Lee1, Sehhoon Park2, Se-Hoon Lee2,3* and Hyunju Lee1* Abstract Background: Thymic adenocarcinoma is an extremely rare subtype of thymic epithelial tumors. Due to its rarity, there is currently no sequencing approach for thymic adenocarcinoma. Methods: We performed whole exome and transcriptome sequencing on a case of thymic adenocarcinoma and performed subsequent validation using Sanger sequencing. Results: The case of thymic adenocarcinoma showed aggressive behaviors with systemic bone metastases. We identified a high incidence of genetic aberrations, which included somatic mutations in RNASEL, PEG10, TNFSF15, TP53, TGFB2, and FAT1. Copy number analysis revealed a complex chromosomal rearrangement of chromosome 8, which resulted in gene fusion between MCM4 and SNTB1 and dramatic amplification of MYC and NDRG1. Focal deletion was detected at human leukocyte antigen (HLA) class II alleles, which was previously observed in thymic epithelial tumors. We further investigated fusion transcripts using RNA-seq data and found an intergenic splicing event between the CTBS and GNG5 transcript. Finally, enrichment analysis using all the variants represented the immune system dysfunction in thymic adenocarcinoma. Conclusion: Thymic adenocarcinoma shows highly malignant characteristics with alterations in several cancer- related genes. Keywords: Thymic adenocarcinoma, Thymic epithelial tumors, Whole exome sequencing, Somatic mutations, Somatic copy number alterations Background With their distinct entities, thymic adenocarcinomas Thymic adenocarcinoma is an extremely rare subtype of have shown higher malignancy than other thymic epi- thymic carcinoma. Thirty-five cases have been reported thelial tumors (TETs).
    [Show full text]
  • Role and Regulation of the P53-Homolog P73 in the Transformation of Normal Human Fibroblasts
    Role and regulation of the p53-homolog p73 in the transformation of normal human fibroblasts Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Bayerischen Julius-Maximilians-Universität Würzburg vorgelegt von Lars Hofmann aus Aschaffenburg Würzburg 2007 Eingereicht am Mitglieder der Promotionskommission: Vorsitzender: Prof. Dr. Dr. Martin J. Müller Gutachter: Prof. Dr. Michael P. Schön Gutachter : Prof. Dr. Georg Krohne Tag des Promotionskolloquiums: Doktorurkunde ausgehändigt am Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit selbständig angefertigt und keine anderen als die angegebenen Hilfsmittel und Quellen verwendet habe. Diese Arbeit wurde weder in gleicher noch in ähnlicher Form in einem anderen Prüfungsverfahren vorgelegt. Ich habe früher, außer den mit dem Zulassungsgesuch urkundlichen Graden, keine weiteren akademischen Grade erworben und zu erwerben gesucht. Würzburg, Lars Hofmann Content SUMMARY ................................................................................................................ IV ZUSAMMENFASSUNG ............................................................................................. V 1. INTRODUCTION ................................................................................................. 1 1.1. Molecular basics of cancer .......................................................................................... 1 1.2. Early research on tumorigenesis ................................................................................. 3 1.3. Developing
    [Show full text]
  • Dottorato Di Ricerca Toscano Di Neuroscienze Profilo
    DOTTORATO DI RICERCA TOSCANO DI NEUROSCIENZE CICLO XXVIII COORDINATORE Prof. Renato Corradetti PROFILO GENETICO ED EPIGENETICO IN PAZIENTI CON DEMENZA FRONTOTEMPORALE Settore Scientifico Disciplinare MED/26 Dottorando Tutor Dott.ssa Piaceri Irene Prof. Sorbi Sandro Coordinatore Prof. Renato Corradetti Anni 2012/2015 Indice INDICE INTRODUZIONE .............................................................................................1 1. DEMENZA FRONTOTEMPORALE ..................................................................2 1.1 Diagnosi Clinica ....................................................................................4 1.1.1 Variante comportamentale (bvFTD) ............................................5 1.1.2 Afasia primaria progressiva (PPA) ..............................................6 1.1.2.1 Afasia progressiva non fluente (PNFA) ...............................7 1.1.2.2 Demenza Semantica (SD) ......................................................8 1.1.3 Degenerazione corticobasale (CBD) e Paralisi sopranucleare progressiva (PSP) ....................................................................................9 1.2 FTD/SLA spectrum ............................................................................. 10 1.3 Aspetti Neuropatologici e Istopatologici ............................................... 11 2. LA GENETICA DELLA DEMENZA FRONTOTEMPORALE ............................... 14 2.1 MAPT ................................................................................................. 16 2.2 GRN...................................................................................................
