DOCSLIB.ORG

A Genetic, Epigenetic and Transcriptomic Study of 22Q11.2 Deletion Syndrome and Its Schizophrenia Phenotype

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Genetic, Epigenetic and Transcriptomic Study of 22Q11.2 Deletion Syndrome and Its Schizophrenia Phenotype A genetic, epigenetic and transcriptomic study of 22q11.2 Deletion Syndrome and its schizophrenia phenotype Thesis submitted for the degree of Doctor of Philosophy at the School of Medicine, Cardiff University (2017) By Thomas Monfeuga Supervised by: Professor Nigel Williams MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University and: Professor Meng Li Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University Declaration This work has not been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed ………………………………… (candidate) Date…………………. Statement 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD Signed ………………………………… (candidate) Date…………………. Statement 2 This thesis is the result of my own independent work/investigation, except where otherwise stated, and the thesis has not been edited by a third party beyond what is permitted by Cardiff University’s Policy on the Use of Third Party Editors by Research Degree Students. Other sources are acknowledged by explicit references. The views expressed are my own. Signed ………………………………… (candidate) Date…………………. Statement 3 I hereby give consent for my thesis, if accepted, to be available online in the University’s Open Access repository and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed ………………………………… (candidate) Date…………………. Statement 4: previously approved bar on access I hereby give consent for my thesis, if accepted, to be available online in the University’s Open Access repository and for inter-library loans after expiry of a bar on access previously approved by the Academic Standards & Quality Committee. Signed ………………………………… (candidate) Date…………………. I Statement of contribution Part of the data, work and results presented in this thesis have been generated/performed/analysed by different individuals. These instances are detailed in the relevant sections of the thesis and are recapitulated here. Chapter 2: Schizophrenia polygenic risk score analysis in 22q11.2 deletion syndrome patients (p.31). 22q11.2 IBBC cohort samples have been provided by the International 22q11.2 Brain Behavior Consortium (raw .CEL files). The imputation of the 22q11.2 IBBC cohort data has been performed by Dr. Leon Hubbard (Cardiff University) (Genotype calling, pre- and post-imputation quality control and processing of the data were performed by the writer of this thesis). The CLOZUK data has been provided after imputation by Dr. James Walters (Cardiff University). Chapter 3: Effect of the 22q11.2 deletion on DNA methylation (p.49). Samples from the two cohorts’ groups (Cardiff University’s ECHO cohort, led by Prof. Marianne van den Bree and Prof. Michael Owen; and King’s College London’s BBAG study, led by Dr. Michael Craig) were provided after DNA extraction by the MRC Core team of the Centre for Neuropsychiatric Genetics and Genomics (Cardiff University). 450K DNA methylation arrays were prepared and run by Dr Afnan Salaka and Catherine Bresner (Cardiff University); EPIC DNA methylation arrays were prepared and run with the help of Catherine Bresner. Chapter 4: CRISPR/Cas9 genome editing of DGCR8 in human embryonic stem cells (p.81). DNA sequencing was performed by GATC Biotech. Chapter 5: Transcriptome analysis of DGCR8 knock-out lines (p.106). The induced pluripotent cell lines have been generated by Dr. Craig Joyce (Cardiff University) from dermal fibroblasts originated from skin biopsies provided by the National Centre for Mental Health (NCMH). Cell culture and RNA extraction in “Experiment 2” was done collaboratively with Matthieu Trigano (Cardiff University) (but different cell lines and experiments were analysed by Matthieu Trigano and the writer of this thesis independently). Post-extraction RNA integrity was assessed by Dr. Amanda Redfern (Central Biotechnology Services, Cardiff University). Sample preparation and sequencing was performed by Joanne Morgan (NGS Co-ordinator, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University). Alignment of RNA-sequencing reads was performed by Daniel Cabezas De La Fuente (Cardiff University). II Acknowledgements First of all, I would like to thank my primary supervisor, Prof. Nigel Williams, for his guidance and his support throughout this PhD. I really appreciated the numerous discussions we have had during these 3 years; they were always constructive and interesting and will, I am sure, have a great impact for the rest of my scientific career. I would also like to thank my second supervisor, Prof. Meng Li, for all her help and feedback on my