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Chromosomal Abnormalities and Putative Susceptibility Genes in Autism Spectrum Disorders

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Chromosomal Abnormalities and Putative Susceptibility Genes in Autism Spectrum Disorders Chromosomal Abnormalities and Putative Susceptibility Genes in Autism Spectrum Disorders Nielsen, Mette Gilling Publication date: 2007 Document version Publisher's PDF, also known as Version of record Citation for published version (APA): Nielsen, M. G. (2007). Chromosomal Abnormalities and Putative Susceptibility Genes in Autism Spectrum Disorders. Museum Tusculanum. Download date: 26. Sep. 2021 Acknowledgments................................................................................................................ 2 List of included papers.........................................................................................................3 List of abbreviations............................................................................................................. 4 English summary ............................................................................................................... 10 Dansk resumé....................................................................................................................11 1 Introduction ............................................................................................................. 12 1.1 Classification of Autism Spectrum Disorders (ASDs) ................................... 12 1.1.1 Childhood autism ....................................................................................... 13 1.1.2 Atypical autism........................................................................................... 14 1.1.3 Asperger’s syndrome................................................................................. 14 1.2 Genetics ......................................................................................................... 14 1.2.1 Family and Twin studies ............................................................................ 14 1.2.2 Comorbid disorders ................................................................................... 15 1.2.3 Possible genetic inheritance models......................................................... 16 1.2.3.1 Single gene (major locus) model....................................................... 16 1.2.3.2 Poly- or multigenic inheritance models ............................................. 17 1.2.3.3 Interplay between genetic and environmental factors ...................... 17 1.2.3.4 X-linkage ............................................................................................ 18 1.3 Biological changes identified in ASDs........................................................... 19 1.4 Strategies to identify susceptibility genes for ASDs...................................... 20 1.4.1 Linkage analyses ....................................................................................... 20 1.4.2 Mapping of chromosomal rearrangements ............................................... 21 1.4.3 ASDs associated with disorders with known genetic origin...................... 22 1.4.4 Candidate gene approach ......................................................................... 25 1.5 Proposed susceptibility genes for ASDs and their functions ........................ 25 2 Objectives of present study .................................................................................... 28 3 Paper I..................................................................................................................... 30 4 Paper II.................................................................................................................... 48 5 Paper III................................................................................................................... 55 6 Paper IV .................................................................................................................. 66 7 Paper V ................................................................................................................... 83 8 Discussion............................................................................................................... 95 9 Conclusions and perspectives.............................................................................. 100 10 Appendix A ........................................................................................................ 102 11 Appendix B ........................................................................................................ 103 12 Reference List ................................................................................................... 