DOCSLIB.ORG

Genetic Variation at the 22Q11 PRODH2 DGCR6 Locus Presents an Unusual Pattern and Increases Susceptibility to Schizophrenia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetic Variation at the 22Q11 PRODH2 DGCR6 Locus Presents an Unusual Pattern and Increases Susceptibility to Schizophrenia Genetic variation at the 22q11 PRODH2͞DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia Hui Liu†, Simon C. Heath‡, Christina Sobin†, J. Louw Roos§, Brandi L. Galke†, Maude L. Blundell†, Marge Lenane¶, Brian Robertsonʈ, Ellen M. Wijsman**, Judith L. Rapoport¶, Joseph A. Gogos††, and Maria Karayiorgou†‡‡ †Human Neurogenetics Laboratory, The Rockefeller University, New York, NY 10021; ‡Memorial Sloan Kettering Cancer Center, New York, NY 10021; §Department of Psychiatry and Weskoppies Hospital, University of Pretoria, Pretoria 0083, Republic of South Africa; ¶Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892; ʈDepartment of Psychiatry and Valkenberg Hospital, University of Capetown, Capetown 7925, Republic of South Africa; **Division of Medical Genetics and Department of Biostatistics, University of Washington, Seattle, WA 98195; and ††College of Physicians and Surgeons, Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032 Communicated by David E. Housman, Massachusetts Institute of Technology, Cambridge, MA, December 26, 2001 (received for review September 25, 2001) The location of a schizophrenia susceptibility locus at chromosome region harbors genes that alone, or in combination, are causally 22q11 has been suggested by genome-wide linkage studies. Addi- implicated in schizophrenia in a certain proportion of patients. The tional support was provided by the observation of a higher-than- overwhelming majority of the 22q11 deletions are 3 Mb in size, expected frequency of 22q11 microdeletions in patients with schizo- whereas a smaller percentage (Ϸ8%) involve the same proximal Ϸ phrenia and the demonstration that 20–30% of individuals with breakpoint but a different distal breakpoint resulting in a smaller 22q11 microdeletions develop schizophrenia or schizoaffective dis- 1.5-Mb deletion (9, 10). At least one schizophrenic patient has been order in adolescence and adulthood. Analysis of the extent of these described as carrying the smaller 22q11 microdeletion, and there- microdeletions by using polymorphic markers afforded further re- fore the ‘‘schizophrenia critical region’’ has been defined to 1.5 Mb finement of this locus to a region of Ϸ1.5 Mb. Recently, a high rate of (ref. 6). The majority of the genes in the region are known (11). To GENETICS 22q11 microdeletions was also reported for a cohort of 47 patients with Childhood Onset Schizophrenia, a rare and severe form of address the role of individual genes from this chromosomal region, schizophrenia with onset by age 13. It is therefore likely that this we are undertaking systematic mutational screening of these genes 1.5-Mb region contains one or more genes that predispose to schizo- in combination with linkage disequilibrium (LD) studies in family phrenia. In three independent samples, we provide evidence for a samples (triads) that test for preferential transmission of single- contribution of the PRODH2͞DGCR6 locus in 22q11-associated schizo- nucleotide polymorphisms (SNPs) and multi-SNP haplotypes from phrenia. We also uncover an unusual pattern of PRODH2 gene parents to affected individuals. variation that mimics the sequence of a linked pseudogene. Several Materials and Methods of the pseudogene-like variants we identified result in missense changes at conserved residues and may prevent synthesis of a fully Patient Samples. Detailed information about the adult schizo- functional enzyme. Our results have implications for understanding phrenic (AS) sample is provided in ref. 12. The South African the genetic basis of the 22q11-associated psychiatric phenotypes and sample is part of our ongoing collection of schizophrenia patients provide further insights into the genomic instability of this region. of Afrikaner origin and will be described in detail elsewhere (M.K., M. Torrington, C.S., B.R., S.C.H., M.L.B., H. Pretorius, S. Lay, chizophrenia is a common severe mental illness that affects 1% J.A.G., and J.L.R., unpublished work). Probands in both samples Sof the population and is characterized by disordered thinking as met lifetime criteria for Diagnostic and Statistical Manual of well as deficits in emotional and social