DOCSLIB.ORG

CCDC88A Mutations Cause PEHO-Like Syndrome in Humans and Mouse

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
CCDC88A Mutations Cause PEHO-Like Syndrome in Humans and Mouse doi:10.1093/brain/aww014 BRAIN 2016: 139; 1036–1044 | 1036 REPORT CCDC88A mutations cause PEHO-like syndrome in humans and mouse Michael S. Nahorski,1,Ã Masato Asai,2,Ã Emma Wakeling,3 Alasdair Parker,4 Naoya Asai,2 Natalie Canham,3 Susan E. Holder,3 Ya-Chun Chen,1 Joshua Dyer,1 Angela F. Brady,3 Masahide Takahashi2 and C. Geoffrey Woods1 ÃThese authors contributed equally to this work. Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a rare Mendelian phenotype comprising severe retardation, early onset epileptic seizures, optic nerve/cerebellar atrophy, pedal oedema, and early death. Atypical cases are often known as PEHO-like, and there is an overlap with ‘early infantile epileptic encephalopathy’. PEHO is considered to be recessive, but surprisingly since initial description in 1991, no causative recessive gene(s) have been described. Hence, we report a multiplex consanguineous family with the PEHO phenotype where affected individuals had a homozygous frame-shift deletion in CCDC88A (c.2313delT, p.Leu772Ãter). Analysis of cDNA extracted from patient lymphocytes unexpectedly failed to show non-sense mediated decay, and we demonstrate that the mutation produces a truncated protein lacking the crucial C-terminal half of CCDC88A (girdin). To further investigate the possible role of CCDC88A in human neurodevelopment we re- examined the behaviour and neuroanatomy of Ccdc88a knockout pups. These mice had mesial-temporal lobe epilepsy, micro- cephaly and corpus callosum deficiency, and by postnatal Day 21, microcephaly; the mice died at an early age. As the mouse knockout phenotype mimics the human PEHO phenotype this suggests that loss of CCDC88A is a cause of the PEHO phenotype, and that CCDC88A is essential for multiple aspects of normal human neurodevelopment. 1 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK 2 Department of Pathology, Centre for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466N, Japan 3 North West Thames Regional Genetics Service, Level 8V, London North West Healthcare NHS Trust, Watford Road, Harrow, HA1 3UJ, UK 4 Department of Paediatric Neuroscience, Addenbrooke’s Hospital, Hills Rd, Cambridge, CB2 0QQ, UK Correspondence to: C. Geoffrey Woods, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK E-mail: [email protected] Correspondence may also be addressed to: Angela F. Brady, North West Thames Regional Genetics Service, Level 8V, London North West Healthcare NHS Trust, Watford Road, Harrow HA1 3UJ, UK E-mail: [email protected] Masahide Takahashi, Department of Pathology, Centre for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Received November 17, 2015. Revised December 09, 2015. Accepted December 23, 2015. Advance Access publication February 25, 2016 ß The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. CCDC88A mutations cause PEHO-like syndrome BRAIN 2016: 139; 1036–1044 | 1037 Nagoya, Aichi 466-8550, Japan E-mail: [email protected] Keywords: PEHO syndrome; girdin; neurodevelopmental disorder; epilepsy; microcephaly Abbreviation: PEHO = progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy authors cared for the family for over a decade; all medical care Introduction was within the National Health Service. Results and notes Progressive encephalopathy with oedema, hypsarrhythmia were examined and recorded. and optic atrophy (PEHO) syndrome is rare, of unknown origin, and causes profound intellectual disability with little Exome sequencing if any developmental progress. It was first described in Genomic DNA from affected Patients 1 and 2 (Fig. 2A) was Finnish children in 1991, from where the most complete extracted and analysed by exome sequencing (SureSelect phenotypic data originates (Salonen et al., 1991). Onset Human All Exon 50Mb Kit, Agilent Technologies). occurs usually within the first few weeks of life with affected Potentially pathogenic mutations were identified by compari- children displaying seizures, hypotonia and lack of visual son with the GRCh37 reference human genome, filtering for fixation (Somer, 1993; D’Arrigo et al., 2005). Those affected changes with allele frequencies of 5 1 in 500 in the 1000 thence exhibit early arrest of motor and mental development, Genomes project, and focused on homozygous changes affect- optic atrophy, with radiological examination demonstrating ing both siblings. Any changes were confirmed and tested for severe cerebellar and brainstem atrophy from birth, with expected segregation, by polymerase chain reaction (PCR) and cerebral atrophy developing at a later stage (D’Arrigo et Sanger sequencing. al., 2005). Usually microcephaly is