The Role of Mecp2 in Learning and Memory
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Developmental Delay and the Methyl Binding Genes H Turner, F Macdonald, S Warburton, F Latif, T Webb
1of3 ELECTRONIC LETTER J Med Genet: first published as 10.1136/jmg.40.2.e13 on 1 February 2003. Downloaded from Developmental delay and the methyl binding genes H Turner, F MacDonald, S Warburton, F Latif, T Webb ............................................................................................................................. J Med Genet 2003;40:e13(http://www.jmedgenet.com/cgi/content/full/40/2/e13) he report by Amir et al1 that Rett syndrome (RS) is associ- children referred with a clinical diagnosis of Angelman ated with mutations in the MECP2 gene permitted labora- syndrome (AS) but without an abnormality in 15q11q13 tory diagnosis of this devastating yet common neurode- showed that 4/46 of the girls in one case8 and 5/40 in the T 9 velopmental disorder. Hitherto the paucity of familial cases of other actually had Rett syndrome. Of these nine probands, the syndrome and the failure to identify the syndrome in only one was later found to have a clinical presentation incon- males despite fairly wide clinical criteria had defined it as an sistent with the laboratory diagnosis. This may not be surpris- X linked dominant disorder with male lethality.2 Soon, ing given that in very small girls the two syndromes may however, reports from the few families in which RS is present with overlapping clinical features and so be difficult to segregating showed that male family members who inherited differentiate on clinical grounds alone. the same mutation in the MECP2 gene as their affected female Familial cases of developmental handicap -
The Ski Oncoprotein Interacts with Skip, the Human Homolog of Drosophila Bx42
Oncogene (1998) 16, 1579 ± 1586 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 The Ski oncoprotein interacts with Skip, the human homolog of Drosophila Bx42 Richard Dahl, Bushra Wani and Michael J Hayman Department of Microbiology, State University of New York, Stony Brook, New York 11794, USA The v-Ski avian retroviral oncogene is postulated to act Little is known about how Ski functions. Both the as a transcription factor. Since protein ± protein interac- cellular and the viral genes share transforming and tions have been shown to play an important role in the muscle inducing ability. Ski localizes to the nucleus and transcription process, we attempted to identify Ski is observed to associate with chromatin (Barkas et al., protein partners with the yeast two-hybrid system. Using 1986; Sutrave et al., 1990a). Because of its nuclear v-Ski sequence as bait, the human gene skip (Ski localization and its ability to induce expression of Interacting Protein) was identi®ed as encoding a protein muscle speci®c genes in quail cells (Colmenares and which interacts with both the cellular and viral forms of Stavnezer, 1989), Ski has been assumed to be a Ski in the two-hybrid system. Skip is highly homologous transcription factor. Consistent with this assumption, to the Drosophila melanogaster protein Bx42 which is c-Ski has been shown to bind DNA in vitro with the found associated with chromatin in transcriptionally help of an unknown protein factor (Nagase et al., active pus of salivary glands. The Ski-Skip interaction 1990), and has been recently shown to enhance MyoD is potentially important in Ski's transforming activity dependent transactivation of a myosin light chain since Skip was demonstrated to interact with a highly enhancer linked reporter gene in muscle cells (Engert conserved region of Ski required for transforming et al., 1995). -
Mutations in SKI in Shprintzen–Goldberg Syndrome Lead to Attenuated TGF-B Responses Through SKI Stabilization
RESEARCH ARTICLE Mutations in SKI in Shprintzen–Goldberg syndrome lead to attenuated TGF-b responses through SKI stabilization Ilaria Gori1, Roger George2, Andrew G Purkiss2, Stephanie Strohbuecker3, Rebecca A Randall1, Roksana Ogrodowicz2, Virginie Carmignac4, Laurence Faivre4, Dhira Joshi5, Svend Kjær2, Caroline S Hill1* 1Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom; 2Structural Biology Facility, The Francis Crick Institute, London, United Kingdom; 3Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom; 4INSERM - Universite´ de Bourgogne UMR1231 GAD, FHU-TRANSLAD, Dijon, France; 5Peptide Chemistry Facility, The Francis Crick Institute, London, United Kingdom Abstract Shprintzen–Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys–Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-b signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-b signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-b responses, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-b- *For correspondence: induced transcriptional responses, and not enhancement, which has important implications for [email protected] other Marfan-related syndromes. Competing interests: The authors declare that no competing interests exist. -
