DOCSLIB.ORG

Discovering Novel Hearing Loss Genes: Roles for Esrp1 and Gas2 in Inner Ear Development and Auditory Function

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Discovering Novel Hearing Loss Genes: Roles for Esrp1 and Gas2 in Inner Ear Development and Auditory Function University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2018 Discovering Novel Hearing Loss Genes: Roles For Esrp1 And Gas2 In Inner Ear Development And Auditory Function Alex Martin Rohacek University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Cell Biology Commons, Developmental Biology Commons, and the Molecular Biology Commons Recommended Citation Rohacek, Alex Martin, "Discovering Novel Hearing Loss Genes: Roles For Esrp1 And Gas2 In Inner Ear Development And Auditory Function" (2018). Publicly Accessible Penn Dissertations. 2843. https://repository.upenn.edu/edissertations/2843 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2843 For more information, please contact [email protected]. Discovering Novel Hearing Loss Genes: Roles For Esrp1 And Gas2 In Inner Ear Development And Auditory Function Abstract Hearing loss is the most common form of congenital birth defect, affecting an estimated 35 million children worldwide. To date, nearly 100 genes have been identified which contribute to a deafness phenotype in humans, however, many cases remain in which a causative mutation has yet to be found. In addition, the exact mechanism by which hearing loss occurs in the presence of many of these mutations is still not understood. This is due, in part, to the complex nature of the development and function of the cochlear duct, the organ of hearing. The cochlea undergoes an intricate morphogenetic development and requires the proper specification and maintenance of dozens of different cell types in order to function correctly. In the mature duct, an interplay between mechanotransducing sensory hair cells, supporting pillar and Dieters' cells, and generation of electrochemical potential by the stria vascularis are necessary to respond to sound stimuli. We utilized exome and RNA-sequencing experiments combined with mouse genetics in order to discover novel genes that play roles in cochlear development and function. Exome sequencing of families with profound hearing loss uncovered mutations in Epithelial Splicing Regulatory Protein 1 (ESRP1), a critical regulator of alternative mRNA splicing. Analysis of Esrp1 mutant mice revealed a shortened cochlear duct, delay in hair cell differentiation and maturation, and loss of the stria vascularis due to inappropriate Fgf ligand usage, stemming from an alternatively spliced receptor, in these cells. To identify additional regulators of inner ear development we performed an RNA-seq experiment comparing the gene expression profiles of control and Smoecko otic vesicles, which lack a cochlear duct. This generated a dataset of hundreds of cochlear enriched transcripts including Growth Arrest Specific 2 (Gas2) a cytoskeletal binding protein with the potential to act as a regulator of cochlear development. We generated a Gas2 null mouse line and discovered that these animals have severe hearing impairment likely due to defects in microtubule organization in the pillar cells. Taken together, these studies implicate Esrp1 and Gas2 as novel hearing loss genes that regulate aspects of cochlear development and function. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Douglas J. Epstein Keywords Alternative Splicing, Cytoskeleton, FGF Signaling, Hearing loss, Inner Ear Subject Categories Cell Biology | Developmental Biology | Molecular Biology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2843 DISCOVERING NOVEL HEARING LOSS GENES: ROLES FOR ESRP1 AND GAS2 IN INNER EAR DEVELOPMENT AND AUDITORY FUNCTION Alex M. Rohacek A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2018 Supervisor of Dissertation __________________________________ Douglas J. Epstein, Ph.D., Professor of Genetics Graduate Group Chairperson __________________________________ Daniel S. Kessler, Ph.D., Associate Professor of Cell and Developmental Biology Dissertation Committee Stewart A Anderson, M.D., Professor of Psychiatry Russ P. Carstens, M.D., Associate Professor of Medicine Christopher J. Lengner, Ph.D., Associate Professor of Cell and Developmental Biology Stephen A. Liebhaber, M.D., Professor of Genetics DISCOVERING NOVEL HEARING LOSS GENES: ROLES FOR ESRP1 AND GAS2 IN INNER EAR DEVELOPMENT AND AUDITORY FUNCTION COPYRIGHT 2018 Alex Martin Rohacek This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-sa/3.0/us/ Dedication page This work is dedicated to my family: my Mother, who is my most vocal supporter and my greatest