behavior. Microdeletions of Mental Disorders, 4th Ed. (DSM-IV) (13) schizophrenia or schizo- chromosome 22q11 are associated with variable phenotypic expres- affective disorder. Participants were interviewed by specially sion that often includes learning disabilities, palatal abnormalities, trained clinicians by using the Diagnostic Interview for Genetic congenital heart defects, and mildly dysmorphic facial features (1). Studies (DIGS) (14). Detailed information about the COS sample One of the first clues that psychiatric symptomatology may also be is provided in refs. 7 and 15. All COS probands met unmodified associated with this microdeletion was a report of expressionless criteria for schizophrenia with onset of psychotic symptoms before face, monotonous speech, and flattened affect among children with their 13th birthday and mean age of onset of psychosis at 10.1 (Ϯ1.8 the microdeletion (2). In light of the evidence for suggestive linkage yr). The protocol and the consent forms were approved by the for schizophrenia on chromosome 22 (reviewed in ref. 3), patients Institutional Review Boards (IRBs) at all participating sites. The with the 22q11 microdeletion were evaluated for psychiatric symp- National Institute of Mental Health (NIMH) samples have been toms or disorders, and a relatively high frequency of severe mental obtained from the NIMH Human Genetics Inititative dataset illness has since been reported. Specifically, two independent (http:͞͞ zork.wustl.edu͞nimh). [Acknowledgment for this sample studies have reported that 25–31% of patients with the 22q11 can be found in the Appendix, which is published as supporting microdeletion met diagnostic criteria for schizophrenia or schizo- information on the PNAS web site (www.pnas.org)]. affective disorder (4, 5). Although the microdeletion occurs in the population at a rate of 0.025%, it has been found in 2% of adult schizophrenic patients (6) and in 6% of cases with childhood onset Abbreviations: LD, linkage disequilibrium; COS, childhood onset schizophrenia; SNP, single- schizophrenia (COS) (7). In addition, several studies have described nucleotide polymorphism; AS, adult schizophrenic; DSM-IV, Diagnostic and Statistical 22q11 microdeletions among schizophrenic patients of various Manual of Mental Disorders, fourth edition; NIMH, National Institute of Mental Health; LCR, low copy repeat sequence; RFLP, restriction fragment length polymorphism; HHRR, ethnic origins (8). These studies collectively suggest that the morbid haplotype-based haplotype relative risk; TDT, Transmission Disequilibrium Test; T͞nT, risk of schizophrenia for a patient with a 22q11 microdeletion may Transmitted͞non-Transmitted; CI, confidence interval. be approximately 20–30 times the general population risk of 1%, ‡‡To whom reprint requests should be addressed. E-mail: [email protected]. and that the rate of 22q11 microdeletions in schizophrenia, al- The publication costs of this article were defrayed in part by page charge payment. This though relatively low, may be approximately 80 times the estimated article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. general population rate. It therefore seems likely that the 22q11 §1734 solely to indicate this fact. www.pnas.org͞cgi͞doi͞10.1073͞pnas.042700699 PNAS ͉ March 19, 2002 ͉ vol. 99 ͉ no. 6 ͉ 3717–3722 Downloaded by guest on September 24, 2021 SNP Identification and Genotyping. Methods (16, 17), primers, and PCR conditions can be found in the Appendix, which is published as supporting information on the PNAS web site, www.pnas.org. Somatic Cell Hybrids. Somatic cell hybrid methods are as described in ref. 6. Statistical Analysis. Haplotype probabilities for each individual were calculated assuming no recombination between SNPs, summing over ambiguous haplotypes caused by missing phase information or genotype data. Haplotype frequences were estimated by using the Expectation Maximization algorithm (18) simultaneously with the calculation of haplotype probabilities. For the analyses on multilo- cus SNP haplotypes, trios with ambiguous haplotype reconstruc- tions were used only if there was one reconstruction with a probability of Ͼ0.95. Transmissions of single SNPs were analyzed by using both the haplotype-based Haplotype Relative Risk (HHRR) statistic (19) and the Transmission Disequilibrium Test (TDT) (20) (where the TDT considered only transmissions from heterozygous parents). The significance of the TDT analyses was assessed by