Methyl-Cpg2-Binding Protein 2 Mediates Overlapping Mechanisms Across Brain Disorders
bioRxiv preprint doi: https://doi.org/10.1101/819573; this version posted October 28, 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. Methyl-CpG2-binding protein 2 mediates overlapping mechanisms across brain disorders. Snow Bach1,2, Niamh M. Ryan2, Paolo Guasoni1,3, Aiden Corvin2, Daniela Tropea2,4* 1 School of Mathematical Sciences, Dublin City University, Glasnevin, Dublin 9, D09 W6Y4, Ireland 2 Neuropsychiatric Genetics, Department of Psychiatry, Trinity College Dublin, School of Medicine, Trinity Translational Medicine Institute, St James Hospital, Dublin, Ireland 3 Department of Mathematics and Statistics, Boston University, 111 Cummington Street, Boston, MA 02215, USA 4 Trinity College Institute of Neuroscience, Trinity College Dublin, Lloyd Building, Dublin 2, Dublin, Ireland *Correspondence should be addressed to D.T. (email: [email protected]) bioRxiv preprint doi: https://doi.org/10.1101/819573; this version posted October 28, 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. Abstract Methyl-CpG binding protein 2 (MeCP2) is a chromatin-binding protein and a modulator of gene expression. Initially identified as an oncogene, MECP2 is now mostly associated to Rett Syndrome, a neurodevelopmental condition, though there is evidence of its influence in other brain disorders. We design a procedure that considers several binding properties of MeCP2 and we screen for potential targets across neurological and neuropsychiatric conditions. We find MeCP2 target genes associated to a range of disorders, including - among others- Alzheimer Disease, Autism, Attention Deficit Hyperactivity Disorder and Multiple Sclerosis. -
Soothing Sensory Sensitivity May Ease Social Problems in Mice
Spectrum | Autism Research News https://www.spectrumnews.org NEWS Soothing sensory sensitivity may ease social problems in mice BY NICHOLETTE ZELIADT 12 NOVEMBER 2017 Dampening the signals that relay touch from the limbs to the brain can ease anxiety and social problems in two mouse models of autism, a new study suggests. Peripheral neurons typically relay these signals. The findings suggest that some features of autism arise from malfunctioning neurons outside the brain and spinal cord, says Lauren Orefice, a research fellow in David Ginty’s lab at Harvard University. They also hint that treatments targeting these peripheral neurons could help to ease some features of the condition. Orefice presented the unpublished findings yesterday at the 2017 Society for Neuroscience annual meeting in Washington, D.C. Last year, Orefice and her colleagues showed that mice with mutations in various genes tied to autism — including MECP2, GABRB3 and SHANK3 — in only their touch neurons are hypersensitive to small puffs of air on their backs early in life. The animals later show signs of anxiety and social difficulties. In the new work, the researchers explored how loss of any of these genes affects the function of touch neurons. They found that touch neurons lacking a copy of either MECP2 or GABRB3 have decreased levels of GABRB3 protein. This protein helps to dampen signals relayed by touch neurons to the spinal cord. Touch neurons in the mutant mice also fire unusually easily when stimulated with electricity. “The flow of information from those neurons to the spinal cord and brain is enhanced,” Orefice says. -
The New Melanoma: a Novel Model for Disease Progression
DISS. ETH NO. 17606 The new melanoma: A novel model for disease progression A dissertation submitted to SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZÜRICH for the degree of DOCTOR OF SCIENCES presented by Natalie Schlegel Master of Science, Otago University (New Zealand) born on January 20th 1976 citizen of Zürich (ZH) accepted on the recommendation of Professor Sabine Werner, examinor Professor Reinhard Dummer, co-examinor Professor Josef Jiricny, co-examinor 2008 22 Table of Contents Abstract ...................................................................................................................................... 6 Résumé....................................................................................................................................... 8 Abbreviations ........................................................................................................................... 10 1. Introduction ...................................................................................................................... 13 1.1 Definition ................................................................................................................. 14 1.2 Clinical features........................................................................................................ 14 1.3 Pathological features and staging............................................................................. 16 1.3.2 Clark’s level of invasion and Breslow’s thickness........................................... 16 1.3.3 TNM staging ................................................................................................... -