source of advice; my Father, who always pushes me to do the things I think are impossible; my Sister, who is always my friend and ally; and our pets (both here and who have gone), who were always there to bring me a smile. I couldn’t have done it without all of you. iii ACKNOWLEDGMENT This work would not have been possible without the help from many people who I’d like to take the time to thank. My advisor, Doug Epstein, for seeing me through my graduate work with the equal measures of pressure and guidance that I needed. My undergraduate advisors Bryant Buchannan and Sharon Wise who encouraged me to apply to graduate school and gave me my start in science. My lab mates who provided me with advice and friendship over the years. And, all of my collaborators who helped my along the way with experiments and contributed to this body of work. iv ABSTRACT DISCOVERING NOVEL HEARING LOSS GENES: ROLES FOR ESRP1 AND GAS2 IN INNER EAR DEVELOPMENT AND AUDITORY FUNCTION Alex M Rohacek Douglas J Epstein Hearing loss is the most common form of congenital birth defect, affecting an estimated 35 million children worldwide. To date, nearly 100 genes have been identified which contribute to a deafness phenotype in humans, however, many cases remain in which a causative mutation has yet to be found. In addition, the exact mechanism by which hearing loss occurs in the presence of many of these mutations is still not understood. This is due, in part, to the complex nature of the development and function of the cochlear duct, the organ of hearing. The cochlea undergoes an intricate morphogenetic development and requires the proper specification and maintenance of dozens of different cell types in order to function correctly. In the mature duct, an interplay between mechanotransducing sensory hair cells, supporting pillar and Dieters’ cells, and generation of electrochemical potential by the stria vascularis are necessary to respond to sound stimuli. We utilized exome and RNA-sequencing experiments combined with mouse genetics in order to discover novel genes that play roles in cochlear development and function. Exome sequencing of families with profound hearing loss uncovered mutations in Epithelial Splicing Regulatory Protein 1 (ESRP1), a critical regulator of alternative mRNA splicing. Analysis of Esrp1 mutant mice revealed a shortened cochlear duct, delay in hair cell differentiation and maturation, and loss of the stria vascularis due to inappropriate Fgf ligand usage, stemming from an alternatively spliced receptor, in these cells. To identify additional regulators of inner ear development we performed an v RNA-seq experiment comparing the gene expression profiles of control and Smoecko otic vesicles, which lack a cochlear duct. This generated a dataset of hundreds of cochlear enriched transcripts including Growth Arrest Specific 2 (Gas2) a cytoskeletal binding protein with the potential to act as a regulator of cochlear development. We generated a Gas2 null mouse line and discovered that these animals have severe hearing impairment likely due to defects in microtubule organization in the pillar cells. Taken together, these studies implicate Esrp1 and Gas2 as novel hearing loss genes that regulate aspects of cochlear development and function. vi TABLE OF CONTENTS ACKNOWLEDGMENT ................................................................................................................... IV ABSTRACT ..................................................................................................................................... V LIST OF TABLES ............................................................................................................................ X LIST OF ILLUSTRATIONS............................................................................................................. XI CHAPTER 1: INTRODUCTION ....................................................................................................... 1 The inner ear ........................................................................................................................... 1 Induction and patterning of the inner ear ............................................................................ 1 Morphogenesis of the vestibular apparatus and cochlear duct ....................................... 4 The structures of hearing ...................................................................................................... 7 Development of cochlear sensory structures ................................................................... 10 Development of the cochlear lateral wall..........................................................................