work. I am very grateful to the Wellcome Trust for funding my project and offering me this great opportunity. I would like to thank everyone that helped me during my PhD, who are probably too many to name here. I would like in particular to express my gratitude to Dr. Leon Hubbard, for all his assistance in bioinformatics. I am also thankful to everyone in the Li Lab for teaching me all I know about stem cell culture and being wonderful colleagues and friends; in particular it was a pleasure to work closely with my friend Matthieu Trigano during this PhD. I would also like to thank the people that helped me in various way in the last three years, especially Catherine Bresner and Dr. Afnan Salaka for generating the DNA methylation array data and helping me with the project, as well as Dr. Antonio Pardinas, Mark Einon, Prof. Peter Holmans and Dr. Elliot Rees for their help in bioinformatics and statistics. I am also grateful to all the researchers who collected the biological samples and generated the data analysed in this thesis and granted me permission to use it; and I am grateful to the patients who provided these samples. Last but not least, I want to thank everyone in the core team of the MRC Centre for Neuropsychiatric Genetics and Genomics for everything they taught me and their invaluable assistance. Then I would like to thank my friends, who are an essential part of who I am. In Cardiff, of course, Matthieu, Michal, Liad, Jamie and everyone else that I have met since I arrived in the UK; but also every friend I have made in Grenoble, Lyon, Marseille, Boston and all around the world. Most of all, I want to thank Peggy, for always being there for me. Finally, I want to thank my family. They got me to where I am now; and despite the distance, their support was always crucial for me. I dedicate this thesis to my grand- parents. I know they are or would have been proud of me and I cherish every moment I had with them. III Abstract 22q11.2 Deletion Syndrome (22q11.2DS) is a genetic disorder that results from a hemizygous deletion at chromosome 22q11.2, occurring at an incidence of 1 in 4000 live births. It is associated with a wide range of clinical features, such as congenital heart disorders and abnormal facial features. 22q11.2DS patients also have an increased risk of neuropsychiatric disorders, with deletions at 22q11.2 being the highest known risk factor for schizophrenia. However, the mechanisms underlying 22q11.2DS symptomatic variability are still unclear. This thesis addresses this issue by investigating genetic, epigenetic and transcriptomic changes related to 22q11.2DS. Firstly, by using a polygenic risk score profiling approach it shows that the increased risk of schizophrenia in 22q11.2DS patients is partly due to an increased burden of common genetic variants associated with this neuropsychiatric disorder. This thesis also presents evidence that DNA methylation, an epigenetic mark, is altered in 22q11.2DS patients compared to a control population that do not carry a deletion at 22q11.2. Microarray-based whole epigenome analysis showed that these patients have an altered DNA methylation profile that affects genes and biological pathway relevant to schizophrenia. Finally, the CRISPR/Cas9 genome editing technology has been employed in human embryonic stem cells to delete one of the genes spanned by the 22q11.2 deletion. This gene, DGCR8, is a major component of the microRNA biogenesis pathway that is involved in the regulation of gene expression. The knock-out cell lines generated in this study were differentiated into neural progenitor cells to investigate transcriptome changes due the deletion of this gene during neurodevelopment. In conclusion, this thesis shows that the increased risk for schizophrenia in 22q11.2DS patients depends in parts on common genetic variants located outside of the deletion. Moreover, different mechanisms involved in genetic regulation (DNA methylation, microRNAs) can possibly modulate the schizophrenia phenotype by affecting relevant genes and pathways. IV Contents Declaration ......................................................................................................................................I Statement of contribution .............................................................................................................II Acknowledgements .......................................................................................................................III Abstract ........................................................................................................................................ IV Contents .......................................................................................................................................