104 1 ACKNOWLEDGMENTS The work forming the basis of this PhD thesis was carried out at the Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Genetics, Institute of Molecular and Cellular Medicine, University of Copenhagen, Denmark. I was employed as an integrated PhD student (Master’s project and PhD project as one project) from March 2002 to September 2005 but the project was prolonged to January 2007 due to the birth of my son, Noah. I would like to thank University of Copenhagen and Professor, Niels Tommerup for providing funding for this work. First of all, I would like to thank Professor, dr.med Niels Tommerup and Associate Professor, PhD Zeynep Tümer for their excellent supervision and continuous support and inspiration. I would also like to thank the patients and their families for participating in the studies, medical doctors Marlene Briciet Lauritsen, Iben Bache, Merete Bugge, Erik Niebuhr, Ulf Kristoffersson, Karen Brøndum-Nielsen, James Lespinasse, Guiomar Oliveira, Christina Cintin de Aguiar as well as Astrid Vicente, Hans Eiberg and Paal Skytt Andersen for collecting patient and control DNA and for providing me with invaluable clinical information about the patients. Moreover, I want to thank the technicians for help and advice during the project and Marlene Briciet Lauritsen for expert guidance in clinical assessment of ASD patients and for reading and commenting the introduction of this report. In addition, I am grateful for all the help, fruitful discussions and for the friendly atmosphere provided by my colleagues at the Wilhelm Johannsen Centre. In this regard I especially want to thank Iben Bache and Elisabete Engenheiro for cozy lunch appointments and Elin Erichsen and Lene Løgstrup for caring for everybody. Last, but not least, I want to thank my family and friends for care and encouragement throughout the project, in particular my husband, Tommy, for being the solid support in my life and our son, Noah, for bringing invaluable joy and love into my life. 2 LIST OF INCLUDED PAPERS I. Gilling M, Briciet Lauritsen M, Møller M, Henriksen KF, Vicente A, Oliveira G, de Aguiar CC, Eiberg H, Andersen PS, Mors O, Brøndum-Nielsen K, Cotterill R, Lundsteen C, Ropers H-H, Ullmann R, Bache I, Tümer Z, Tommerup N. Identification of several putative susceptibility genes for childhood autism. In preparation. II. Gilling M, Ullmann R, Boonen SE, Brøndum-Nielsen K, Kalscheuer V, Tommerup N, Tümer Z. KCNQ3 is disrupted in a male patient with childhood autism. In preparation. III. Gilling M, Bache I, Niebuhr E, Ullmann R, Tümer Z, Tommerup N. FGF2 antisense gene disrupted in a male with autism spectrum disorder. In preparation. IV. Gilling M, Ullmann R, Kristoffersson U, Møller M, Henriksen KF, Bugge M, Kalscheuer VM, Lundsteen C, Tümer Z, Tommerup N. Indication of abnormal synapse formation in male twins with autism spectrum disorder. In preparation. V. Gilling M, Dullinger JS, Gesk S, Metzke-Heidemann S, Siebert R, Meyer T, Brondum-Nielsen K, Tommerup N, Ropers H-H, Tumer Z, Kalscheuer VM, Thomas NS. Breakpoint cloning and haplotype analysis indicate a single origin of the common Inv(10)(p11.2q21.2) mutation among northern Europeans. Am J Hum Genet 2006 May;78(5):878-83. 3 LIST OF ABBREVIATIONS ADAM23 A disintegrin and metalloproteinase domain 23 protein ADHD Attention deficit and hyperactivity disorder ADI-R Autism diagnostic interview-revised ADOS Autism diagnostic observation schedule ARX Aristaless related homeobox ASDs Autism spectrum disorders ATOH1 Homolog of atonal 1 AUTS2 Susceptibility to autism 2 AVPR1A Arginine vasopressin receptor 1A BAC Bacterial artificial chromosome BCL2 B-cell CLL/lymphoma 2 BFNC Benign familial neonatal convulsions BRUNOL4 Bruno-like 4 RNA binding protein BAALC Brain and acute leukaemia gene c18orf10 Chromosome 18 open reading frame 10 c18orf37 Chromosome 18 open reading frame 37 CDH9 Cadherin 9 cDNA Complementary DNA CGH Comparative genome hybridization CHRNA1 Cholinergic receptor, nicotinic, alpha 1 CJ070 Zinc finger CDGSH-type domain 1 CNV Copy number variations CREB1 cAMP responsive element binding protein 1 CYLN2 Cytoplasmic linker 2 dATP 2’-deoxyadenosine 5’-triphosphate DCAMKL1 Doublecortin and CaM kinase-like 1 DEPC Diethylpyrocarbonate DHCR7 7-dehydrocholesterol reductase DHPLC Denaturing high performance liquid chromatography DLG1 Homolog of disc large 1 DLG3 Homolog of disc large 3 DSCAM Down syndrome cell adhesion molecule isoform 4 DSM-IV Diagnostic and Statistical Manual of Mental Disorders, fourth revision DTNA Dystrobrevin alpha DZ Dizygotic ELAV Embryonic lethal abnormal visual system EN2 Engrailed homolog 2 ERBB4 V-erb-a erythroblastic leukaemia viral oncogene ERK Extracellular signal regulated kinase EST Expressed sequence tag FAT Human homolog of the Drosophila fat tumour suppressor gene FGF12 Fibroblast growth factor 12 FGF2 Fibroblast growth factor 2 FGF2AS FGF2 antisense FGF5 Fibroblast growth factor 5 FGFR Fibroblast Growth Factor receptors FHOD3 Formin homology domain 3 FISH Fluorescence In
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