Load more

Recommended publications
  • Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice
    Loyola University Chicago Loyola eCommons Biology: Faculty Publications and Other Works Faculty Publications 2013 Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice Mihaela Palicev Gunter P. Wagner James P. Noonan Benedikt Hallgrimsson James M. Cheverud Loyola University Chicago, [email protected] Follow this and additional works at: https://ecommons.luc.edu/biology_facpubs Part of the Biology Commons Recommended Citation Palicev, M, GP Wagner, JP Noonan, B Hallgrimsson, and JM Cheverud. "Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice." Genome Biology and Evolution 5(10), 2013. This Article is brought to you for free and open access by the Faculty Publications at Loyola eCommons. It has been accepted for inclusion in Biology: Faculty Publications and Other Works by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. © Palicev et al., 2013. GBE Genomic Correlates of Relationship QTL Involved in Fore- versus Hind Limb Divergence in Mice Mihaela Pavlicev1,2,*, Gu¨ nter P. Wagner3, James P. Noonan4, Benedikt Hallgrı´msson5,and James M. Cheverud6 1Konrad Lorenz Institute for Evolution and Cognition Research, Altenberg, Austria 2Department of Pediatrics, Cincinnati Children‘s Hospital Medical Center, Cincinnati, Ohio 3Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University 4Department of Genetics, Yale University School of Medicine 5Department of Cell Biology and Anatomy, The McCaig Institute for Bone and Joint Health and the Alberta Children’s Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Canada 6Department of Anatomy and Neurobiology, Washington University *Corresponding author: E-mail: [email protected].
    [Show full text]
  • Caspases and Mitochondria in C-Myc-Induced Apoptosis: Identi®Cation of ATM As a New Target of Caspases
    Oncogene (2000) 19, 2354 ± 2362 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Caspases and mitochondria in c-Myc-induced apoptosis: identi®cation of ATM as a new target of caspases Anneli Hotti1,2, Kristiina JaÈ rvinen1,2, Pirjo Siivola1 and Erkki HoÈ lttaÈ *,1 1Haartman Institute, Department of Pathology, University of Helsinki, P.O. Box 21 (Haartmaninkatu 3), FIN- 00014, Finland The mechanism(s) of c-Myc transcription factor-induced transcription of the target genes (Galaktionov et al., apoptosis is still obscure. The activation of c-Myc has 1996; Packham and Cleveland, 1994; Shim et al., 1997). been found to lead into the processing/activation of On the other hand, c-Myc has been reported to induce caspases (caspase-3), but the signi®cance of this for the apoptosis without transcriptional activation (Evan et al., cell demise is debatable. Here we report that several 1992; Xiao et al., 1998). Also, it is not clear whether the targets of caspases (PKCd, MDM2, PARP, replication tumour suppressor p53, a transcriptional target for c- factor C, 70 kDa U1snRNP, fodrin and lamins) are Myc, is needed for apoptosis induced by c-Myc (Lotem cleaved during c-Myc-induced apoptosis in Rat-1 and Sachs, 1995; Shim et al., 1998; Wagner et al., 1994; MycERTM cells, indicating an important role for caspases Zindy et al., 1998; reviewed in Prendergast, 1999; in the apoptotic process. We further found that the ATM Thompson, 1998). Recently, c-Myc-induced apoptosis (ataxia telangiectasia mutated) ± protein is a novel key has been shown either indirectly (Kagaya et al., 1997; substrate of caspases.
    [Show full text]
  • Gas2 Is a Multifunctional Gene Involved in the Regulation of Apoptosis and Chondrogenesis in the Developing Mouse Limb
    Developmental Biology 207, 14–25 (1999) Article ID dbio.1998.9086, available online at http://www.idealibrary.com on View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector gas2 Is a Multifunctional Gene Involved in the Regulation of Apoptosis and Chondrogenesis in the Developing Mouse Limb K. K. H. Lee,*,1,2 M. K. Tang,* D. T. W. Yew,* P. H. Chow,* S. P. Yee,† C. Schneider,‡,§ and C. Brancolini‡,§,1 *Department of Anatomy, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong, People’s Republic of China; †Cancer Research Laboratories, London Regional Cancer Centre, 790 Commissioners Road East, London, Ontario, Canada; ‡Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie Area, Science Park Padriciano 99, Trieste, Italy; and §Dipartimento Scienze e Tecnologie Biomediche Facolta’ di Medicina, University of Udine, p. Kolbe 4, Udine, Italy The growth-arrest-specific 2 (gas2) gene was initially identified on account of its high level of expression in murine fibroblasts under growth arrest conditions, followed by downregulation upon reentry into the cell cycle (Schneider et al., Cell 54, 787–793, 1988). In this study, the expression patterns of the gas2 gene and the Gas2 peptide were established in the developing limbs of 11.5- to 14.5-day mouse embryos. It was found that gas2 was expressed in the interdigital tissues, the chondrogenic regions, and the myogenic regions. Low-density limb culture and Brdu incorporation assays revealed that gas2 might play an important role in regulating chondrocyte proliferation and differentiation. Moreover, it might play a similar role during limb myogenesis.
