|Title / Titel||Biochemistry and neuropathophysiology of tetrahydrobiopterin metabolism and deficiencies|
|Abstract (PDF, 14 KB)|
|Summary / Zusammenfassung||The study of inherited metabolic diseases often permits better understanding of the normal metabolism. These investigations are not only of theoretical interest but a precondition for early diagnosis and possible therapy of the patients. Tetrahydrobiopterin (BH4)-dependent phenylketonuria, characterized by a deficiency of the neurotransmitters dopamine and serotonin is today a treatable disease. This is an ideal precondition for a selective screening and our laboratory in Zürich has become one of a very few international centers for the investigation of this inherited disease.
The objective of this project is to discover through a series of experiments and collaborative efforts the underlying mechanisms by which BH4 regulates phenylalanine and neurotransmitter homeostases as well as nitric oxide synthase (NOS) activity in different cells. So far the patients with inherited BH4 deficiency were investigated as a model to study the function and therapeutic efficiency of BH4 as well as the phenotype-genotype correlation. The present research project will focus on our major efforts in the molecular understanding of BH4 deficiency by generating the transgenic mice and it will cover the following topics:
1. Molecular analysis of patients’ fibroblasts including mutation analysis and recombinant expression of BH4 pathway genes
2. Targeted mutagenesis of the mouse BH4 genes by homologous recombination in embryonic stem cells
3. Effect of BH4 on genes expression
|Publications / Publikationen||Zurflüh, M. R., J. Zschocke, M. Lindner, F. Feillet, C. Chery, A. Burlina, R.C. Stevens, B. Thöny, and N. Blau (2008). "Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency". Human Mutat 29: 167-175.Thöny, B. and N. Blau (2006). "Mutations in the BH4-metabolizing genes GTP cyclohydroalse I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase genes." Human Mutat 27: 870-878.
Zurflüh, M., L. Fiori, B. Fiege, M. Giovannini, Y. Gokdemir, T. Baykal, L. Kierat, K. H. Gärtner, B. Thöny and N. Blau (2005). "Screening for tetrahydrobiopterin deficiencies using dried blood spots on filter paper." Mol Genet Metab 86: 96-103.
Scavelli, R., Z. Ding, N. Blau, J. Haavik, A. Martínez and B. Thöny (2005). "Stimulation of hepatic phenylalanine hydroxylase activity but not Pah-mRNA expression upon oral loading of tetrahydrobiopterin in normal mice." Mol Genet Metab 86: S153-S155.
Fiege, B., D. Ballhausen, L. Kierat, W. Leimbacher, D. Goriounov, B. Schircks, B. Thöny and N. Blau (2004). "Plasma tetrahydrobiopterin and its pharmacokinetics following oral administration." Mol Genet Metab 81: 45-51.Elzaouk, L., S. Laufs, D. Heerklotz, W. Leimbacher, N. Blau, A. Résibois and B. Thöny (2004). "Nuclear localization of tetrahydrobiopterin biosynthetic enzymes." Biochim Biophys Acta 1670: 56-68.
Elzaouk, L., W. Leimbacher, M. Turri, B. Ledermann, K. Bürki, N. Blau and B. Thöny (2003). "Dwarfism and low IGF-1 due to dopamine depletion in Pts-/- mice rescued by feeding neurotransmitter precursors and H4-biopterin." J Biol Chem 278: 28303-28311.
Bonafé, L., B. Thöny, J. M. Penzien, B. Czarnecki and N. Blau (2001). "Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine neurotransmitter deficiency without hyperphenylalaninemia." Am J Hum Genet 69: 269-277.Weitere Informationen
|Keywords / Suchbegriffe||tetrahydrobiopterin, nitic oxide synthase, catecholamines, PKU, animal model, targeted mutagenesis|
|Project leadership and contacts /
Projektleitung und Kontakte
|Funding source(s) /
|SNF (Personen- und Projektförderung)
|In collaboration with /
In Zusammenarbeit mit
|Duration of Project / Projektdauer||Mar 2002 to Nov 2011|