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Technische Universität München TECHNISCHE UNIVERSITÄT MÜNCHEN LEHRSTUHL FÜR EXPERIMENTELLE GENETIK Identification and verification of novel disease-causing genes and therapy options for patients with mitochondrial disorders – Focus on ACAD9 Birgit Monika Repp Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) genehmigten Dissertation. Vorsitzende: Prof. Angelika Schnieke, Ph.D. Prüfer der Dissertation: 1. apl. Prof. Dr. Jerzy Adamski 2. Prof. Dr. Heiko Witt Die Dissertation wurde am 24.01.2019 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 21.06.2019 angenommen. „Das schönste Glück des denkenden Menschen ist, das Erforschliche erforscht zu haben und das Unerforschliche ruhig zu verehren“ (Johann Wolfgang von Goethe) Table of contents TABLE OF CONTENTS ABSTRACT ................................................................................................................................................................ 1 ZUSAMMENFASSUNG ............................................................................................................................................ 3 1. INTRODUCTION .................................................................................................................................................. 5 1.1 MITOCHONDRIA .................................................................................................................................................. 5 1.2 RESPIRATORY CHAIN .......................................................................................................................................... 6 1.3 COMPLEX I - NADH-UBIQUINONE OXIDOREDUCTASE ........................................................................................ 7 1.4 MITOCHONDRIAL DISORDERS ............................................................................................................................ 10 1.4.1 General information ................................................................................................................................. 10 1.4.2 Inheritance ................................................................................................................................................ 11 1.4.3 Respiratory Chain Complex I – Deficiency .............................................................................................. 12 1.4.3.1 Clinical spectrum of complex-I defect patients ................................................................................................... 12 1.4.3.2 Known disease-causing genes ............................................................................................................................. 13 1.5 DIAGNOSTIC FOR MITOCHONDRIAL DISORDER .................................................................................................. 15 1.5.1 General information ................................................................................................................................. 15 1.5.2 Routine diagnostics ................................................................................................................................... 15 1.5.3 Next-Generation-Sequencing .................................................................................................................... 16 1.6 THERAPY FOR MITOCHONDRIAL DISORDERS ..................................................................................................... 19 1.6.1 General information ................................................................................................................................. 19 1.6.2 Bezafibrate treatment in vitro and in vivo ................................................................................................ 19 1.6.3. Riboflavin treatment ................................................................................................................................ 22 1.6.4 Further treatment options ......................................................................................................................... 23 1.7 PURPOSE OF THE WORK ..................................................................................................................................... 25 2 MATERIALS AND METHODS .......................................................................................................................... 28 2.1 MATERIALS ....................................................................................................................................................... 28 2.1.1 Reagents, media and buffers ..................................................................................................................... 28 2.1.2 Antibodies, ladders and enzymes .............................................................................................................. 30 2.1.3 Kits ............................................................................................................................................................ 31 2.1.4 Equipment and Software ........................................................................................................................... 32 2.1.5 Material .................................................................................................................................................... 33 2.2 MOLECULAR BIOLOGY METHODS ...................................................................................................................... 34 2.2.1 DNA/RNA isolation ................................................................................................................................... 34 2.2.1.1 DNA and RNA isolation from cells ..................................................................................................................... 34 2.2.1.2 Isolation from plasmid-DNA from bacteria ......................................................................................................... 35 2.2.2 Determination of DNA and RNA purity and concentration ...................................................................... 35 2.2.3 Reverse transcription of RNA ................................................................................................................... 35 2.2.4 Polymerase chain reaction (PCR) ............................................................................................................ 36 i Table of contents 2.2.4.1 Amplification of DNA sequences by PCR .......................................................................................................... 36 2.2.4.2 Agarose gel electrophoresis ................................................................................................................................. 36 2.3 CELL BIOLOGICAL METHODS ............................................................................................................................. 37 2.3.1 Cultivation of HEK 293T cells .................................................................................................................. 37 2.3.2 Growth and maintenance of Human fibroblasts ....................................................................................... 37 2.3.2.1 Contamination test for mycoplasma .................................................................................................................... 37 2.3.2.2 Contamination tests for HBV, HCV and HIV ..................................................................................................... 38 2.4 DIAGNOSTICS IN PATIENTS WITH MITOCHONDRIAL DISORDERS ......................................................................... 38 2.4.1. Sanger Sequencing................................................................................................................................... 38 2.4.2 Whole Exome Sequencing ......................................................................................................................... 39 2.5 DETERMINATION OF THE PATHOGENICITY OF THE FOUNDED VARIANTS VIA LENTIVIRAL GENE TRANSFER........ 40 2.5.1 Cloning of cDNA ...................................................................................................................................... 41 2.5.2 Lentiviral transduction ............................................................................................................................. 42 2.6 CELL CULTURE TREATMENT .............................................................................................................................. 43 2.6.1 Bezafibrate ................................................................................................................................................ 43 2.6.2 Riboflavin ................................................................................................................................................. 43 2.6.3 Resveratrol................................................................................................................................................ 43 2.6.4 AICAR ....................................................................................................................................................... 43 2.7. OXYGEN CONSUMPTION MEASUREMENTS IN CELLS ........................................................................................
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