    [Show full text]
  • ANALYSIS Doi:10.1038/Nature14663
    ANALYSIS doi:10.1038/nature14663 Universal allosteric mechanism for Ga activation by GPCRs Tilman Flock1, Charles N. J. Ravarani1*, Dawei Sun2,3*, A. J. Venkatakrishnan1{, Melis Kayikci1, Christopher G. Tate1, Dmitry B. Veprintsev2,3 & M. Madan Babu1 G protein-coupled receptors (GPCRs) allosterically activate heterotrimeric G proteins and trigger GDP release. Given that there are 800 human GPCRs and 16 different Ga genes, this raises the question of whether a universal allosteric mechanism governs Ga activation. Here we show that different GPCRs interact with and activate Ga proteins through a highly conserved mechanism. Comparison of Ga with the small G protein Ras reveals how the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity. This might explain how the GPCR–Ga system diversified rapidly, while conserving the allosteric activation mechanism. proteins bind guanine nucleotides and act as molecular switches almost 30 A˚ away from the GDP binding region5 and allosterically trig- in a number of signalling pathways by interconverting between ger GDP release to activate them. 1,2 G a GDP-bound inactive and a GTP-bound active state . They The high-resolution structure of the Gas-bound b2-adrenergic recep- 3 5 consist of two major classes: monomeric small G proteins and hetero- tor (b2AR) provided crucial insights into the receptor–G protein inter- trimeric G proteins4. While small G proteins and the a-subunit (Ga)of face and conformational changes in Ga upon receptor binding6,7. Recent 6 8 heterotrimeric G proteins both contain a GTPase domain (G-domain), studies described dynamic regions in Gas and Gai , the importance of ˚ Ga contains an additional helical domain (H-domain) and also forms a displacement of helix 5 (H5) of Gas and Gat by up to 6 A into the complex with the Gb and Gc subunits.
    [Show full text]
  • Protein Products of Human Gas2-Related Genes on Chromosomes 17 and 22 (Hgar17 and Hgar22) Associate with Both Microfilaments and Microtubules
    Research Article 1045 Protein products of human Gas2-related genes on chromosomes 17 and 22 (hGAR17 and hGAR22) associate with both microfilaments and microtubules Dmitri Goriounov1, Conrad L. Leung2 and Ronald K. H. Liem2,3,* 1Integrated Program in Cellular, Molecular, and Biophysical Studies, 2Department of Pathology, 3Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA *Author for correspondence (e-mail: [email protected]) Accepted 14 November 2002 Journal of Cell Science 116, 1045-1058 © 2003 The Company of Biologists Ltd doi:10.1242/jcs.00272 Summary The human Gas2-related gene on chromosome 22 remarkably similar. hGAR17 mRNA expression is limited (hGAR22) encodes two alternatively spliced mRNA species. to skeletal muscle. Although hGAR22 and mGAR22 The longer mRNA encodes a protein with a deduced mRNAs are expressed nearly ubiquitously, mGAR22 molecular mass of 36.3 kDa (GAR22α), whereas the protein can only be detected in testis and brain. shorter mRNA encodes a larger protein with a deduced Furthermore, only the β isoform is present in these tissues. molecular mass of 72.6 kDa (GAR22β). We show that both GAR22β expression is induced in a variety of cultured cells hGAR22 proteins contain a calponin homology actin- by growth arrest. The absolute amounts of GAR22β binding domain and a Gas2-related microtubule-binding protein expressed are low. The β isoforms of hGAR17 and domain. Using rapid amplification of cDNA ends, we have hGAR22 appear to be able to crosslink microtubules and cloned the mouse orthologue of hGAR22, mGAR22, and microfilaments in transfected cells.