Load more

Recommended publications
  • Gene Discovery and Functional Assessment of Rare Copy-Number Variants in Neurodevelopmental Disorders
    bioRxiv preprint doi: https://doi.org/10.1101/011510; this version posted November 17, 2014. 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 4.0 International license. Gene discovery and functional assessment of rare copy-number variants in neurodevelopmental disorders Janani Iyer and Santhosh Girirajan Corresponding author: Santhosh Girirajan, 205A Life Sciences Building, Departments of Biochemistry and Molecular Biology and Anthropology, The Pennsylvania State University, University Park, PA 16802, Tel: 814-865-0674, E-mail: [email protected], Word count: 4,608 AUTHOR BIOGRAPHY Janani Iyer is a postdoctoral fellow in the laboratory of Santhosh Girirajan at The Pennsylvania State University. She is studying the role of dosage sensitive genes within rare CNVs using Drosophila melanogaster. Santhosh Girirajan is an Assistant Professor of Biochemistry and Molecular Biology and Anthropology at The Pennsylvania State University. His laboratory is studying the molecular genetic basis of neurodevelopmental disorders by combining work on the discovery of genetic variants in affected children with functional characterization using model organisms. bioRxiv preprint doi: https://doi.org/10.1101/011510; this version posted November 17, 2014. 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 4.0 International license. ABSTRACT Rare copy-number variants (CNVs) are a significant cause of neurodevelopmental disorders.
    [Show full text]
  • Genevista Microdeletion and Microduplication Syndromes
    GeNeViSTA Microdeletion and Microduplication Syndromes: An Update Priya Ranganath, Prajnya Ranganath Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad, India Correspondence to: Dr Prajnya Ranganath Email: [email protected] Abstract containing dosage sensitive genes responsible for the phenotype is generally involved (Goldenberg, Microdeletion and microduplication syndromes 2018). Theoretically, for every microdeletion (MMS) also known as ‘contiguous gene syndrome there should be a reciprocal syndromes’ are a group of disorders caused microduplication syndrome, but microdeletions by sub-microscopic chromosomal deletions or are more common. Microduplications appear to duplications. Most of these conditions are typically result in a milder or no clinical phenotype. associated with developmental delay, autism, multiple congenital anomalies, and characteristic Molecular Etiopathology phenotypic features. These chromosomal abnormalities cannot be detected by conventional Copy number variation (CNV) is defined as the gain cytogenetic techniques like karyotyping and or loss of a stretch of DNA when compared with require higher resolution ‘molecular cytogenetic’ the reference human genome and may range in techniques. The advent of high throughput tests size from a kilobase to several megabases or even such as chromosomal microarray in the past one an entire chromosome. The CNVs associated with or two decades has led to a continuously growing MMS constitute only a small fraction of the total list of microdeletions and microduplication number of possible copy-number variants. There syndromes along with identification of the ‘critical are two major classes of CNVs: recurrent and region’ responsible for the main phenotypic non-recurrent. Recurrent CNVs generally result features associated with these syndromes. This from Non-Allelic Homologous Recombination review discusses the etiopathogenic mechanisms (NAHR) during meiosis.