using a standard 1 degree of freedom ␹2 test, and the significance of the HHRR tests was assessed by using Fisher’s exact test. Multilocus SNP haplotype transmissions were analyzed by using the HHRR, with the significance being estimated by using Fisher’s exact test. Because of the relatively small size of the COS sample and the stratified adult samples, exact P values are given only for P Ͼ 0.001. Results Association Between PRODH2͞HsPOX2 Locus Variation and Schizophre- nia. A first-stage scan of the 22q11 region involved a set of 18 SNPs from nine gene loci distributed across the entire 1.5 Mb (Fig. 1b, green shading). The inheritance of these variants by probands affected with schizophrenia from parents was examined in 107 independent triads from the U.S. (AS
Load more

Recommended publications
  • Association of Gene Ontology Categories with Decay Rate for Hepg2 Experiments These Tables Show Details for All Gene Ontology Categories
    Supplementary Table 1: Association of Gene Ontology Categories with Decay Rate for HepG2 Experiments These tables show details for all Gene Ontology categories. Inferences for manual classification scheme shown at the bottom. Those categories used in Figure 1A are highlighted in bold. Standard Deviations are shown in parentheses. P-values less than 1E-20 are indicated with a "0". Rate r (hour^-1) Half-life < 2hr. Decay % GO Number Category Name Probe Sets Group Non-Group Distribution p-value In-Group Non-Group Representation p-value GO:0006350 transcription 1523 0.221 (0.009) 0.127 (0.002) FASTER 0 13.1 (0.4) 4.5 (0.1) OVER 0 GO:0006351 transcription, DNA-dependent 1498 0.220 (0.009) 0.127 (0.002) FASTER 0 13.0 (0.4) 4.5 (0.1) OVER 0 GO:0006355 regulation of transcription, DNA-dependent 1163 0.230 (0.011) 0.128 (0.002) FASTER 5.00E-21 14.2 (0.5) 4.6 (0.1) OVER 0 GO:0006366 transcription from Pol II promoter 845 0.225 (0.012) 0.130 (0.002) FASTER 1.88E-14 13.0 (0.5) 4.8 (0.1) OVER 0 GO:0006139 nucleobase, nucleoside, nucleotide and nucleic acid metabolism3004 0.173 (0.006) 0.127 (0.002) FASTER 1.28E-12 8.4 (0.2) 4.5 (0.1) OVER 0 GO:0006357 regulation of transcription from Pol II promoter 487 0.231 (0.016) 0.132 (0.002) FASTER 6.05E-10 13.5 (0.6) 4.9 (0.1) OVER 0 GO:0008283 cell proliferation 625 0.189 (0.014) 0.132 (0.002) FASTER 1.95E-05 10.1 (0.6) 5.0 (0.1) OVER 1.50E-20 GO:0006513 monoubiquitination 36 0.305 (0.049) 0.134 (0.002) FASTER 2.69E-04 25.4 (4.4) 5.1 (0.1) OVER 2.04E-06 GO:0007050 cell cycle arrest 57 0.311 (0.054) 0.133 (0.002)
    [Show full text]
  • DGCR6 at the Proximal Part of the Digeorge Critical Region Is Involved in Conotruncal Heart Defects
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Institutional Repository : the EHIME area OPEN Citation: Human Genome Variation (2015) 2, 15004; doi:10.1038/hgv.2015.4 © 2015 The Japan Society of Human Genetics All rights reserved 2054-345X/15 www.nature.com/hgv ARTICLE DGCR6 at the proximal part of the DiGeorge critical region is involved in conotruncal heart defects Wenming Gao1, Takashi Higaki1, Minenori Eguchi-Ishimae1, Hidehiko Iwabuki1, Zhouying Wu1, Eiichi Yamamoto2, Hidemi Takata1, Masaaki Ohta1, Issei Imoto3, Eiichi Ishii1 and Mariko Eguchi1 Cardiac anomaly is one of the hallmarks of DiGeorge syndrome (DGS), observed in approximately 80% of patients. It often shows a characteristic morphology, termed as conotruncal heart defects. In many cases showing only the conotruncal heart defect, deletion of 22q11.2 region cannot be detected by fluorescence in situ hybridization (FISH), which is used to detect deletion in DGS. We investigated the presence of genomic aberrations in six patients with congenital conotruncal heart defects, who show no deletion at 22q11.2 in an initial screening by FISH. In these patients, no abnormalities were identified in the coding region of the TBX1 gene, one of the key genes responsible for the phenotype of DGS. However, when copy number alteration was analyzed by high-resolution array analysis, a small deletion or duplication in the proximal end of DiGeorge critical region was detected in two patients. The affected region contains the DGCR6 and PRODH genes. DGCR6 has been reported to affect the expression of the TBX1 gene. Our results suggest that altered dosage of gene(s) other than TBX1, possibly DGCR6, may also be responsible for the development of conotruncal heart defects observed in patients with DGS and, in particular, in those with stand-alone conotruncal heart defects.