The Role of Drosophila Bx42/SKIP in Cell Cycle
The Role of Drosophila Bx42/SKIP in Cell Cycle D i s s e r t a t i o n zur Erlangung des akademischen Grades d o c t o r r e r u m n a t u r a l i u m (Dr. rer. nat.) im Fach Biologie eingereicht an der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin von Diplom-Biologin Shaza Dehne Präsidentin der Humboldt-Universität zu Berlin Prof. Dr.-Ing. Dr. Sabine Kunst Dekanin/Dekan der Lebenswissenschaftlichen Fakultät Prof. Dr. Richard Lucius Gutachter/innen: 1. Prof. Dr. Harald Saumweber 2. Prof. Dr. Christian Schmitz-Linneweber 3. Prof. Dr. Achim Leutz Tag der mündlichen Prüfung: 30.11.2016 Contents Abstract Abstrakt 1 Introduction .................................................................. 10 1.1 Bx42: Identification, protein structure and function .................................................. 11 1.2 Bx42/SNW/SKIP is an essential protein family, conserved in evolution and involved in several biological processes ............................................................................................ 13 1.2.1 Involvement of Bx42/SNW/SKIP in signaling pathways ................................ 16 1.2.1.1 Involvement in nuclear receptor pathways ................................................ 16 1.2.1.2 Involvement in the Notch signaling pathway ............................................ 17 1.2.1.3 Involvement in the TGF-ß/Dpp signal pathway ........................................ 19 1.2.2 Involvement of Bx42/SNW/SKIP in RNA splicing ......................................... 20 1.2.3 Bx42/SNW/SKIP protein family and cell cycle regulation .............................. 22 1.2.3.1 Short overview on cell cycle regulation. ................................................... 22 1.2.3.2 Evidence for Bx42/SNW/SKIP contribution to cell cycle regulation ....... 24 1.3 Drosophila eye imaginal disc: a model to study proliferation and cell cycle regulation during development. -
(Cxxc5) a Thesis Submitted to the Graduate
STRUCTURAL AND FUNCTIONAL CHARACTERIZATION OF THE CXXC-TYPE ZINC FINGER PROTEIN 5 (CXXC5) A THESIS SUBMITTED TO THE GRADUATE SCHOOL OF NATURAL AND APPLIED SCIENCES OF MIDDLE EAST TECHNICAL UNIVERSITY BY GAMZE AYAZ ŞEN IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN BIOLOGY NOVEMBER 2018 Approval of the thesis: STRUCTURAL AND FUNCTIONAL CHARACTERIZATION OF THE CXXC-TYPE ZINC FINGER PROTEIN 5 (CXXC5) submitted by GAMZE AYAZ ŞEN in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biology Department, Middle East Technical University by, Prof. Dr. Halil Kalıpçılar Dean, Graduate School of Natural and Applied Sciences Prof. Dr. Orhan Adalı Head of Department, Biological Sciences Prof. Dr. Mesut Muyan Supervisor, Biological Sciences Dept., METU Examining Committee Members: Prof. Dr. A. Elif Erson Bensan Biological Sciences Dept., METU Prof. Dr. Mesut Muyan Biological Sciences Dept., METU Asst. Prof. Dr. Murat Alper Cevher Molecular Biology and Genetics Dept., Bilkent University Assoc. Prof. Dr. Nurcan Tunçbağ Informatics Institute, METU Asst. Prof. Dr. Onur Çizmecioğlu Molecular Biology and Genetics Dept., Bilkent University Date: 16.11.2018 I hereby declare that all information in this document has been obtained and presented in accordance with academic rules and ethical conduct. I also declare that, as required by these rules and conduct, I have fully cited and referenced all material and results that are not original to this work. Name, Last name: Gamze Ayaz Şen Signature: iv To All Women Who Pursue Their Dreams In Science v ABSTRACT STRUCTURAL AND FUNCTIONAL CHARACTERIZATION OF THE CXXC-TYPE ZINC FINGER PROTEIN 5 (CXXC5) Ayaz Şen, Gamze Ph.D., Biology Department Supervisor: Prof. -
The SMAD-Binding Domain of SKI: a Hotspot for De Novo Mutations Causing Shprintzen&Ndash