    [Show full text]
  • Duchenne Muscular Dystrophy (DMD)
    Pediatric Residents Review Session A bit of a hodge podge to keep you guessing December 20, 2018 Natarie Liu, FRCPC, Pediatric Neurology Email me for resources (OSCE handbook, etc) Thanks to Dr. K. Smyth and Dr. K Murias for inspiration for some of the slides Case 3mo girl with hypotonia, hypotonic facies, 1+ symmetric DTR. What is the most likely diagnosis? a. Congenital muscular dystrophy b. Myotonic dystrophy c. SMA1 d. Nemaline rod Stem not giving this picture OR this picture What is this? Dystrophinopathies Duchenne Muscular Dystrophy Becker Muscular Dystrophy Dystrophinopathies By convention, if boy stops walking before age 12, this is Duchenne Muscular Dystrophy (DMD) If they remain ambulatory after their 16th birthday, are typically considered to have Becker Muscular Dystrophy (BMD) Anything in between is an intermediate phenotype Some centres transition to using Dystrophinopathies as the term Dystrophinopathies are X-linked disorders Dystrophinopathies: Epidemiology Duchenne Muscular Dystrophy 1:3500 live male births but newborn screening places the incidence closer to 1:5000 live male births Mean lifespan 19 years traditionally, now greater than 25 years (with multidisciplinary team management and corticosteroid use) Becker Muscular Dystrophy Incidence 1/10th-1/5th of DMD Prevalence 60-90% more than DMD DMD: Clinical Features Boys often present between 3-5 years of age Delayed motor milestones and falls, difficulty running and jumping Gain motor milestones through 6-7 years of age, progressive weakness after Wheelchair before age 12, historically Examination Calf hypertrophy Mild lordotic posture Waddling of gait Poor hip excursion during running Head lag when pulled from sitting from supine Partial Gower maneuver when rising from floor.
    [Show full text]
  • B-Catenin Deficiency Causes Digeorge Syndrome-Like Phenotypes Through Regulation of Tbx1 Sung-Ho Huh and David M
    RESEARCH ARTICLE 1137 Development 137, 1137-1147 (2010) doi:10.1242/dev.045534 © 2010. Published by The Company of Biologists Ltd b-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1 Sung-Ho Huh and David M. Ornitz* SUMMARY DiGeorge syndrome (DGS) is a common genetic disease characterized by pharyngeal apparatus malformations and defects in cardiovascular, craniofacial and glandular development. TBX1 is the most likely candidate disease-causing gene and is located within a 22q11.2 chromosomal deletion that is associated with most cases of DGS. Here, we show that canonical Wnt–b-catenin signaling negatively regulates Tbx1 expression and that mesenchymal inactivation of b-catenin (Ctnnb1) in mice caused abnormalities within the DGS phenotypic spectrum, including great vessel malformations, hypoplastic pulmonary and aortic arch arteries, cardiac malformations, micrognathia, thymus hypoplasia and mislocalization of the parathyroid gland. In a heterozygous Fgf8 or Tbx1 genetic background, ectopic activation of Wnt–b-catenin signaling caused an increased incidence and severity of DGS- like phenotypes. Additionally, reducing the gene dosage of Fgf8 rescued pharyngeal arch artery defects caused by loss of Ctnnb1. These findings identify Wnt–b-catenin signaling as a crucial upstream regulator of a Tbx1–Fgf8 signaling pathway and suggest that factors that affect Wnt–b-catenin signaling could modify the incidence and severity of DGS. KEY WORDS: b-catenin, Tbx1, Fgf8, Pharyngeal arch, DiGeorge syndrome INTRODUCTION is expressed in the pharyngeal arch endoderm, core mesoderm, DiGeorge syndrome (DGS) is one of the most common genetic anterior heart field and head mesenchyme, but is absent in neural disorders with an incidence of 1 in 4000 live births.
    [Show full text]
  • Complete Sequence of the 22Q11.2 Allele in 1,053 Subjects with 22Q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects
    ARTICLE Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects Yingjie Zhao,1 Alexander Diacou,1 H. Richard Johnston,2 Fadi I. Musfee,3 Donna M. McDonald-McGinn,4,5 Daniel McGinn,4,5 T. Blaine Crowley,4,5 Gabriela M. Repetto,6 Ann Swillen,7 Jeroen Breckpot,7 Joris R. Vermeesch,7 Wendy R. Kates,8,9 M. Cristina Digilio,10 Marta Unolt,10,11 Bruno Marino,11 Maria Pontillo,12 Marco Armando,12,13 Fabio Di Fabio,11 Stefano Vicari,12,14 Marianne van den Bree,15 Hayley Moss,15 Michael J. Owen,15 Kieran C. Murphy,16 Clodagh M. Murphy,17,18 Declan Murphy,17,18 Kelly Schoch,19 Vandana Shashi,19 Flora Tassone,20 (Author list continued on next page) The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%–70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizy- gous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequi- librium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64–4.75).