    [Show full text]
  • SZDB: a Database for Schizophrenia Genetic Research
    Schizophrenia Bulletin vol. 43 no. 2 pp. 459–471, 2017 doi:10.1093/schbul/sbw102 Advance Access publication July 22, 2016 SZDB: A Database for Schizophrenia Genetic Research Yong Wu1,2, Yong-Gang Yao1–4, and Xiong-Jian Luo*,1,2,4 1Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, China; 2Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China; 3CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China 4YGY and XJL are co-corresponding authors who jointly directed this work. *To whom correspondence should be addressed; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; tel: +86-871-68125413, fax: +86-871-68125413, e-mail: [email protected] Schizophrenia (SZ) is a debilitating brain disorder with a Introduction complex genetic architecture. Genetic studies, especially Schizophrenia (SZ) is a severe mental disorder charac- recent genome-wide association studies (GWAS), have terized by abnormal perceptions, incoherent or illogi- identified multiple variants (loci) conferring risk to SZ. cal thoughts, and disorganized speech and behavior. It However, how to efficiently extract meaningful biological affects approximately 0.5%–1% of the world populations1 information from bulk genetic findings of SZ remains a and is one of the leading causes of disability worldwide.2–4 major challenge. There is a pressing
    [Show full text]
  • Mouse Ift74 Conditional Knockout Project (CRISPR/Cas9)
    https://www.alphaknockout.com Mouse Ift74 Conditional Knockout Project (CRISPR/Cas9) Objective: To create a Ift74 conditional knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Ift74 gene (NCBI Reference Sequence: NM_026319 ; Ensembl: ENSMUSG00000028576 ) is located on Mouse chromosome 4. 20 exons are identified, with the ATG start codon in exon 2 and the TGA stop codon in exon 20 (Transcript: ENSMUST00000030311). Exon 5~6 will be selected as conditional knockout region (cKO region). Deletion of this region should result in the loss of function of the Mouse Ift74 gene. To engineer the targeting vector, homologous arms and cKO region will be generated by PCR using BAC clone RP23-173G7 as template. Cas9, gRNA and targeting vector will be co-injected into fertilized eggs for cKO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mice homozygous for an ENU-induced mutation exhibit complex congenital heart disease associated with heterotaxy. Exon 5 starts from about 17.0% of the coding region. The knockout of Exon 5~6 will result in frameshift of the gene. The size of intron 4 for 5'-loxP site insertion: 2197 bp, and the size of intron 6 for 3'-loxP site insertion: 5364 bp. The size of effective cKO region: ~836 bp. The cKO region does not have any other known gene. Page 1 of 7 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 4 5 6 20 Targeting vector Targeted allele Constitutive KO allele (After Cre recombination) Legends Exon of mouse Ift74 Homology arm cKO region loxP site Page 2 of 7 https://www.alphaknockout.com Overview of the Dot Plot Window size: 10 bp Forward Reverse Complement Sequence 12 Note: The sequence of homologous arms and cKO region is aligned with itself to determine if there are tandem repeats.
    [Show full text]
  • Essential Genes Shape Cancer Genomes Through Linear Limitation of Homozygous Deletions
    ARTICLE https://doi.org/10.1038/s42003-019-0517-0 OPEN Essential genes shape cancer genomes through linear limitation of homozygous deletions Maroulio Pertesi1,3, Ludvig Ekdahl1,3, Angelica Palm1, Ellinor Johnsson1, Linnea Järvstråt1, Anna-Karin Wihlborg1 & Björn Nilsson1,2 1234567890():,; The landscape of somatic acquired deletions in cancer cells is shaped by positive and negative selection. Recurrent deletions typically target tumor suppressor, leading to positive selection. Simultaneously, loss of a nearby essential gene can lead to negative selection, and introduce latent vulnerabilities specific to cancer cells. Here we show that, under basic assumptions on positive and negative selection, deletion limitation gives rise to a statistical pattern where the frequency of homozygous deletions decreases approximately linearly between the deletion target gene and the nearest essential genes. Using DNA copy number data from 9,744 human cancer specimens, we demonstrate that linear deletion limitation exists and exposes deletion-limiting genes for seven known deletion targets (CDKN2A, RB1, PTEN, MAP2K4, NF1, SMAD4, and LINC00290). Downstream analysis of pooled CRISPR/Cas9 data provide further evidence of essentiality. Our results provide further insight into how the deletion landscape is shaped and identify potentially targetable vulnerabilities. 1 Hematology and Transfusion Medicine Department of Laboratory Medicine, BMC, SE-221 84 Lund, Sweden. 2 Broad Institute, 415 Main Street, Cambridge, MA 02142, USA. 3These authors contributed equally: Maroulio Pertesi, Ludvig Ekdahl. Correspondence and requests for materials should be addressed to B.N. (email: [email protected]) COMMUNICATIONS BIOLOGY | (2019) 2:262 | https://doi.org/10.1038/s42003-019-0517-0 | www.nature.com/commsbio 1 ARTICLE COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-019-0517-0 eletion of chromosomal material is a common feature of we developed a pattern-based method to identify essential genes Dcancer genomes1.
    [Show full text]