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Dissection of the Genetic Background of Childhood Onset Progressive Myoclonic Epilepsies

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Dissection of the Genetic Background of Childhood Onset Progressive Myoclonic Epilepsies DISSECTION OF THE GENETIC BACKGROUND OF CHILDHOOD ONSET PROGRESSIVE MYOCLONIC EPILEPSIES Maria Kousi ACADEMIC DISSERTATION To be publicly discussed, with the permission of the Faculty of Medicine of the University of Helsinki in Biomedicum Helsinki Lecture Hall 1, on Friday January 13th, at 12 noon Neuroscience Center and Department of Medical Genetics, University of Helsinki, and Folkhälsan Institute of Genetics Helsinki, 2011 Supervised by Professor Anna-Elina Lehesjoki, M.D., Ph.D. Folkhälsan Institute of Genetics and Neuroscience Center University of Helsinki Helsinki, Finland Reviewed by Professor Mark Gardiner, MD, FRCPCH Department of Paediatrics and Child Health Royal Free and University College Medical School University College London London, UK Docent Marjo Kestilä, Ph.D. Department of Chronic Disease Prevention Public Health Genomics National Institute for Health and Welfare Helsinki, Finland Official opponent Professor James R. Lupski, M.D., Ph.D. Department of Molecular and Human Genetics Baylor College of Medicine Houston, TX, USA ISBN 978-952-10-7560-5 (Paperback) ISBN 978-952-10-7561-2 (PDF) http://ethesis.helsinki.fi Unigrafia Oy Helsinki 2011 “The genes: our heritability, are the paper and pen we are born with. The story we will write is up to us.” Leena Peltonen-Palotie To my parents 4 TABLE OF CONTENTS TABLE OF CONTENTS TABLE OF CONTENTS ...............................................................................................................4 LIST OF ORIGINAL PUBLICATIONS .....................................................................................7 ABBREVIATIONS.........................................................................................................................8 ABSTRACT ..................................................................................................................................11 1. INTRODUCTION ................................................................................................................13 2. REVIEW OF THE LITERATURE ....................................................................................15 2.1 FROM CHROMOSOME DISCOVERY TO THE WHOLE GENOME SEQUENCING ERA ...............15 2.2 THE HUMAN GENOME PROJECT..........................................................................................16 2.3 TYPES OF SEQUENCE VARIATION.......................................................................................19 2.4 PRINCIPLES FOR IDENTIFICATION OF HUMAN DISEASE-ASSOCIATED GENES.....................21 2.4.1 Position-independent approaches .............................................................................21 2.4.2 Position-dependent approaches ................................................................................23 2.4.3 Confirmation of a disease-causing gene ...................................................................28 2.4.4 Factors complicating disease gene identification .....................................................31 2.5 CHILDHOOD-ONSET PMES ................................................................................................32 2.6 NEURONAL CEROID LIPOFUSCINOSES................................................................................35 2.6.1 NCL subtypes with congenital onset: CLN10 disease...............................................36 2.6.2 NCL subtypes with infantile onset: CLN1 disease ....................................................38 2.6.3 NCL subtypes with late infantile onset ......................................................................39 2.6.3.1 CLN2 disease....................................................................................................................................39 2.6.3.2 CLN5 disease....................................................................................................................................40 2.6.3.3 CLN6 disease....................................................................................................................................41 2.6.3.4 CLN7 disease....................................................................................................................................42 2.6.3.5 CLN8 disease....................................................................................................................................43 2.6.4 NCL subtypes with juvenile onset..............................................................................45 2.6.4.1 CLN3 disease....................................................................................................................................45 TABLE OF CONTENTS 5 2.6.4.2 CLN9 disease....................................................................................................................................46 2.6.5 NCL subtypes with adult onset: CLN4 disease..........................................................47 2.6.6 Atypical phenotypes caused by mutations in known NCL genes...............................48 2.6.7 Animal models with NCL-like phenotypes.................................................................50 2.6.8 Trafficking and localization of the NCL proteins......................................................51 2.6.8.1 The secretory pathway......................................................................................................................52 2.6.8.2 The endocytic pathway.....................................................................................................................54 2.6.8.3 Lysosomal targeting .........................................................................................................................55 3. AIMS OF THE STUDY .......................................................................................................57 4. MATERIALS AND METHODS .........................................................................................58 4.1 PATIENTS AND CONTROLS .................................................................................................58 4.2 METHODS USED .................................................................................................................60 4.2.1 Nucleic acids extraction and purification (I, II, IV)..................................................60 4.2.2 PCR-based amplification and mutation analysis (I-IV) ............................................62 4.2.3 Microsatellite genotyping (II)....................................................................................62 4.2.4 Genomewide SNP scan and next-generation sequencing (IV and unpublished) ......62 4.2.5 Homozygosity mapping (IV) ......................................................................................63 4.2.6 Expression constructs and site-directed mutagenesis (II, III, IV) .............................63 4.2.7 Cell culture and transfections (II, III, IV) .................................................................66 4.2.8 Immunofluorescence stainings (IF) and microscopy (II, IV) ....................................66 4.2.9 Western blot (III, IV) .................................................................................................67 4.2.10 Co-immunoprecipitation assays (III) ........................................................................69 4.2.11 Deglycosylation assay (III)........................................................................................69 4.2.12 Immunohistochemistry (III, IV) .................................................................................70 4.2.13 In situ hybridization (III) ...........................................................................................70 4.2.14 In silico analyses (I-IV) .............................................................................................70 5. RESULTS AND DISCUSSION ...........................................................................................72 5.1 MUTATIONS IN SIX NCL GENES (I, II) ...............................................................................72 6 TABLE OF CONTENTS 5.2 GENETIC AND MOLECULAR CHARACTERIZATION OF MFSD8, THE GENE DEFECTIVE IN CLN7 DISEASE...................................................................................................................74 5.2.1 Mutations identified in MFSD8 (I, II, III) .................................................................74 5.2.2 Geographical distribution of MFSD8 defects (I, II)..................................................78 5.2.3 Clinical phenotype in CLN7 disease (I, II)................................................................81 5.2.4 Atypical phenotypes caused by MFSD8 defects (II)..................................................82 5.2.5 The MFSD8 protein: Glycosylation (III)...................................................................83 5.2.6 Subcellular localization of MFSD8 (III) ...................................................................84 5.2.7 Sorting mechanisms of MFSD8 targeting (III)..........................................................84 5.2.8 Expression of MFSD8 in rodent brain (III)...............................................................87 5.2.9 Neuropathological findings in postmortem human brains of MFSD8 positive patients (III)...............................................................................................................89 5.3 THE HYPOTHESIS OF NCL GENES ACTING AS MODIFIERS OF PHENOTYPE (UNPUBLISHED)..................................................................................................................91 5.4 IDENTIFICATION
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