    [Show full text]
  • Network Effects of the Neuropsychiatric 15Q13.3 Microdeletion on the Transcriptome and Epigenome in Human Induced Neurons
    bioRxiv preprint doi: https://doi.org/10.1101/772541; this version posted September 19, 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. Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons Siming Zhang (B.S., Stanford University), Xianglong Zhang (Ph.D., Stanford University), Shining Ma (Ph.D., Stanford University), Carolin Purmann (Ph.D., Stanford University), Kasey Davis (Ph.D., Stanford University), Wing Hung Wong (Ph.D., Stanford University), Jonathan Bernstein (MD, Ph.D., Stanford University), Joachim Hallmayer (MD, Stanford University), Alexander E Urban (Ph.D., Stanford University) Corresponding author: Alexander E Urban Address: 3165 Porter Drive, Stanford CA 94304 Phone: (650) 736-9528, Fax: (650) 725-4913 email: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/772541; this version posted September 19, 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. Abstract Heterozygous deletions in the 15q13.3 region are associated with several neuropsychiatric disorders including autism, schizophrenia, and attention deficit hyperactivity disorder. Several genes within the 15q13.3 deletion region may play a role in neuronal dysfunction, based on association studies in humans and functional studies in mice, but the intermediate molecular mechanisms remain unknown.
    [Show full text]
  • Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications
    Stem Cell Rev and Rep DOI 10.1007/s12015-016-9662-8 Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications Behnam Ahmadian Baghbaderani 1 & Adhikarla Syama2 & Renuka Sivapatham3 & Ying Pei4 & Odity Mukherjee2 & Thomas Fellner1 & Xianmin Zeng3,4 & Mahendra S. Rao5,6 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract We have recently described manufacturing of hu- help determine which set of tests will be most useful in mon- man induced pluripotent stem cells (iPSC) master cell banks itoring the cells and establishing criteria for discarding a line. (MCB) generated by a clinically compliant process using cord blood as a starting material (Baghbaderani et al. in Stem Cell Keywords Induced pluripotent stem cells . Embryonic stem Reports, 5(4), 647–659, 2015). In this manuscript, we de- cells . Manufacturing . cGMP . Consent . Markers scribe the detailed characterization of the two iPSC clones generated using this process, including whole genome se- quencing (WGS), microarray, and comparative genomic hy- Introduction bridization (aCGH) single nucleotide polymorphism (SNP) analysis. We compare their profiles with a proposed calibra- Induced pluripotent stem cells (iPSCs) are akin to embryonic tion material and with a reporter subclone and lines made by a stem cells (ESC) [2] in their developmental potential, but dif- similar process from different donors. We believe that iPSCs fer from ESC in the starting cell used and the requirement of a are likely to be used to make multiple clinical products. We set of proteins to induce pluripotency [3]. Although function- further believe that the lines used as input material will be used ally identical, iPSCs may differ from ESC in subtle ways, at different sites and, given their immortal status, will be used including in their epigenetic profile, exposure to the environ- for many years or even decades.
    [Show full text]
  • Unraveling the Genetic and Developmental Mysteries of 22Q11 Deletion Syndrome
    Review TRENDS in Molecular Medicine Vol.9 No.9 September 2003 383 Unraveling the genetic and developmental mysteries of 22q11 deletion syndrome Hiroyuki Yamagishi1 and Deepak Srivastava2 1Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan 2Departments of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Rm NA8.124, Dallas, TX 75390-9148, USA Birth defects occur in nearly 5% of all live births and are susceptibilities that predispose individuals to a variety the major cause of infant mortality and morbidity. of birth defects. Here, we review the recent advances that Despite the recent progress in molecular and develop- have begun to reveal the human genetic, developmental mental biology, the underlying genetic etiology of most biology and molecular biology underpinnings of this congenital anomalies remains unknown. Heterozygous common syndrome. deletion of the 22q11.2 locus results in the most com- mon human genetic deletion syndrome, known as Clinical features of 22q11DS DiGeorge syndrome, and has served as an entry to The clinical findings associated with del22q11 are highly understanding the basis for numerous congenital heart variable. Approximately 75% of patients with 22q11DS are and craniofacial anomalies, among many other defects. born with congenital heart defects (CHD), mainly of the Extensive human genetic analyses, mouse modeling cardiac outflow tract and aortic arch. Other common and studies of developmental molecular cascades features of 22q11DS include a characteristic facial involved in 22q11 deletion syndrome are revealing com- appearance, immunodeficiency from thymic hypoplasia, plex networks of signaling and transcriptional events velopharyngeal dysfunction with or without cleft palate, that are essential for normal embryonic development.
