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Novel Pathomechanisms Implicated in Defects of Neuromuscular Transmission

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Novel Pathomechanisms Implicated in Defects of Neuromuscular Transmission Aus der Medizinischen Klinik und Poliklinik I der Ludwig-Maximilians-Universität München Direktor: Prof. Dr. med. Steffen Massberg und der Neurologischen Klinik und Poliklinik der Ludwig-Maximilians-Universität München Direktorin: Prof. Dr. med. Marianne Dieterich Novel pathomechanisms implicated in defects of neuromuscular transmission Dissertation zum Erwerb des Doktorgrades der Naturwissenschaften an der Medizinischen Fakultät der Ludwig-Maximilians-Universität München vorgelegt von Marina Dusl aus Freising 2014 Gedruckt mit Genehmigung der Medizinischen Fakultät der Ludwig-Maximilians-Universität München Eingereicht am: 06. Mai 2014 Betreuer: Prof. Dr. rer. nat. Robert David Zweitgutachter: Prof. Dr. rer. nat. Roland Kappler Mitbetreuung durch die habilitierte Mitarbeiterin: Priv.-Doz. Dr. med. Angela Abicht Dekan: Prof. Dr. med. Dr. h.c. Maximilian Reiser, FACR, FRCR Tag der mündlichen Prüfung: 23. Februar 2015 Teile dieser Arbeit wurden veröffentlicht in oder sind in Vorbereitung zur Publikation: Senderek J#, Muller JS#, Dusl M, Strom TM, Guergueltcheva V, Diepolder I, Laval SH, Maxwell S, Cossins J, Krause S, Muelas N, Vilchez JJ, Colomer J, Mallebrera CJ, Nascimento A, Nafissi S, Kariminejad A, Nilipour Y, Bozorgmehr B, Najmabadi H, Rodolico C, Sieb JP, Steinlein OK, Schlotter B, Schoser B, Kirschner J, Herrmann R, Voit T, Oldfors A, Lindbergh C, Urtizberea A, von der Hagen M, Hubner A, Palace J, Bushby K, Straub V, Beeson D, Abicht A, Lochmuller H. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet 2011;88(2):162-72. Chaouch A, Muller JS, Guergueltcheva V, Dusl M, Schara U, Rakocevic-Stojanovic V, Lindberg C, Scola RH, Werneck LC, Colomer J, Nascimento A, Vilchez JJ, Muelas N, Argov Z, Abicht A, Lochmuller H. A retrospective clinical study of the treatment of slow-channel congenital myasthenic syndrome. J Neurol 2012;259(3):474-81. Guergueltcheva V#, Muller JS#, Dusl M, Senderek J, Oldfors A, Lindbergh C, Maxwell S, Colomer J, Mallebrera CJ, Nascimento A, Vilchez JJ, Muelas N, Kirschner J, Nafissi S, Kariminejad A, Nilipour Y, Bozorgmehr B, Najmabadi H, Rodolico C, Sieb JP, Schlotter B, Schoser B, Herrmann R, Voit T, Steinlein OK, Najafi A, Urtizberea A, Soler DM, Muntoni F, Hanna MG, Chaouch A, Straub V, Bushby K, Palace J, Beeson D, Abicht A, Lochmuller H. Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations. J Neurol 2011;259(5):838-50. Abicht A, Dusl M, Gallenmuller C, Guergueltcheva V, Schara U, Della Marina A, Wibbeler E, Almaras S, Mihaylova V, von der Hagen M, Huebner A, Chaouch A, Muller JS, Lochmuller H. Congenital myasthenic syndromes: achievements and limitations of phenotype-guided gene- after-gene sequencing in diagnostic practice: a study of 680 patients. Hum Mutat 2012;33(10):1474-84. Gallenmuller C, Muller-Felber W, Dusl M, Stucka R, Guergueltcheva V, Blaschek A, von der Hagen M, Huebner A, Muller JS, Lochmuller H, Abicht A. Salbutamol-responsive limb-girdle congenital myasthenic syndrome due to a novel missense mutation and heteroallelic deletion in MUSK. Neuromuscul Disord 2014;24(1):31-5. Dusl M, Senderek J, Müller JS, Vogel JG, Pertl A, Stucka R, Lochmüller H, David R#, Abicht A#. A 3’-UTR mutation creates a potential microRNA target site in the GFPT1 gene of LG-CMS patients. Im Begutachtungsverfahren. # These authors contributed equally to this work Poster Präsentation: M. Dusl, V. Guergueltcheva, J. Müller, S., C. Rodolico, J.P. Sieb, J.J. Vilchez, Kirschner, J., T. Voit, O.K. Steinlein, A. Abicht, H. Lochmüller (November 2009) Limb-girdle congenital myasthenic syndrome with tubular aggregates – phenotypic clues for the entity. TREAT-NMD International Conference, Brussels, Belgium Vortrag: M. Dusl, V. Guergueltcheva, J. Müller, S. Nafissi, A. Kariminejad, C. Rodolico, J.P. Sieb, J.J. Vilchez, J. Colomer, J. Kirschner, B. Schlotter, B. Schoser, R. Herrmann, T. Voit, O.K. Steinlein, M. von der Hagen, A. Huebner, J. Senderek, A. Abicht, H. Lochmüller (April 2011) Limb-girdle congenital myasthenic syndrome with frequent tubular aggregates. 20th Congress of the German Society for Muscle Diseases, Neu-Ulm, Germany Meinen Eltern Marina Dusl TABLE OF CONTENTS Table of contents A Acknowledgments ............................................................................................................. 1 B Summary ........................................................................................................................... 3 C Zusammenfassung ............................................................................................................ 5 D Introduction ...................................................................................................................... 