    [Show full text]
  • Digeorge Syndrome
    [Downloaded free from http://www.jpgmonline.com on Thursday, October 22, 2015, IP: 120.62.21.80] Grand Round Case “FISHed” out the diagnosis: A case of DiGeorge syndrome Bajaj S, Thombare TS, Tullu MS, Agrawal M Department of Pediatrics, ABSTRACT Seth Gordhandas Our patient presented with congenital heart disease (CHD: Tetralogy of Fallot), hypocalcemia, hypoparathyroidism, Sunderdas Medical College and King Edward and facial dysmorphisms. Suspecting DiGeorge syndrome (DGS), a fluorescence in situ hybridization (FISH) Memorial Hospital, analysis for 22q11.2 deletion was made. The child had a hemizygous deletion in the 22q11.2 region, diagnostic Mumbai, Maharashtra, of DGS. Unfortunately, the patient succumbed to the heart disease. DGS is the most common microdeletion India syndrome, and probably underrecognized due to the varied manifestations. This case stresses the importance of a detailed physical examination and a high index of suspicion for diagnosing this genetic condition. Timely Address for correspondence: diagnosis can help manage and monitor these patients better and also offer prenatal diagnosis in the next Dr. Milind S Tullu, pregnancy. E-mail: milindtullu@ yahoo.com Received : 18-05-2015 Review completed : 19-06-2015 KEY WORDS: Child, congenital heart disease (CHD), DiGeorge syndrome (DGS), dysmorphism, genetic Accepted : 05-10-2015 counseling, microdeletion Case Details were below the third percentile for his age (weight 3.5 kg, length 61 cm, head circumference 37 cm). A closer look, ur patient was an 8-month-old male child of Indian however, revealed some alerting dysmorphic features in Oorigin and the first issue of a nonconsanguineous the child. He had narrow and upslanting palpebral fissures, marriage.
    [Show full text]
  • Clinical Findings in 32 Patients with 22Qll.2 Microdeletion Attended in the City of Córdoba, Argentina
    Brief report Arch Argent Pediatr 2013;111(5):423-427 / 423 Clinical findings in 32 patients with 22qll.2 microdeletion attended in the city of Córdoba, Argentina Cecilia del Carmen Montes, M.D.a,b, Alicia Sturich, Biologista,b,Alejandra Chaves, B.S.a, Ernesto Juaneda, M.D.c, Julio Orellana, M.D.d, Roberto De Rossi, M.D.e, Blanca Pereyra, B.S.a, Luis Alday, M.D.c, and Norma Teresa Rossi, M.D.a,b ABSTRACT INTRODUCTION The 22q11.2 microdeletion is the most common deletion The 22q11.2 microdeletion is the most syndrome, with a prevalence of 1/4000-1/6000 among newborn infants and a wide phenotypic variability. The diagnosis of common cause of microdeletion in human beings the 22q11.2 microdeletion is made through cytogenetics or and has a prevalence of 1/4000-1/6000 among fluorescence in situ hybridization (FISH). The objectives of this live newborn infants. Approximately 95% of article were to describe the clinical features of 32 patients with the cases are diagnosed when a loss of genetic 22q11.2 microdeletion and the findings of other chromosomal abnormalities and genetic syndromes in phenotypically similar material is observed through the fluorescence in patients. This series was made up of 268 patients with clinical situ hybridization (FISH) technique. Tobías, et al. criteria supporting the diagnostic suspicion attended at the recommend the use of the FISH technique for the Hospital de Niños and Hospital Privado, of Córdoba, between 22q11.2 microdeletion in patients with conotruncal March 1st, 2004 and August 31st, 2011. The following parameters were analyzed: age at the time of the diagnosis, sex, clinical heart defects, or in the parents of patients with manifestations, and mortality.