    [Show full text]
  • CREB-Dependent Transcription in Astrocytes: Signalling Pathways, Gene Profiles and Neuroprotective Role in Brain Injury
    CREB-dependent transcription in astrocytes: signalling pathways, gene profiles and neuroprotective role in brain injury. Tesis doctoral Luis Pardo Fernández Bellaterra, Septiembre 2015 Instituto de Neurociencias Departamento de Bioquímica i Biologia Molecular Unidad de Bioquímica y Biologia Molecular Facultad de Medicina CREB-dependent transcription in astrocytes: signalling pathways, gene profiles and neuroprotective role in brain injury. Memoria del trabajo experimental para optar al grado de doctor, correspondiente al Programa de Doctorado en Neurociencias del Instituto de Neurociencias de la Universidad Autónoma de Barcelona, llevado a cabo por Luis Pardo Fernández bajo la dirección de la Dra. Elena Galea Rodríguez de Velasco y la Dra. Roser Masgrau Juanola, en el Instituto de Neurociencias de la Universidad Autónoma de Barcelona. Doctorando Directoras de tesis Luis Pardo Fernández Dra. Elena Galea Dra. Roser Masgrau In memoriam María Dolores Álvarez Durán Abuela, eres la culpable de que haya decidido recorrer el camino de la ciencia. Que estas líneas ayuden a conservar tu recuerdo. A mis padres y hermanos, A Meri INDEX I Summary 1 II Introduction 3 1 Astrocytes: physiology and pathology 5 1.1 Anatomical organization 6 1.2 Origins and heterogeneity 6 1.3 Astrocyte functions 8 1.3.1 Developmental functions 8 1.3.2 Neurovascular functions 9 1.3.3 Metabolic support 11 1.3.4 Homeostatic functions 13 1.3.5 Antioxidant functions 15 1.3.6 Signalling functions 15 1.4 Astrocytes in brain pathology 20 1.5 Reactive astrogliosis 22 2 The transcription
    [Show full text]
  • Content Based Search in Gene Expression Databases and a Meta-Analysis of Host Responses to Infection
    Content Based Search in Gene Expression Databases and a Meta-analysis of Host Responses to Infection A Thesis Submitted to the Faculty of Drexel University by Francis X. Bell in partial fulfillment of the requirements for the degree of Doctor of Philosophy November 2015 c Copyright 2015 Francis X. Bell. All Rights Reserved. ii Acknowledgments I would like to acknowledge and thank my advisor, Dr. Ahmet Sacan. Without his advice, support, and patience I would not have been able to accomplish all that I have. I would also like to thank my committee members and the Biomed Faculty that have guided me. I would like to give a special thanks for the members of the bioinformatics lab, in particular the members of the Sacan lab: Rehman Qureshi, Daisy Heng Yang, April Chunyu Zhao, and Yiqian Zhou. Thank you for creating a pleasant and friendly environment in the lab. I give the members of my family my sincerest gratitude for all that they have done for me. I cannot begin to repay my parents for their sacrifices. I am eternally grateful for everything they have done. The support of my sisters and their encouragement gave me the strength to persevere to the end. iii Table of Contents LIST OF TABLES.......................................................................... vii LIST OF FIGURES ........................................................................ xiv ABSTRACT ................................................................................ xvii 1. A BRIEF INTRODUCTION TO GENE EXPRESSION............................. 1 1.1 Central Dogma of Molecular Biology........................................... 1 1.1.1 Basic Transfers .......................................................... 1 1.1.2 Uncommon Transfers ................................................... 3 1.2 Gene Expression ................................................................. 4 1.2.1 Estimating Gene Expression ............................................ 4 1.2.2 DNA Microarrays ......................................................