present at birth, but in- evitably there is a progressive reduction in brain growth Reverse transcription polymerase (secondary microcephaly). Prognosis is poor with most pa- chain reaction analysis tients dying before 10 years of age. Inheritance is predicted to be autosomal recessive (Somer, 1993). Clinically there is To analyse possible nonsense mediated decay of mutant CCDC88A, blood samples were taken from Patient 1 and their phenotypic overlap of PEHO syndrome with the early-in- parents, mRNA extracted and reverse transcribed to cDNA. Full fantile epileptic encephalopathies (Cross and Guerrini, details of reverse transcription PCRs (RT-PCRs) undertaken and 2013). Cases lacking either optic atrophy or cerebellar hypo- primers used are detailed in the Supplementary material. plasia are often termed PEHO-like (Chitty et al., 1996). The genetic cause(s) and the underlying pathophysiology of PEHO syndrome are unknown; and there is no known CCDC88A cloning and expression curative therapy. We report a large consanguineous family CCDC88A cloned into the pCAGGS vector has been described with three affected members in two nuclear families. In previously (Enomoto et al., 2005). The c.2313delT mutation affected individuals we identified a homozygous frameshift was introduced into the wild-type CCDC88A sequence by site- mutation in CCDC88A, the gene that encodes the actin directed mutagenesis using the QuikChange II Site-Directed binding protein girdin (GIRDers of actIN filament, also Mutagenesis kit (Agilent), and a haemagglutinin (HA) tag known as APE GIV and HkPP) (Anai et al., 2005; added to the N-terminus. Expression of wild-type and mutant proteins were analysed by western blot. Enomoto et al., 2005; Le-Niculescu et al., 2005; Simpson et al., 2005). We show that the mutation results in the absence of full length, functional CCDC88A protein. To CCDC88A knockout mouse further investigate the function of CCDC88A in mamma- The CCDC88A knockout mice and conditional Nestin–cre lian brain function we examined CCDC88A-deficient mice knockout mice strains have been reported previously and compare their phenotype and CNS architecture to our (Kitamura et al., 2008; Asai et al., 2012). Full details of patients. Our results reveal novel insights into the under- brain dissection, staining and analysis are described in the lying developmental, neuroanatomical and molecular de- Supplementary material. fects of CCDC88A deficiency in mammals. Materials and methods Results Materials and methods are described in detail in the Clinical features of the family Supplementary material. The clinical features of the affected children are summar- ized in Table 1, and individual histories are given in the Subjects Supplementary material. The UK National Research Ethics Service, Cambridge Central All affected children presented at birth with microcephaly Research Ethics committee gave permission for our study. The [Occipito-frontal head circumference (OFHC) of À 3 1038 | BRAIN 2016: 139; 1036–1044 M. S. Nahorski et al. standard deviation (SD) to À 4 SD, typically 529 cm] and considered that the better phenotypic diagnosis for the moderately severe hypotonia. Weight and length at birth family was PEHO-like syndrome. were normal. Excepting the microcephaly, they were not dysmorphic, nor did they have any extracranial congenital Identification of CCDC88A mutation anomalies. All spent 2–4 weeks in hospital until satisfactory breathing and feeding were established. All developed seiz- To identify the causative gene mutation in this family, ures associated with anoxia presenting at birth or by 1 exome analysis was performed on genomic DNA from month. In all three subjects this progressed to flexion in- two affected children (Patients 1 and 2, Fig. 2A), the raw fantile spasms with hypsarrhythmia on EEG within the first sequences mapped to the GRCh37 reference human year of life. Seizures became tonic/clonic by the third year, genome, and any possible mutations shared in both chil- fits occurred frequently (at least weekly throughout life), dren analysed for their potential to cause PEHO syndrome. status epilepticus necessitating hospital admission at least We prioritized the search for mutations that would poten- once in all three, and their seizures were persistently diffi- tially alter the encoded protein (nonsense/frameshift/splice cult to control necessitating frequent changes
Load more

Recommended publications
  • Biological Models of Colorectal Cancer Metastasis and Tumor Suppression