    [Show full text]
  • Sequence-Based Protein Stabilization in the Absence of Glycosylation
    ARTICLE Received 14 Aug 2013 | Accepted 12 Dec 2013 | Published 17 Jan 2014 DOI: 10.1038/ncomms4099 Sequence-based protein stabilization in the absence of glycosylation Nikki Y. Tan1, Ulla-Maja Bailey1, M Fairuz Jamaluddin1, S Halimah Binte Mahmud1, Suresh C. Raman1 & Benjamin L. Schulz1 Asparagine-linked N-glycosylation is a common modification of proteins that promotes productive protein folding and increases protein stability. Although N-glycosylation is important for glycoprotein folding, the precise sites of glycosylation are often not conserved between protein homologues. Here we show that, in Saccharomyces cerevisiae, proteins upregulated during sporulation under nutrient deprivation have few N-glycosylation sequons and in their place tend to contain clusters of like-charged amino-acid residues. Incorporation of such sequences complements loss of in vivo protein function in the absence of glyco- sylation. Targeted point mutation to create such sequence stretches at glycosylation sequons in model glycoproteins increases in vitro protein stability and activity. A dependence on glycosylation for protein stability or activity can therefore be rescued with a small number of local point mutations, providing evolutionary flexibility in the precise location of N-glycans, allowing protein expression under nutrient-limiting conditions, and improving recombinant protein production. 1 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia. Correspondence and requests for materials should
    [Show full text]
  • Comparative Transcriptomics Reveals Similarities and Differences
    Seifert et al. BMC Cancer (2015) 15:952 DOI 10.1186/s12885-015-1939-9 RESEARCH ARTICLE Open Access Comparative transcriptomics reveals similarities and differences between astrocytoma grades Michael Seifert1,2,5*, Martin Garbe1, Betty Friedrich1,3, Michel Mittelbronn4 and Barbara Klink5,6,7 Abstract Background: Astrocytomas are the most common primary brain tumors distinguished into four histological grades. Molecular analyses of individual astrocytoma grades have revealed detailed insights into genetic, transcriptomic and epigenetic alterations. This provides an excellent basis to identify similarities and differences between astrocytoma grades. Methods: We utilized public omics data of all four astrocytoma grades focusing on pilocytic astrocytomas (PA I), diffuse astrocytomas (AS II), anaplastic astrocytomas (AS III) and glioblastomas (GBM IV) to identify similarities and differences using well-established bioinformatics and systems biology approaches. We further validated the expression and localization of Ang2 involved in angiogenesis using immunohistochemistry. Results: Our analyses show similarities and differences between astrocytoma grades at the level of individual genes, signaling pathways and regulatory networks. We identified many differentially expressed genes that were either exclusively observed in a specific astrocytoma grade or commonly affected in specific subsets of astrocytoma grades in comparison to normal brain. Further, the number of differentially expressed genes generally increased with the astrocytoma grade with one major exception. The cytokine receptor pathway showed nearly the same number of differentially expressed genes in PA I and GBM IV and was further characterized by a significant overlap of commonly altered genes and an exclusive enrichment of overexpressed cancer genes in GBM IV. Additional analyses revealed a strong exclusive overexpression of CX3CL1 (fractalkine) and its receptor CX3CR1 in PA I possibly contributing to the absence of invasive growth.
    [Show full text]
  • CREG1: Its Role As a Master Regulator of Liver Function Iffat Jahan Eastern Illinois University
    Eastern Illinois University The Keep Masters Theses Student Theses & Publications 2019 CREG1: Its Role as a Master Regulator of Liver Function Iffat Jahan Eastern Illinois University Recommended Citation Jahan, Iffat, "CREG1: Its Role as a Master Regulator of Liver Function" (2019). Masters Theses. 4477. https://thekeep.eiu.edu/theses/4477 This Dissertation/Thesis is brought to you for free and open access by the Student Theses & Publications at The Keep. It has been accepted for inclusion in Masters Theses by an authorized administrator of The Keep. For more information, please contact [email protected]. TheGraduate School� E>srf.RN111 1�11\USl\ 'F.R.S1n· Thesis Maintenance and Reproduction Certificate FOR: Graduate Candidates Completing Theses in Partial Fulfillment of the Degree Graduate Faculty Advisors Directing the Theses RE: Preservation, Reproduction, and Distribution of Thesis Research Preserving, reproducing, and distributing thesis research is an important part of Booth Library's responsibility to provide access to scholarship. In order to further this goal, Booth Library makes all graduate theses completed as part of a degree program at Eastern Illinois University available for personal study, research, and other not-for­ profit educational purposes. Under 17 U.S.C. § 108, the library may reproduce and distribute a copy without infringing on copyright; however, professional courtesy dictates that permission be requested from the author before doing so. Your signatures affirm the following: • The graduate candidate is the author of this thesis. •The graduate candidate retains the copyright and intellectual property rights associated with the original research, creative activity, and intellectual or artistic content of the thesis.