    [Show full text]
  • 393LN V 393P 344SQ V 393P Probe Set Entrez Gene
    393LN v 393P 344SQ v 393P Entrez fold fold probe set Gene Gene Symbol Gene cluster Gene Title p-value change p-value change chemokine (C-C motif) ligand 21b /// chemokine (C-C motif) ligand 21a /// chemokine (C-C motif) ligand 21c 1419426_s_at 18829 /// Ccl21b /// Ccl2 1 - up 393 LN only (leucine) 0.0047 9.199837 0.45212 6.847887 nuclear factor of activated T-cells, cytoplasmic, calcineurin- 1447085_s_at 18018 Nfatc1 1 - up 393 LN only dependent 1 0.009048 12.065 0.13718 4.81 RIKEN cDNA 1453647_at 78668 9530059J11Rik1 - up 393 LN only 9530059J11 gene 0.002208 5.482897 0.27642 3.45171 transient receptor potential cation channel, subfamily 1457164_at 277328 Trpa1 1 - up 393 LN only A, member 1 0.000111 9.180344 0.01771 3.048114 regulating synaptic membrane 1422809_at 116838 Rims2 1 - up 393 LN only exocytosis 2 0.001891 8.560424 0.13159 2.980501 glial cell line derived neurotrophic factor family receptor alpha 1433716_x_at 14586 Gfra2 1 - up 393 LN only 2 0.006868 30.88736 0.01066 2.811211 1446936_at --- --- 1 - up 393 LN only --- 0.007695 6.373955 0.11733 2.480287 zinc finger protein 1438742_at 320683 Zfp629 1 - up 393 LN only 629 0.002644 5.231855 0.38124 2.377016 phospholipase A2, 1426019_at 18786 Plaa 1 - up 393 LN only activating protein 0.008657 6.2364 0.12336 2.262117 1445314_at 14009 Etv1 1 - up 393 LN only ets variant gene 1 0.007224 3.643646 0.36434 2.01989 ciliary rootlet coiled- 1427338_at 230872 Crocc 1 - up 393 LN only coil, rootletin 0.002482 7.783242 0.49977 1.794171 expressed sequence 1436585_at 99463 BB182297 1 - up 393
    [Show full text]
  • REVIEW the 22Q11.2 Deletion Syndrome
    REVIEW The 22q11.2 deletion syndrome Hiroyuki Yamagishi Department of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center, TX, USA Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan (Receivedfor publicationon March27, 2002) Abstract. The 22q11.2 deletion syndrome (22q11DS) encompasses DiGeorge syndrome, velo-cardio facial syndrome and conotruncal anomaly face syndrome and is due to a microdeletion of chromosome 22q11.2. This is the most frequent known interstitial deletion found in human with an incidence of 1 in 4,000 live births. A large number of clinical findings have been reported in affected patients, including cardiac defects, characteristic facial features, thymic hypoplasia, cleft palate, hypoparathyroidism, learning difficulties and psychiatric disorders. A comprehensive evaluation and follow-up program is necessary for patients with 22q11DS. A striking aspect of the 22q11DS phenotype is its variability, the basis of which remains unclear, and no phenotype-genotype correlation has been made. The structures primarily affected in patients with 22q11DS are derivatives of the embryonic pharyngeal arches and pouches suggesting that haploinsufficiency of the gene(s) on the deleted region, spanning 2-3 Mb, is important in pharyngeal arch/pouch development. Extensive gene searches have been successful in identifying more than 30 genes in the deleted segment. Although standard positional cloning has failed to demonstrate a role for any of these genes in the syndrome, the use of experimental animal models and advanced genome manipulation technologies in mice have been providing an insight into the developmental role of some of these genes, including TBX1. In this review, the clinical features and management of patients with 22q11DS are integrated with our current understanding of the embryo logical and molecular basis of this syndrome, as presented at the 1235th Meeting of The Keio Medical Society.