    BIOLOGICAL MODELS OF COLORECTAL CANCER METASTASIS AND TUMOR SUPPRESSION PROVIDE MECHANISTIC INSIGHTS TO GUIDE PERSONALIZED CARE OF THE COLORECTAL CANCER PATIENT By Jesse Joshua Smith Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University In partial fulfillment of the requirements For the degree of DOCTOR OF PHILOSOPHY In Cell and Developmental Biology May, 2010 Nashville, Tennessee Approved: Professor R. Daniel Beauchamp Professor Robert J. Coffey Professor Mark deCaestecker Professor Ethan Lee Professor Steven K. Hanks Copyright 2010 by Jesse Joshua Smith All Rights Reserved To my grandparents, Gladys and A.L. Lyth and Juanda Ruth and J.E. Smith, fully supportive and never in doubt. To my amazing and enduring parents, Rebecca Lyth and Jesse E. Smith, Jr., always there for me. .my sure foundation. To Jeannine, Bill and Reagan for encouragement, patience, love, trust and a solid backing. To Granny George and Shawn for loving support and care. And To my beautiful wife, Kelly, My heart, soul and great love, Infinitely supportive, patient and graceful. ii ACKNOWLEDGEMENTS This work would not have been possible without the financial support of the Vanderbilt Medical Scientist Training Program through the Clinical and Translational Science Award (Clinical Investigator Track), the Society of University Surgeons-Ethicon Scholarship Fund and the Surgical Oncology T32 grant and the Vanderbilt Medical Center Section of Surgical Sciences and the Department of Surgical Oncology. I am especially indebted to Drs. R. Daniel Beauchamp, Chairman of the Section of Surgical Sciences, Dr. James R. Goldenring, Vice Chairman of Research of the Department of Surgery, Dr. Naji N.
    [Show full text]
  • A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family
    Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2018 A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family Linda Molla Follow this and additional works at: https://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Linda Molla June 2018 © Copyright by Linda Molla 2018 A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY Linda Molla, Ph.D. The Rockefeller University 2018 APOBEC2 is a member of the AID/APOBEC cytidine deaminase family of proteins. Unlike most of AID/APOBEC, however, APOBEC2’s function remains elusive. Previous research has implicated APOBEC2 in diverse organisms and cellular processes such as muscle biology (in Mus musculus), regeneration (in Danio rerio), and development (in Xenopus laevis). APOBEC2 has also been implicated in cancer. However the enzymatic activity, substrate or physiological target(s) of APOBEC2 are unknown. For this thesis, I have combined Next Generation Sequencing (NGS) techniques with state-of-the-art molecular biology to determine the physiological targets of APOBEC2. Using a cell culture muscle differentiation system, and RNA sequencing (RNA-Seq) by polyA capture, I demonstrated that unlike the AID/APOBEC family member APOBEC1, APOBEC2 is not an RNA editor. Using the same system combined with enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analyses I showed that, unlike the AID/APOBEC family member AID, APOBEC2 does not act as a 5-methyl-C deaminase.
    [Show full text]
  • Combinatorial Strategies Using CRISPR/Cas9 for Gene Mutagenesis in Adult Mice
    Combinatorial strategies using CRISPR/Cas9 for gene mutagenesis in adult mice Avery C. Hunker A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2019 Reading Committee: Larry S. Zweifel, Chair Sheri J. Mizumori G. Stanley McKnight Program Authorized to Offer Degree: Pharmacology 2 © Copyright 2019 Avery C. Hunker 3 University of Washington ABSTRACT Combinatorial strategies using CRISPR/Cas9 for gene mutagenesis in adult mice Avery C. Hunker Chair of the Supervisory Committee: Larry Zweifel Department of Pharmacology A major challenge to understanding how genes modulate complex behaviors is the inability to restrict genetic manipulations to defined cell populations or circuits. To circumvent this, we created a simple strategy for limiting gene knockout to specific cell populations using a viral-mediated, conditional CRISPR/SaCas9 system in combination with intersectional genetic strategies. A small single guide RNA (sgRNA) directs Staphylococcus aureus CRISPR-associated protein (SaCas9) to unique sites on DNA in a Cre-dependent manner resulting in double strand breaks and gene mutagenesis in vivo. To validate this technique we targeted nine different genes of diverse function in distinct cell types in mice and performed an array of analyses to confirm gene mutagenesis and subsequent protein loss, including IHC, cell-type specific DNA sequencing, electrophysiology, Western blots, and behavior. We show that these vectors are as efficient as conventional conditional gene knockout and provide a viable alternative to complex genetic crosses. This strategy provides additional benefits of 4 targeting gene mutagenesis to cell types previously difficult to isolate, and the ability to target genes in specific neural projections for gene inactivation.