    [Show full text]
  • Gas2 CRISPR/Cas9 KO Plasmid (H): Sc-418122
    SANTA CRUZ BIOTECHNOLOGY, INC. Gas2 CRISPR/Cas9 KO Plasmid (h): sc-418122 BACKGROUND APPLICATIONS The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and Gas2 CRISPR/Cas9 KO Plasmid (h) is recommended for the disruption of CRISPR-associated protein (Cas9) system is an adaptive immune response gene expression in human cells. defense mechanism used by archea and bacteria for the degradation of foreign genetic material (4,6). This mechanism can be repurposed for other 20 nt non-coding RNA sequence: guides Cas9 functions, including genomic engineering for mammalian systems, such as to a specific target location in the genomic DNA gene knockout (KO) (1,2,3,5). CRISPR/Cas9 KO Plasmid products enable the U6 promoter: drives gRNA scaffold: helps Cas9 identification and cleavage of specific genes by utilizing guide RNA (gRNA) expression of gRNA bind to target DNA sequences derived from the Genome-scale CRISPR Knock-Out (GeCKO) v2 library developed in the Zhang Laboratory at the Broad Institute (3,5). Termination signal Green Fluorescent Protein: to visually REFERENCES verify transfection CRISPR/Cas9 Knockout Plasmid CBh (chicken β-Actin 1. Cong, L., et al. 2013. Multiplex genome engineering using CRISPR/Cas hybrid) promoter: drives systems. Science 339: 819-823. 2A peptide: expression of Cas9 allows production of both Cas9 and GFP from the 2. Mali, P., et al. 2013. RNA-guided human genome engineering via Cas9. same CBh promoter Science 339: 823-826. Nuclear localization signal 3. Ran, F.A., et al. 2013. Genome engineering using the CRISPR-Cas9 system. Nuclear localization signal SpCas9 ribonuclease Nat. Protoc. 8: 2281-2308.
    [Show full text]
  • Dissecting the Genetics of Human Communication
    DISSECTING THE GENETICS OF HUMAN COMMUNICATION: INSIGHTS INTO SPEECH, LANGUAGE, AND READING by HEATHER ASHLEY VOSS-HOYNES Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Epidemiology and Biostatistics CASE WESTERN RESERVE UNIVERSITY January 2017 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We herby approve the dissertation of Heather Ashely Voss-Hoynes Candidate for the degree of Doctor of Philosophy*. Committee Chair Sudha K. Iyengar Committee Member William Bush Committee Member Barbara Lewis Committee Member Catherine Stein Date of Defense July 13, 2016 *We also certify that written approval has been obtained for any proprietary material contained therein Table of Contents List of Tables 3 List of Figures 5 Acknowledgements 7 List of Abbreviations 9 Abstract 10 CHAPTER 1: Introduction and Specific Aims 12 CHAPTER 2: Review of speech sound disorders: epidemiology, quantitative components, and genetics 15 1. Basic Epidemiology 15 2. Endophenotypes of Speech Sound Disorders 17 3. Evidence for Genetic Basis Of Speech Sound Disorders 22 4. Genetic Studies of Speech Sound Disorders 23 5. Limitations of Previous Studies 32 CHAPTER 3: Methods 33 1. Phenotype Data 33 2. Tests For Quantitative Traits 36 4. Analytical Methods 42 CHAPTER 4: Aim I- Genome Wide Association Study 49 1. Introduction 49 2. Methods 49 3. Sample 50 5. Statistical Procedures 53 6. Results 53 8. Discussion 71 CHAPTER 5: Accounting for comorbid conditions 84 1. Introduction 84 2. Methods 86 3. Results 87 4. Discussion 105 CHAPTER 6: Hypothesis driven pathway analysis 111 1. Introduction 111 2. Methods 112 3. Results 116 4.