    [Show full text]
  • Juvenile Rheumatoid Arthritis and Del(22Ql 1) Syndrome: a Non
    JMed Genet 1998;35:943-947 943 Juvenile rheumatoid arthritis and del(22ql 1) J Med Genet: first published as 10.1136/jmg.35.11.943 on 1 November 1998. Downloaded from syndrome: a non-random association Alain Verloes, Cynthia Curry, Mauricette Jamar, Christian Herens, Patricia O'Lague, James Marks, Pierre Sarda, Patricia Blanchet Abstract mal part of the long arm of chromosome 22, Del(22qll) is a common microdeletion encompassing in its phenotype Shprintzen syndrome with an extremely variable phe- velocardiofacial syndrome,' Takao conotruncal notype. Besides classical manifestations, anomalies face syndrome, DiGeorge anomaly,2 such as velocardiofacial (Shprintzen) or some instances of Opitz GBBB syndrome type DiGeorge syndromes, del(22ql 1) syn- 2,' and isolated outflow tract defects (such as drome may be associated with unusual but truncus arteriosus, tetralogy of Fallot, or inter- probably causally related anomalies that rupted aortic arch). The incidence could be as expand its phenotype and complicate its high as 1/3500 births. recognition. We report here three children The spectrum of clinical anomalies associ- with the deletion and a chronic, erosive ated with 22ql 1 monosomy is remarkably vari- polyarthritis resembling idiopathic cases able. Recently, juvenile rheumatoid arthritis ofjuvenile rheumatoid arthritis (JRA). (TRA) has been reported in association with Patient 1, born in 1983, initially pre- del(22ql 1) in five children.4 We report here sented with developmental delay, facial three further cases of this association, indicat- dysmorphism, velopharyngeal insuffi- ing that the presence of a JRA-like disorder ciency, and severe gastro-oesophageal re- may not be fortuitous, but rather causally flux requiring G tube feeding.
    [Show full text]
  • Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations Fall 2010 Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress Renuka Nayak University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Computational Biology Commons, and the Genomics Commons Recommended Citation Nayak, Renuka, "Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress" (2010). Publicly Accessible Penn Dissertations. 1559. https://repository.upenn.edu/edissertations/1559 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1559 For more information, please contact [email protected]. Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress Abstract Genes interact in networks to orchestrate cellular processes. Here, we used coexpression networks based on natural variation in gene expression to study the functions and interactions of human genes. We asked how these networks change in response to stress. First, we studied human coexpression networks at baseline. We constructed networks by identifying correlations in expression levels of 8.9 million gene pairs in immortalized B cells from 295 individuals comprising three independent samples. The resulting networks allowed us to infer interactions between biological processes. We used the network to predict the functions of poorly-characterized human genes, and provided some experimental support. Examining genes implicated in disease, we found that IFIH1, a diabetes susceptibility gene, interacts with YES1, which affects glucose transport. Genes predisposing to the same diseases are clustered non-randomly in the network, suggesting that the network may be used to identify candidate genes that influence disease susceptibility.
    [Show full text]
  • Genetic Variation at the 22Q11 PRODH2 DGCR6 Locus Presents an Unusual Pattern and Increases Susceptibility to Schizophrenia
    Genetic variation at the 22q11 PRODH2͞DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia Hui Liu†, Simon C. Heath‡, Christina Sobin†, J. Louw Roos§, Brandi L. Galke†, Maude L. Blundell†, Marge Lenane¶, Brian Robertsonʈ, Ellen M. Wijsman**, Judith L. Rapoport¶, Joseph A. Gogos††, and Maria Karayiorgou†‡‡ †Human Neurogenetics Laboratory, The Rockefeller University, New York, NY 10021; ‡Memorial Sloan Kettering Cancer Center, New York, NY 10021; §Department of Psychiatry and Weskoppies Hospital, University of Pretoria, Pretoria 0083, Republic of South Africa; ¶Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892; ʈDepartment of Psychiatry and Valkenberg Hospital, University of Capetown, Capetown 7925, Republic of South Africa; **Division of Medical Genetics and Department of Biostatistics, University of Washington, Seattle, WA 98195; and ††College of Physicians and Surgeons, Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032 Communicated by David E. Housman, Massachusetts Institute of Technology, Cambridge, MA, December 26, 2001 (received for review September 25, 2001) The location of a schizophrenia susceptibility locus at chromosome region harbors genes that alone, or in combination, are causally 22q11 has been suggested by genome-wide linkage studies. Addi- implicated in schizophrenia in a certain proportion of patients. The tional support was provided by the observation of a higher-than- overwhelming majority of the 22q11 deletions are 3 Mb in size, expected frequency of 22q11 microdeletions in patients with schizo- whereas a smaller percentage (Ϸ8%) involve the same proximal Ϸ phrenia and the demonstration that 20–30% of individuals with breakpoint but a different distal breakpoint resulting in a smaller 22q11 microdeletions develop schizophrenia or schizoaffective dis- 1.5-Mb deletion (9, 10).
    [Show full text]