    [Show full text]
  • Genes, Hearing, and Deafness : from Molecular Biology to Clinical Practice
    1181 FM 4/4/07 4:16 PM Page i Genes, Hearing, and Deafness From Molecular Biology to Clinical Practice Edited by Alessandro Martini Audiology and ENT Clinical Institute University of Ferrara Ferrara Italy Dafydd Stephens School of Medicine Cardiff University Cardiff Wales Andrew P Read Department of Medical Genetics St Mary’s Hospital Manchester UK 1181 FM 4/4/07 4:16 PM Page ii © 2007 Informa UK Ltd First published in the United Kingdom in 2007 by Informa Healthcare, Telephone House, 69–77 Paul Street, London EC2A 4LQ. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH. Registered in England and Wales number 1072954. Tel: +44 (0)20 7017 6000 Fax: +44 (0)20 7017 6699 Website: www.informahealthcare.com All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or seditions any omissions brought to our attention. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician.
    [Show full text]
  • Evolution by Process. Not by Consequence: Implications of the New Molecular Geneticson Development and Evolution
    The International Journal of Comparative Psychology, Vol. 1, No. 1, Fall 1987 EVOLUTION BY PROCESS. NOT BY CONSEQUENCE: IMPLICATIONS OF THE NEW MOLECULAR GENETICSON DEVELOPMENT AND EVOLUTION Mae-Wan Ho INTRODUCTION There is much in common between comparative psychology and a biological tradition that includes such distinguished figures as poet scien- tist Goethe, evolutionist Lamarck, embryologist Driesch; and closer to our time, D'Arcy Thompson, Alfi-ed North Whitehead, Joseph Needham, Richard Goldschmidt and Conrad Waddington. This tradition has been variously referred to as organized, holist, neovitalist, and so on, though none of the labels are completely accurate. Its chief concern is the study of living organization at different levels each with its own distinctive empha- sis. Nevertheless, these people share a passionate commitment to vital process and a refusal to be seduced by simplistic pseudoexplanations at every turn. The levels of organization apparent in the living world today have emerged in the course of evolution: from molecules and protocells (see Fox, 1984 and refs. therein) to protists; from the first multicellular organ- isms to communities of animals and plants, and finally to intricate human societies. All these products of evolution coexist and are interdependent because they are part of one evolutionary process. The key to the survival of our planet lies in a proper appreciation of the continuity which exists among the physicochemical, biological and sociocultural realms. It is from this perspective of the unity of nature that a biologist like myself may be encouraged to address psychologists on the implications that recent advances in molecular genetics have on our study of development and evolution.
    [Show full text]
  • FOXN1 Compound Heterozygous Mutations Cause Selective Thymic Hypoplasia in Humans
    FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans Qiumei Du, … , M. Teresa de la Morena, Nicolai S.C. van Oers J Clin Invest. 2019;129(11):4724-4738. https://doi.org/10.1172/JCI127565. Research Article Genetics Immunology Graphical abstract Find the latest version: https://jci.me/127565/pdf RESEARCH ARTICLE The Journal of Clinical Investigation FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans Qiumei Du,1 Larry K. Huynh,1 Fatma Coskun,1 Erika Molina,1 Matthew A. King,1 Prithvi Raj,1 Shaheen Khan,1 Igor Dozmorov,1 Christine M. Seroogy,2 Christian A. Wysocki,3,4 Grace T. Padron,5 Tyler R. Yates,6 M. Louise Markert,6,7 M. Teresa de la Morena,8 and Nicolai S.C. van Oers1,3,9 1Departments of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 2Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA. 3Department of Pediatrics, and 4Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 5University of Miami Miller School of Medicine, Miami, Florida, USA. 6Department of Pediatrics and 7Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA. 8Division of Immunology, Department of Pediatrics, University of Washington and Seattle Children’s Hospital, Seattle, Washington , USA. 9Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. We report on 2 patients with compound heterozygous mutations in forkhead box N1 (FOXN1), a transcription factor essential for thymic epithelial cell (TEC) differentiation. TECs are critical for T cell development. Both patients had a presentation consistent with T–/loB+NK+ SCID, with normal hair and nails, distinct from the classic nude/SCID phenotype in individuals with autosomal-recessive FOXN1 mutations.