    [Show full text]
  • The Spectrin Superfamily
    Downloaded from http://cshperspectives.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Cytoskeletal Integrators: The Spectrin Superfamily Ronald K.H. Liem Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032 Correspondence: [email protected] SUMMARY This review discusses the spectrin superfamily of proteins that function to connect cytoskeletal elements to each other, the cell membrane, and the nucleus. The signature domain is the spectrin repeat, a 106–122-amino-acid segment comprising three a-helices. a-actinin is considered to be the ancestral protein and functions to cross-link actin filaments. It then evolved to generate spectrin and dystrophin that function to link the actin cytoskeleton to the cell membrane, as well as the spectraplakins and plakins that link cytoskeletal elements to each other and to junctional complexes. A final class comprises the nesprins, which are able to bind to the nuclear membrane. This review discusses the domain organization of the various spectrin family members, their roles in protein–protein interactions, and their roles in disease, as determined from mutations, and it also describes the functional roles of the family members as determined from null phenotypes. Outline 1 Introduction 5 Spectraplakins and plakins 2 a-actinin 6 Nesprins 3 Spectrins 7 Concluding remarks 4 Dystrophin and utrophin References Editors: Thomas D. Pollard and Robert D. Goldman Additional Perspectives on The Cytoskeleton available at www.cshperspectives.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a018259 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a018259 1 Downloaded from http://cshperspectives.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press R.K.H.
    [Show full text]
  • Growth Arrest-Specific Gene 2 Suppresses Hepatocarcinogenesis by Intervention of Cell Cycle and P53-Dependent Apoptosis
    World Journal of W J G Gastroenterology Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2019 August 28; 25(32): 4715-4726 DOI: 10.3748/wjg.v25.i32.4715 ISSN 1007-9327 (print) ISSN 2219-2840 (online) ORIGINAL ARTICLE Basic Study Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis Ran-Xu Zhu, Alfred Sze Lok Cheng, Henry Lik Yuen Chan, Dong-Ye Yang, Wai-Kay Seto ORCID number: Ran-Xu Zhu Ran-Xu Zhu, Dong-Ye Yang, Wai-Kay Seto, Department of Gastroenterology and Hepatology, (0000-0001-8366-925X); Alfred Sze The University of Hong Kong–Shenzhen Hospital, Shenzhen 518053, Guangdong Province, Lok Cheng (0000-0001-8692-3807); China Henry Lik Yuen Chan (0000-0003-3173-733); Dong-Ye Alfred Sze Lok Cheng, School of Biomedical Sciences, The Chinese University of Hong Kong, Yang (0000-0001-9724-6784); Wai- Hong Kong, China Kay Seto (0000-0003-2474-3055). Henry Lik Yuen Chan, Department of Medicine and Therapeutics, The Chinese University of Author contributions: Zhu RX and Hong Kong, Hong Kong, China Cheng ASL conceived and designed the study; All authors Corresponding author: Ran-Xu Zhu, MD, PhD, Doctor, Department of Gastroenterology and provided material support; Zhu RX Hepatology, The University of Hong Kong–Shenzhen Hospital, No. 1 Haiyuan Road, Futian performed the experiments and District, Shenzhen 518053, Guangdong Province, China. [email protected] collected the data; Zhu RX and Telephone: +86-755-86913333 Cheng ASL analyzed the data; Zhu RX wrote the manuscript; All Fax: +86-755-86913333 authors reviewed the manuscript; Zhu RX and Cheng ASL revised the manuscript; Zhu RX and Chan HLY provided financial support; Abstract Cheng ASL and Chan HLY BACKGROUND provided study supervision; All authors gave final approval of the Growth arrest-specific gene 2 (GAS2) plays a role in modulating in reversible version of the article to published.
    [Show full text]