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PDF Hosted at the Radboud Repository of the Radboud University Nijmegen PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/191858 Please be advised that this information was generated on 2019-01-10 and may be subject to change. CHARACTERIZATIONOFTRANSCRIPTIONFACTORS INMONOGENICDISORDERSOFSPEECHANDLANGUAGE sara busquets estruch © 2018, Sara Busquets Estruch ISBN: 978-90-76203-92-8 Printed and bound by Ipskamp Drukkers Characterization of transcription factors in monogenic disorders of speech and language Proefschriftter ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. dr. J.H.J.M. van Krieken, volgens besluit van het college van decanen in het openbaar te verdedigen op maandag 11 juni 2018 om 14.30 uur precies door Sara Busquets Estruch geboren op 16 maart 1988 te Barcelona (Spanje) Promotor Prof. dr. Simon E. Fisher Copromotor Dr. Sarah A. Graham (Birmingham Women’s and Children’s NHS Foundation Trust, Verenigd Koninkrijk) Manuscriptcommissie Prof. dr. Han G. Brunner Prof. dr. Gudrun Rappold (UniversitätHeidelberg, Duitsland) Prof. dr. Paul Coffer (UMC Utrecht) Characterization of transcription factors in monogenic disorders of speech and language Doctoral Thesis to obtain the degree of doctor from Radboud University Nijmegen on the authority of the Rector Magnificus prof. dr. J.H.J.M. van Krieken, according to the decision of the Council of Deans to be defended in public on Monday, June 11, 2018 at 14.30 hours by Sara Busquets Estruch Born on March 16, 1988 in Barcelona (Spain) Supervisor Prof. dr. Simon E. Fisher Copromotor Dr. Sarah A. Graham (Birmingham Women’s and Children’s NHS Foundation Trust, United Kingdom) Manuscriptcommissie Prof. dr. Han G. Brunner Prof. dr. Gudrun Rappold (University of Heidelberg, Germany) Prof. dr. Paul Coffer (UMC Utrecht) Aprendre Caminar. Caminar més de pressa. Buscar. Palpar. Trobar. Fugir. Perdre’s. Tornar a caminar, però més a poc a poc. by Pep Mita To Learn To walk. To walk faster. To search. To palpate. To find. To run away. To get lost. To walk again, but slower. by Pep Mita CONTENTS 1 introduction 11 1.1 Characterizing the genetic basis of human language . 11 1.2 Monogenic language-related disorders as a window into the molec- ular networks underlying speech and language . 17 1.3 Aims and scope of the thesis . 46 2 the language-related transcription factor foxp2 is post- translationally modified with small ubiquitin-like modi- fiers 49 2.1 Introduction . 50 2.2 Material and Methods . 52 2.3 Results . 56 2.4 Discussion . 77 2.5 Supplementary Material . 81 3 assessment of foxp2-candidate protein interactions iden- tified in previous mass spectrometry screens 85 3.1 Introduction . 86 3.2 Material and Methods . 88 3.3 Results . 91 3.4 Discussion . 100 3.5 Supplementary Material . 104 4 proteomic analysis of foxp proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders 109 4.1 Introduction . 110 4.2 Materials and Methods . 112 4.3 Results . 116 4.4 Discussion . 130 4.5 Supplementary Material . 135 5 functional characterization of bcl11a mutations in neu- rodevelopmental disorders 143 9 10 contents 5.1 Introduction . 145 5.2 Material and Methods . 150 5.3 Results . 152 5.4 Discussion . 166 6 general discussion 171 6.1 Summary . 171 6.2 Fine-tuning FOXP2 with post-translational modifications . 174 6.3 Novel functional regions in FOXP proteins . 178 6.4 A transcription factor network underlying cortical development 180 6.5 The expanding FOXP interactome . 186 6.6 The value of functional characterization studies in language-related disorders . 189 6.7 The big picture of functional genomics in language-related dis- orders. 192 bibliography 197 Appendix I: Functional characterization of rare FOXP2 variants in neurodevelopmental disorder 241 Nederlandse samenvatting 261 Summary 265 acknowledgements 269 biography 273 publications 275 mpi series in psycholinguistics 277 1 1 INTRODUCTION 1.1 characterizing the genetic basis of human language 1.1.1 Human language and language disorders Language is arguably the trait that most clearly distinguishes humans from other species. While other species do communicate and some of them do so using vocalizations, their communication systems are far simpler than human language (Levinson & Holler, 2014). Human language goes beyond transmit- ting simple and practical information about essential aspects of our lives, such as food or imminent danger, it also enables us to share our thoughts, express our feelings, and talk about even the most abstract matters we can imagine. Language allows us to exchange an unlimited number of ideas using a finite set of mental tools, thus it is not surprising that the mental processes underlying this trait are complex (Graham et al. , 2015). Yet, language comes naturally to us, and it is remarkable that, given the adequate environment, any normal child becomes a proficient speaker in their native language without consciously mak- ing any effort or needing formal tuition (Kuhl, 2004). Language is not only a uniquely human trait, but it also appears to be universal to all human beings (Fisher & Vernes, 2015). No human society that lacks complex language has yet been discovered (Hammarström, 2016). Moreover, language has been crucial to human cultural evolution, as it has enabled humans to cooperate and to share knowledge that has been transmitted over many generations (Smith & Kirby, 2008). Our linguistic environment clearly plays a role in developing and shaping our language capacity, but there is also an innate component to these capabili- ties, as evident from heritability studies in twins (Bishop et al. , 1995; Lewis & Thompson, 1992). The first clues about the molecular basis of language came from looking at the genetic make-up of individuals with speech and language impairments. Individuals with speech and/or language impairment do not de- velop adequate skills in this area even if they are raised in a language-rich en- 11 12 introduction vironment and receive appropriate input. Often in individuals with a general- 1 ized neurodevelopmental disorder, language is impaired as a secondary conse- quence of other cognitive deficits, but in some other cases the only cognitive aspect affected in that person is language itself, and those cases are defined as a specific language disorder (Graham & Fisher, 2015). There are several different kinds of developmental disorders that affect speech, language and/or reading (Table 1.1), all of which usually manifest in early childhood and continue into adulthood, affecting many aspects of life, such as educational achievement or social and job opportunities. Because language deficits are often a core feature of neuropsychiatric disorders such as autism-spectrum disorder (ASD) or in- tellectual disability (ID) (Bishop, 2010; Pal, 2011), these neurodevelopmental disorders are also useful conditions to investigate in order to disentangle the genetic basis of speech and language. 1.1.2 The discovery of FOXP2-related language disorder The fact that language-related disorders typically cluster in families provided early indirect evidence that genetic factors may contribute to language (Neils & Aram, 1986; Tomblin, 1989; Barry et al. , 2007; Lewis et al. , 2007). Moreover, twin studies showed that monozygotic twins presented higher rates of concor- dance for language traits and disorders than dizygotic twins (Lewis & Thomp- son, 1992; Bishop et al. , 1995; Bishop & Hayiou-Thomas, 2008), highlighting the genetic contribution to linguistic abilities. Towards the end of the 1990s, with the rise of molecular genetic techniques, specific regions in the genome were identified to be involved in the etiology of language impairment by linkage studies (Fisher et al. , 2003), and followed up by targeted association studies of the specific linked regions and mutation screens of candidate genes (Newbury & Monaco, 2002). A major breakthrough occurred in 2001, when geneticists identified the tran- scription factor FOXP2 as the first gene implicated in a language disorder, thr- ough investigation of a large multigenerational family (the KE family) with se- vere communication problems (Lai et al. , 2001). Half of the members in the KE family suffer from a rare form of speech and language impairment char- acterized by difficulties in coordinating the orofacial movements required for speech (childhood apraxia of speech, CAS; also known as developmental ver- bal dyspraxia DVD). In addition to core deficits in orofacial motor control and characterizing the genetic basis of human language 13 Table 1.1: Disorders of speech, language and/or reading mentioned in this thesis 1 Disorder Definition Childhood apraxia of Deficits in planning and coordination of speech and sound speech (CAS) sequences necessary for fluid speech. Also known as devel- opmental verbal dyspraxia (DVD) Dysarthria Speech that may be abnormally slow, fast, weak or impre- cise caused by affections to muscles and nerves that control speech Dyslexia A difficulty with reading and spelling that cannot be ex- plained by other causes such as low IQ, physical impairment or lack of opportunity to learn Specific language im- Unexplained impairment in acquisition of spoken language, pairment (SLI) affecting one or more of morphology, syntax, semantics and pragmatics. Also known as developmental language disor- der (DLD) Expressive language Type of SLI. Impaired ability to formulate
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