    [Show full text]
  • D. Wangl, R. Sapolsky2,1, Spencer.1, T. Riouxl, L
    Session 20: Plenary Session A3 1 2 Genome-wide screen for Hirschsprung disease susceptibility loci in a Correction of the high-SCE phenotype in Bloom's syndrome (BS) cells Mennonite kindred segregating an endothelin-B receptor mutation. by transfection of the wild-type gene. J. German. M. Proytcheva. T.-Z. Ye. E.G. Puffenberger. A. Lynn, C. Kashuk, and A. Chakravarti. Dept. of Genetics, Case M. Sanz. N. Neff. N. A. Ellis. New York Blood Center, New York, NY. Weserin Reserve Univ., Cleveland, OH. BS is a rare autosomal recessive disorder characterized bv short stature and Genome-wide screens using polymorphic markers in segregating multiplex families are predisposition to developing cancer. An excessive rate of sister-chromatid exchanges now routine for localizing disease genes. In principle, susceptibility loci may even be (SCEs) in proliferating BS cells is a unique and diagnostic feature of the syndrome. mapped in simplex families by searching for allelic associations between genetic Recently, the BS gene, BLM, was isolated and shown to encode a 1417 amino acid markers and disease phenotype. This exercise is most efficient in isolated populations protein product homologous to RecQ helicases (Ellis et aL, 1995). We have introduced where large genomic segments will be shared by affected individuals on the basis of the wild-type BLM cDNA into BS cells in order to test its ability to correct the high- common ancestry. We demonstrate the identification of multiple genomic regions that SCE phenotype of BS cells. harbor putative susceptibility loci for Hirschsprung disease (HSCR) in a large, inbred A full-length BLM cDNA, R 12, was transferred into pOPRSVI-CAT, a mammalian Mennonite kindred by using genome-wide association mapping.
    [Show full text]
  • IJOMCR Vol.||02||Issue||03||Page 14-17||Jul-Sep 2016
    IJOMCR Vol.||02||Issue||03||Page 14-17||Jul-Sep 2016 Congenital Hypoplasia of Depressor Angularis Oris Muscle With Atrial Septal Defect: A Rare Case Report Authors Dr Ajeet Gopchade1, Dr Chetana Gopchade2 Consultant Pediatrician1, Consultant Gynaecologist2 Amrutpath Children Hospital Nanded- (MS)- India. Corresponding Author Dr Ajeet Gopchade Abstract An asymmetric crying facies of newborn is usually of a major concern to parents and treating pediatrician. Hypoplasia of depressor angularis oris musle is one of the common causes of such an asymmetric crying facies. It is moreover a cause of concern because in many cases there is increased incidence of other congenital anomalies especially cardiovascular malformations. A close differential diagnosis of this condition includes partial peripheral facial nerve palsy. Congenital hypoplasia of depressor angularis oris is a condition which is not expected to improve on its own and hence will invariably require surgical correction for cosmetic purposes. Its presence in any newborn make it necessary that treating physician look for any congenital heart disease, head and neck anomalies and genitourinary anomalies. Here we report a case of congenital hypoplasia of depressor angularis oris muscle with Ostium secondum type of atria septal defect. KeyWords : Depressor angularis Oris, Assymetric crying facies, Atrial Septal Defect Introduction musculoskeletal and head neck face anomalies. An asymmetric crying facies in a newborn is a Asymmetric crying facies is also associated with major cause of concern
    [Show full text]