    [Show full text]
  • 1 Fibrillar Αβ Triggers Microglial Proteome Alterations and Dysfunction in Alzheimer Mouse 1 Models 2 3 4 Laura Sebastian
    bioRxiv preprint doi: https://doi.org/10.1101/861146; this version posted December 2, 2019. 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. 1 Fibrillar triggers microglial proteome alterations and dysfunction in Alzheimer mouse 2 models 3 4 5 Laura Sebastian Monasor1,10*, Stephan A. Müller1*, Alessio Colombo1, Jasmin König1,2, Stefan 6 Roth3, Arthur Liesz3,4, Anna Berghofer5, Takashi Saito6,7, Takaomi C. Saido6, Jochen Herms1,4,8, 7 Michael Willem9, Christian Haass1,4,9, Stefan F. Lichtenthaler 1,4,5# & Sabina Tahirovic1# 8 9 1 German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany 10 2 Faculty of Chemistry, Technical University of Munich, Garching, Germany 11 3 Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians Universität München, 12 81377 Munich, Germany 13 4 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany 14 5 Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, 15 Munich, Germany 16 6 Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science Institute, Wako, 17 Saitama 351-0198, Japan 18 7 Department of Neurocognitive Science, Nagoya City University Graduate School of Medical 19 Science, Nagoya, Aichi 467-8601, Japan 20 8 Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, 81377 21 Munich, Germany 22 9 Biomedical Center (BMC), Ludwig-Maximilians Universität München, 81377 Munich, Germany 23 10 Graduate School of Systemic Neuroscience, Ludwig-Maximilians-University Munich, Munich, 24 Germany. 25 *Contributed equally 26 #Correspondence: [email protected] and [email protected] 27 28 Running title: 29 Microglial proteomic signatures of AD 30 Keywords: Alzheimer’s disease / microglia / proteomic signatures / neuroinflammation / 31 phagocytosis 32 1 bioRxiv preprint doi: https://doi.org/10.1101/861146; this version posted December 2, 2019.
    [Show full text]
  • ID AKI Vs Control Fold Change P Value Symbol Entrez Gene Name *In
    ID AKI vs control P value Symbol Entrez Gene Name *In case of multiple probesets per gene, one with the highest fold change was selected. Fold Change 208083_s_at 7.88 0.000932 ITGB6 integrin, beta 6 202376_at 6.12 0.000518 SERPINA3 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 1553575_at 5.62 0.0033 MT-ND6 NADH dehydrogenase, subunit 6 (complex I) 212768_s_at 5.50 0.000896 OLFM4 olfactomedin 4 206157_at 5.26 0.00177 PTX3 pentraxin 3, long 212531_at 4.26 0.00405 LCN2 lipocalin 2 215646_s_at 4.13 0.00408 VCAN versican 202018_s_at 4.12 0.0318 LTF lactotransferrin 203021_at 4.05 0.0129 SLPI secretory leukocyte peptidase inhibitor 222486_s_at 4.03 0.000329 ADAMTS1 ADAM metallopeptidase with thrombospondin type 1 motif, 1 1552439_s_at 3.82 0.000714 MEGF11 multiple EGF-like-domains 11 210602_s_at 3.74 0.000408 CDH6 cadherin 6, type 2, K-cadherin (fetal kidney) 229947_at 3.62 0.00843 PI15 peptidase inhibitor 15 204006_s_at 3.39 0.00241 FCGR3A Fc fragment of IgG, low affinity IIIa, receptor (CD16a) 202238_s_at 3.29 0.00492 NNMT nicotinamide N-methyltransferase 202917_s_at 3.20 0.00369 S100A8 S100 calcium binding protein A8 215223_s_at 3.17 0.000516 SOD2 superoxide dismutase 2, mitochondrial 204627_s_at 3.04 0.00619 ITGB3 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) 223217_s_at 2.99 0.00397 NFKBIZ nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta 231067_s_at 2.97 0.00681 AKAP12 A kinase (PRKA) anchor protein 12 224917_at 2.94 0.00256 VMP1/ mir-21likely ortholog
