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Tetrahydrobiopterin and Monoamine Neurotransmitter Deficiency in Mouse Models and Human Disease

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Tetrahydrobiopterin and Monoamine Neurotransmitter Deficiency in Mouse Models and Human Disease Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2011 Tetrahydrobiopterin and monoamine neurotransmitter deficiency in mouse models and human disease Adamsen, D Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-56733 Dissertation Published Version Originally published at: Adamsen, D. Tetrahydrobiopterin and monoamine neurotransmitter deficiency in mouse models and human disease. 2011, University of Zurich, Faculty of Science. Tetrahydrobiopterin and Monoamine Neurotransmitter Deficiency in Mouse Models and Human Disease Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Dea Adamsen aus Dänemark Promotionskomitee Prof. Dr. Peter Sonderegger (Vorsitz) Prof. Dr. Nenad Blau Prof. Dr. Beat Thöny (Leitung der Dissertation) Zürich, 2011 Table of content Abbreviations............................................................................................................................ 4 Summary................................................................................................................................... 6 Zusammenfassung.................................................................................................................... 9 1 Introduction ..................................................................................................................... 14 1.1 De novo biosynthesis of Tetrahydrobiopterin (BH4)................................................ 14 1.2 Regeneration of BH4 ................................................................................................ 16 1.3 Regulation of BH4 biosynthesis ............................................................................... 17 1.3.1 BH4 regulates its biosynthesis primarily via GTPCH ................................................................... 17 1.3.2 GTP cyclohydrolase feedback regulatory protein (GFRP)............................................................ 17 1.4 BH4 cofactor function............................................................................................... 19 1.5 Human BH4 deficiencies .......................................................................................... 20 1.5.1 PTPS deficiency............................................................................................................................ 21 1.6 Mouse models in the BH4 metabolism..................................................................... 24 1.6.1 German Mouse Clinic (GMC)....................................................................................................... 25 1.7 Metabolism and function of serotonin ..................................................................... 27 1.7.1 Serotonin and brain development.................................................................................................. 28 1.7.2 Neurohormone............................................................................................................................... 28 1.8 Serotonin transporters (SERT and PMAT) ............................................................. 29 1.8.1 Serotonin re-uptake transporter (SERT)........................................................................................ 29 1.8.2 Plasma membrane monoamine transporter (PMAT)..................................................................... 33 1.8.3 SLC6A4 gene variants and neurological behaviour, traits and disorders....................................... 34 1.9 Autism Spectrum Disorder (ASD)........................................................................... 36 1.10 Aim of the thesis ...................................................................................................... 37 1.11 References ................................................................................................................ 38 2 New mouse models to study BH4 deficiency by targeting the 6-pyruvoyl- tetrahydropterin-synthase (Pts) gene ................................................................................... 49 2.1 Abstract .................................................................................................................... 49 2.2 Introduction.............................................................................................................. 50 2.3 Materials and methods ............................................................................................. 52 2.4 Results...................................................................................................................... 58 2.4.1 Generation of Pts-ki/ki mice ......................................................................................................... 58 2.4.2 Biochemical characterization of Pts-ki/ki ..................................................................................... 61 2.4.3 Systemic phenotype analysis by the German Mouse Clinic.......................................................... 63 2.4.4 Abdominal obesity in Pts-ki/ki mice on standard mouse chow and high fat diet.......................... 65 2.4.5 Generation and characterization of compound heterozygous Pts-ki/ko mice ............................... 67 2.4.6 Characterization of newborn Pts-ki/ko mice................................................................................. 70 2 Table of content 2.4.7 Breeding of Pts-ki/ki or Pts-ki/wt males with Pts-ko/wt females ................................................. 71 2.4.8 Allelic effect, mother effect or father effect.................................................................................. 73 2.5 Discussion ................................................................................................................ 75 2.6 Supplementary Information...................................................................................... 79 2.7 References................................................................................................................ 81 3 Targeting of murine Gchfr gene to study the role of GFRP in vivo ............................ 87 3.1 Abstract .................................................................................................................... 87 3.2 Introduction.............................................................................................................. 88 3.3 Method and materials............................................................................................... 89 3.4 Results...................................................................................................................... 91 3.5 Discussion................................................................................................................ 94 3.6 References................................................................................................................ 95 4 Autism associated with low 5-HIAA in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants ............................................................. 99 4.1 Supporting Information on SLC6A4 gene analysis ................................................ 106 5 Autism spectrum disorder associated with low serotonin in CSF, functional mutations in the SLC29A and co-occurrence of mutations in serotonin and/or autism related genes.......................................................................................................................... 111 5.1 Abstract .................................................................................................................. 111 5.2 Introduction............................................................................................................ 112 5.3 Results and Discussion .......................................................................................... 113 5.4 Supplementary Information................................................................................... 124 5.5 Case report.............................................................................................................. 131 5.6 References.............................................................................................................. 140 Acknowledgements............................................................................................................... 144 Curriculum vitae .................................................................................................................. 145 3 Abbreviations Abbreviations AADC, Aromatic amino acid decarboxylase AAAOH, Aromatic amino acid hydroxylase AGMO, Alkylglycerol monooxygenase BH4, ( 6R)-L-erythro-5,6,7,8-tetrahydrobiopterin CNS, Central nervous system CSF, Cerebrospinal fluid DCoH, Dimerization cofactor of hepatocyte nuclear factor-1α DHPR, Dihydropteridine reductase ES cells, Embryonic stem cells GFRP, GTP cyclohydrolase feedback regulatory protein GMC, German Mouse Clinic GTPCH, Guanosine triphosphate cyclohydrolase 5-HIAA, 5-hydroxyindoleacetic acid HVA, Homovanillic acid HPA, Hyperphenylalaninemia 5-HT, Serotonin, 5-hydroxytryptamin 5-OH-Trp, 5-Hydroxytryptophan 5-HTTLPR, 5-HTT gene-linked polymorphic promoter region Het, Heterozygous Homo, Homozygous Ki, Knock-in Ko, Knock-out L-DOPA, L-3,4-dihydroxyphenylalanine MAO-A, Monoamine oxidase A NO, Nitric oxide NOS, Nitric oxide synthase PAH, Phenylalanine hydroxylase PCD/DCoH,
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