European Journal of Human Genetics (2015) 23, 224–228 & 2015 Macmillan Publishers Limited All rights reserved 1018-4813/15 www.nature.com/ejhg ARTICLE The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen–Goldberg syndrome Dorien Schepers1,20, Alexander J Doyle2,3,20,GretchenOswald2, Elizabeth Sparks2,LorethaMyers2,PatrickJWillems4, Sahar Mansour5, Michael A Simpson6,HelenaFrysira7, Anneke Maat-Kievit8,RickVanMinkelen8, Jeanette M Hoogeboom8, Geert R Mortier1, Hannah Titheradge9,LouiseBrueton9,LoisStarr10, Zornitza Stark11, Charlotte Ockeloen12, Charles Marques Lourenco13,EdBlair14, Emma Hobson15,JaneHurst16, Isabelle Maystadt17, Anne Destre´e17, Katta M Girisha18, Michelle Miller19,HarryCDietz2,3,BartLoeys1,20 and Lut Van Laer*,1,20 Shprintzen–Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys–Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFb activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). -
Uva-DARE (Digital Academic Repository)
UvA-DARE (Digital Academic Repository) Inside out Behavioral phenotyping in genetic syndromes Mulder, P.A. Publication date 2020 Document Version Other version License Other Link to publication Citation for published version (APA): Mulder, P. A. (2020). Inside out: Behavioral phenotyping in genetic syndromes. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:25 Sep 2021 6 Further delineation of Malan syndrome Authors: Priolo M, Schanze D, Tatton-Brown K, Mulder PA, Tenorio J, Kooblall K, Acero IH, Alkuraya FS, Arias P, Bernardini L, Bijlsma EK, Cole T, Coubes C, Dapia I, Davies S, Di Donato N, Elcioglu NH, Fahrner JA, Foster A, González NG, Huber I, Iascone M, Kaiser AS, Kamath A, Liebelt J, Lynch SA, Maas SM, Mammì C, Mathijssen IB, McKee S, Menke LA, Mirzaa GM, Montgomery T, Neubauer D, Neumann TE, Pintomalli L, Pisanti MA, Plomp AS, Price S, Salter C, Santos-Simarro F, Sarda P, Segovia M, Shaw-Smith C, Smithson S, Suri M, Valdez RM, Van Haeringen A, Van Hagen JM, Zollino M, Lapunzina P, Thakker RV, Zenker M, Hennekam RC. -
Electronic Letter 1Of4 J Med Genet: First Published As 10.1136/Jmg.37.12.E41 on 1 December 2000
Electronic letter 1of4 J Med Genet: first published as 10.1136/jmg.37.12.e41 on 1 December 2000. Downloaded from Electronic letter J Med Genet 2000;37 (http://jmedgenet.com/cgi/content/full/37/12/e41) Spectrum of mutations in the MECP2 We screened genomic DNA from 13 sporadic RTT patients and 21 patients with autism and mental gene in patients with infantile autism retardation by DHPLC and by direct DNA sequencing. All and Rett syndrome the subjects were unrelated females and were ethnic Chinese, with no family history of the disease. The clinical findings met the criteria of inclusion and exclusion for the diagnosis of RTT.10 Patients with autism and mental retar- dation were obtained from a previous study.11 The diagno- EDITOR—Rett syndrome (RTT, MIM 312750) is a sis of autism was based on clinical features and evaluated progressive neurological disorder, occurring almost exclu- by diagnostic criteria from DSM-IV.12 Most of them had sively in females during their first two years of life . RTT is onset of autistic features at less than 3 years of age. one of the most common causes of mental retardation in Informed consent was obtained from the patients or the females, with an incidence of 1 in 10 000-15 000 female parents. births. Patients with classical RTT appear to develop nor- Genomic DNA was extracted from peripheral blood mally until 6-18 months of age, then gradually lose speech samples using a QIAamp Blood Kit (Qiagen) according to and purposeful hand use, and, eventually, develop the manufacturer’s instructions. -
MECP2 Disorders: from the Clinic to Mice and Back
MECP2 disorders: from the clinic to mice and back Laura Marie Lombardi, … , Steven Andrew Baker, Huda Yahya Zoghbi J Clin Invest. 2015;125(8):2914-2923. https://doi.org/10.1172/JCI78167. Review Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG–binding protein 2 (MECP2). Neurons acutely require the appropriate dose of MECP2 to function properly but do not die in its absence or overexpression. Instead, neuronal dysfunction can be reversed in a Rett syndrome mouse model if MeCP2 function is restored. Thus, MECP2 disorders provide a unique window into the delicate balance of neuronal health, the power of mouse models, and the importance of chromatin regulation in mature neurons. In this Review, we will discuss the clinical profiles of MECP2 disorders, the knowledge acquired from mouse models of the syndromes, and how that knowledge is informing current and future clinical studies. Find the latest version: https://jci.me/78167/pdf REVIEW The Journal of Clinical Investigation MECP2 disorders: from the clinic to mice and back Laura Marie Lombardi,1,2,3 Steven Andrew Baker,2,4,5 and Huda Yahya Zoghbi1,2,3,4 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. 2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, Texas, USA. 3Howard Hughes Medical Institute, 4Program in Developmental Biology, and 5Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA. Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG–binding protein 2 (MECP2).