    [Show full text]
  • 14200 Girdin Antibody
    Revision 1 C 0 2 - t Girdin Antibody a e r o t S Orders: 877-616-CELL (2355) [email protected] 0 Support: 877-678-TECH (8324) 0 2 Web: [email protected] 4 www.cellsignal.com 1 # 3 Trask Lane Danvers Massachusetts 01923 USA For Research Use Only. Not For Use In Diagnostic Procedures. Applications: Reactivity: Sensitivity: MW (kDa): Source: UniProt ID: Entrez-Gene Id: WB, IP H Endogenous 220, 250 Rabbit Q3V6T2 55704 Product Usage Information 3. Enomoto, A. et al. (2005) Dev Cell 9, 389-402. 4. Le-Niculescu, H. et al. (2005) J Biol Chem 280, 22012-20. Application Dilution 5. Ghosh, P. et al. (2010) Mol Biol Cell 21, 2338-54. 6. Lin, C. et al. (2011) Sci Signal 4, ra64. Western Blotting 1:1000 7. Garcia-Marcos, M. et al. (2009) Proc Natl Acad Sci U S A 106, 3178-83. Immunoprecipitation 1:100 8. Miyake, H. et al. (2011) Circ Res 108, 1170-9. 9. Kitamura, T. et al. (2008) Nat Cell Biol 10, 329-37. 10. Jiang, P. et al. (2008) Cancer Res 68, 1310-8. Storage 11. Weng, L. et al. (2010) Cancer Sci 101, 836-42. Supplied in 10 mM sodium HEPES (pH 7.5), 150 mM NaCl, 100 µg/ml BSA and 50% glycerol. Store at –20°C. Do not aliquot the antibody. Specificity / Sensitivity Girdin Antibody recognizes endogenous levels of total girdin protein. Species Reactivity: Human Source / Purification Polyclonal antibodies are produced by immunizing animals with a synthetic peptide corresponding to residues surrounding Glu1451 of human girdin protein.
    [Show full text]
  • Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes
    Published OnlineFirst April 1, 2020; DOI: 10.1158/2159-8290.CD-19-1030 RESEARCH ARTICLE Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes Matthew Clarke1, Alan Mackay1, Britta Ismer2,3,4, Jessica C. Pickles5, Ruth G. Tatevossian6, Scott Newman7, Tejus A. Bale8, Iris Stoler9, Elisa Izquierdo1, Sara Temelso1, Diana M. Carvalho1, Valeria Molinari1, Anna Burford1, Louise Howell1, Alex Virasami5, Amy R. Fairchild5, Aimee Avery5, Jane Chalker5, Mark Kristiansen5, Kelly Haupfear6, James D. Dalton6, Wilda Orisme6, Ji Wen6, Michael Hubank10, Kathreena M. Kurian11, Catherine Rowe11, Mellissa Maybury12,13,14, Stephen Crosier15, Jeffrey Knipstein16, Ulrich Schüller17,18, Uwe Kordes18, David E. Kram19, Matija Snuderl20, Leslie Bridges21, Andrew J. Martin22, Lawrence J. Doey23, Safa Al-Sarraj23, Christopher Chandler24, Bassel Zebian24, Claire Cairns24, Rachael Natrajan25, Jessica K.R. Boult26, Simon P. Robinson26, Martin Sill2, Ira J. Dunkel27, Stephen W. Gilheeney27, Marc K. Rosenblum8, Debbie Hughes10, Paula Z. Proszek10, Tobey J. Macdonald28, Matthias Preusser29, Christine Haberler29,30, Irene Slavc31, Roger Packer32, Ho-Keung Ng33, Shani Caspi34, Mara Popović35, Barbara Faganel Kotnik36, Matthew D. Wood37, Lissa Baird38, Monika Ashok Davare39, David A. Solomon40,41, Thale Kristin Olsen42, Petter Brandal43, Michael Farrell44, Jane B. Cryan44, Michael Capra45, Michael Karremann46, Jens Schittenhelm47, Martin U. Schuhmann48, Martin Ebinger49, Winand N.M. Dinjens50, Kornelius Kerl51, Simone Hettmer52, Torsten Pietsch53, Felipe Andreiuolo53, Pablo Hernáiz Driever54, Andrey Korshunov55, Lotte Hiddingh2, Barbara C. Worst2,4,56, Dominik Sturm2,4,56, Marc Zuckermann2,4, Olaf Witt2,4,56, Tabitha Bloom57, Clare Mitchell57, Evelina Miele58, Giovanna Stefania Colafati59, Francesca Diomedi-Camassei60, Simon Bailey15, Andrew S. Moore12,13,14, Timothy E.G.