7 1 Neuromuscular junction (NMJ) ..................................................................................... 7 2 Congenital myasthenic syndromes (CMS) .................................................................... 8 2.1 Main clinical symptoms ................................................................................................... 9 2.2 Classification of CMS ....................................................................................................... 9 2.2.1 Presynaptic CMS ...................................................................................................... 9 2.2.2 Synaptic CMS .......................................................................................................... 9 2.2.3 Postsynaptic CMS ...................................................................................................10 2.3 Therapeutic strategies for CMS .......................................................................................13 3 Novel clinical and molecular entity ............................................................................. 15 3.1 Limb-girdle (LG-) CMS with frequent tubular aggregates and GFPT1 mutations .................15 3.1.1 LG-CMS symptoms .................................................................................................15 3.1.2 Tubular aggregates ................................................................................................15 3.1.3 GFPT1 ...................................................................................................................16 3.2 Hexosamine biosynthetic pathway (HBP) .........................................................................16 3.2.1 Glycosylation ..........................................................................................................18 E Objectives ........................................................................................................................ 21 F Materials and Methods .................................................................................................... 23 1 Materials ..................................................................................................................... 23 1.1 Laboratory equipment ....................................................................................................23 1.2 Chemicals......................................................................................................................24 1.3 Kits and enzymes ...........................................................................................................24 1.4 Plasmids........................................................................................................................25 1.5 Antibodies .....................................................................................................................27 1.5.1 Primary antibodies ..................................................................................................27 1.5.2 Secondary antibodies ..............................................................................................27 1.6 E.coli strains ..................................................................................................................27 1.7 Nucleic acids .................................................................................................................28 1.7.1 Solution .................................................................................................................28 1.7.2 Size standards ........................................................................................................28 1.7.3 Oligonucleotides for molecular genetic analysis of putative GFPT1 patients ................28 1.7.4 Oligonucleotides for cDNA amplification ...................................................................29 1.7.5 Oligonucleotides for site-directed mutagenesis PCR ..................................................30 I Marina Dusl TABLE OF CONTENTS 1.7.6 Oligonucleotides for plasmid sequencing ..................................................................30 1.7.7 Oligonucleotides for cloning of the miR-600 expression plasmid ................................31 1.7.8 Oligonucleotides for qRT-PCR ..................................................................................31 1.7.9 Mature siRNAs/miRNAs/inhibitors and control miRNA ................................................31 1.8 Patients .........................................................................................................................32 1.8.1 Collection of genomic DNA samples .........................................................................32 2 Methods .....................................................................................................................
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