    [Show full text]
  • Pan-Cancer Network Analysis Identifies Combinations of Rare Somatic Mutations Across Pathways and Protein Complexes
    Pan-Cancer Network Analysis Identifies Combinations of Rare Somatic Mutations across Pathways and Protein Complexes The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Leiserson, M. D., F. Vandin, H. Wu, J. R. Dobson, J. V. Eldridge, J. L. Thomas, A. Papoutsaki, et al. 2014. “Pan-Cancer Network Analysis Identifies Combinations of Rare Somatic Mutations across Pathways and Protein Complexes.” Nature genetics 47 (2): 106-114. doi:10.1038/ng.3168. http://dx.doi.org/10.1038/ng.3168. Published Version doi:10.1038/ng.3168 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:21462211 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author Manuscript Author ManuscriptNat Genet Author Manuscript. Author manuscript; Author Manuscript available in PMC 2015 August 01. Published in final edited form as: Nat Genet. 2015 February ; 47(2): 106–114. doi:10.1038/ng.3168. Pan-Cancer Network Analysis Identifies Combinations of Rare Somatic Mutations across Pathways and Protein Complexes Mark D.M. Leiserson1,2,*, Fabio Vandin1,2,3,*, Hsin-Ta Wu1,2, Jason R. Dobson1,2,4, Jonathan V. Eldridge1, Jacob L. Thomas1, Alexandra Papoutsaki1, Younhun Kim1, Beifang Niu5, Michael McLellan5, Michael S. Lawrence6, Abel Gonzalez-Perez7, David Tamborero7, Yuwei Cheng8, Gregory A. Ryslik9, Nuria Lopez-Bigas7,10, Gad Getz6,11, Li Ding5,12,13, and Benjamin J.
    [Show full text]
  • Assessing Mitochondrial Theory of Aging on the Transcriptome Level
    Supplemental Material MicroRNA, mRNA, and Protein Expression Link Development and Aging in Human and Macaque Brain Supplemental Tables......................................................................................................... 3 Table S1. Sample characteristics (human). ......................................................................................... 3 Table S2. Sample characteristics (macaque). ...................................................................................... 4 Table S3. Proportions of transition genes in mRNA, miRNA and protein datasets. ........................... 5 Table S4. miRNA changes with age in human and mouse.................................................................. 6 Table S5. miRNA-target pairs involved in human cortex development and aging............................. 7 Table S6. miRNA-target pairs overlapping with experimentally verified target sets........................ 10 Table S7. Gene Ontology categories enriched among gene groups. ................................................. 12 Table S8. KEGG pathways enriched among gene groups................................................................. 13 Supplemental Figures ..................................................................................................... 15 Figure S1. Age effect on expression and correlation between datasets............................................. 15 Figure S2. Correlation among genes within gene groups. ................................................................ 17 Figure
    [Show full text]
  • Systematic Detection of Brain Protein-Coding Genes Under Positive Selection During Primate Evolution and Their Roles in Cognition
    Downloaded from genome.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Title: Systematic detection of brain protein-coding genes under positive selection during primate evolution and their roles in cognition Short title: Evolution of brain protein-coding genes in humans Guillaume Dumasa,b, Simon Malesysa, and Thomas Bourgerona a Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, (75015) France b Department of Psychiatry, Université de Montreal, CHU Ste Justine Hospital, Montreal, QC, Canada. Corresponding author: Guillaume Dumas Human Genetics and Cognitive Functions Institut Pasteur 75015 Paris, France Phone: +33 6 28 25 56 65 [email protected] Dumas, Malesys, and Bourgeron 1 of 40 Downloaded from genome.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Abstract The human brain differs from that of other primates, but the genetic basis of these differences remains unclear. We investigated the evolutionary pressures acting on almost all human protein-coding genes (N=11,667; 1:1 orthologs in primates) based on their divergence from those of early hominins, such as Neanderthals, and non-human primates. We confirm that genes encoding brain-related proteins are among the most strongly conserved protein-coding genes in the human genome. Combining our evolutionary pressure metrics for the protein- coding genome with recent datasets, we found that this conservation applied to genes functionally associated with the synapse and expressed in brain structures such as the prefrontal cortex and the cerebellum. Conversely, several genes presenting signatures commonly associated with positive selection appear as causing brain diseases or conditions, such as micro/macrocephaly, Joubert syndrome, dyslexia, and autism.
    [Show full text]
  • Genome-Wide Association Study of Alcohol Dependence: Significant findings in African- and European-Americans Including Novel Risk Loci
    Molecular Psychiatry (2014) 19, 41–49 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp IMMEDIATE COMMUNICATION Genome-wide association study of alcohol dependence: significant findings in African- and European-Americans including novel risk loci J Gelernter1,2, HR Kranzler3, R Sherva4, L Almasy5, R Koesterer4, AH Smith1, R Anton6, UW Preuss7, M Ridinger8, D Rujescu7, N Wodarz8, P Zill9, H Zhao10,11 and LA Farrer4,12 We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P ¼ 1.17 Â 10 À 31; AAs: Arg369Cys, P ¼ 6.33 Â 10 À 17) and ADH1C in AAs (Thr151Thr, P ¼ 4.94 Â 10 À 10), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P ¼ 2.63 Â 10 À 11), PDLIM5 in EAs (P ¼ 2.01 Â 10 À 8), and METAP in AAs (P ¼ 3.35 Â 10 À 8). We also identified a novel GWS association (1.17 Â 10 À 10) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19.
    [Show full text]
  • A CRISPR Screen to Identify Combination Therapies of Cytotoxic
    CRISPRi Screens to Identify Combination Therapies for the Improved Treatment of Ovarian Cancer By Erika Daphne Handly B.S. Chemical Engineering Brigham Young University, 2014 Submitted to the Department of Biological Engineering in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biological Engineering at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY February 2021 © 2020 Massachusetts Institute of Technology. All rights reserved. Signature of author………………………………………………………………………………… Erika Handly Department of Biological Engineering February 2021 Certified by………………………………………………………………………………………… Michael Yaffe Director MIT Center for Precision Cancer Medicine Department of Biological Engineering and Biology Thesis Supervisor Accepted by………………………………………………………………………………………... Katharina Ribbeck Professor of Biological Engineering Chair of Graduate Program, Department of Biological Engineering Thesis Committee members Michael T. Hemann, Ph.D. Associate Professor of Biology Massachusetts Institute of Technology Douglas A. Lauffenburger, Ph.D. (Chair) Ford Professor of Biological Engineering, Chemical Engineering, and Biology Massachusetts Institute of Technology Michael B. Yaffe, M.D., Ph.D. (Thesis Supervisor) David H. Koch Professor of Science Prof. of Biology and Biological Engineering Massachusetts Institute of Technology 2 CRISPRi Screens to Identify Combination Therapies for the Improved Treatment of Ovarian Cancer By Erika Daphne Handly B.S. Chemical Engineering Brigham Young University, 2014 Submitted to the Department of Biological Engineering in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biological Engineering ABSTRACT Ovarian cancer is the fifth leading cause of cancer death for women in the United States, with only modest improvements in patient survival in the past few decades. Standard-of-care consists of surgical debulking followed by a combination of platinum and taxane agents, but relapse and resistance frequently occur.
    [Show full text]