Prof. Dr. Beat Thöny

 

Main Goals, Keywords

Exploration of complex single-gene disorders in the metabolism of tetrahydrobiopterin (BH4), NOS, and folates, including neurobiochemical and pathophysiological aspects in humans and (transgenic) mice models, laboratory diagnosis and treatment of such diseases in newborns, studies of blood-brain barrier penetration of pterins and folates, and gene therapeutic approaches for phenylketonuria.

Keywords: hyperphenylalaninemias, neurotransmitter deficiency, folate deficiency, Dopa-responsive dystonia, phenylketonuria (PKU), Aicardi-Goutieres syndrome

Group Members

1 senior research fellow (PD), 1 professor, 2 postdoctoral fellows, 2 PhD students, 2 technicians

Previous and Current Research

Our interests are molecular mechanisms of inherited neurogenetic diseases, dystonias and dementias involving alterations in the biogenic amine neutrotransmitters, folates, and NO. We have today only a limited understanding for a few of these neurological defects. Moreover, for the few diseases that have assigned a specific genetic lesion, it exist a limited understanding of the phenotype-genotype correlation and an enigmatic variability among patients’ phenotypes.

The model diseases we are investigating are tetrahydrobiopterin (BH4) deficiencies, genetic defects that not only effects peripheral organs, but also are a major problem in the central nervous system, leading to severe neurological disorders and mental retardation in man. The BH4 redox-cofactor is essential for the nitric oxide synthase enzymes and the aromatic amino acid hydroxylases, the latter being responsible for the biosynthesis of the neurotransmitters serotonin and catecholamines (Fig. 1). Besides genetic lesions in the metabolism of BH4 that lead to cofactor shortage, a number of neuro-degenerative diseases such as Alzheimer and Parkinson appear to have reduced cofactor levels.

The past and current objective of our projects is to discover through a series of experiments and collaborative efforts the underlying mechanisms by which BH4 regulates phenylalanine and neurotransmitter homeostasis as well as nitric oxide synthase (NOS) activity in different cells and in the organism. So far patients and animal models with inherited BH4 deficiency were investigated to study the function and therapeutic efficiency of BH4 as well as the phenotype-genotype correlation.

Future Projects

Targeted mutagenesis of the mouse BH₄ genes by homologous recombination in ES cells and characterization of (neurometabolic) phenotypes. Pediatric neurotransmitter diseases and molecular studies on disorders of catechol and serotonin homeostasis with neuro-developmental and psychiatric abnormalities including attention-deficit/hyperactivity (ADHD) and/or autism spectrum disorder (ASD).

Techniques and Equipment

In addition to diagnostic analyses for genetic alterations and for metabolic compounds (neurotransmitters, folates, amino acids, organic acids in body fluids such as CSF, serum, and urine), we are generating and experimenting with cell cultures and transgenic animals (knock-in and knock-outs). Techniques involve a wide range of modern protein chemistry, immunological, and molecular biology techniques including FPLC, HPLC, mass spectrometry, Western and Southern analyses, DNA cloning, amplification and sequencing. Regarding gene therapeutic techniques, we are generating retroviral, adeno-associated viral, lentiviral and non-viral (mini-circle) vectors.

Selected Publications

• Sarkissian CN, Ying M, Scherer T, Thöny B, Martinez A. The mechanism of BH4 -responsive hyperphenylalaninemia--as it occurs in the ENU1/2 genetic mouse model. Hum Mutat. 2012 Oct;33(10):1464-73. doi: 10.1002/humu.22128. Epub 2012 Jul 2.
• Heintz C, Troxler H, Martinez A, Thöny B, Blau N. Quantification of phenylalanine hydroxylase activity by isotope-dilution liquid chromatography-electrospray ionization tandem mass spectrometry. Mol Genet Metab. 2012 Apr;105(4):559-65. doi: 10.1016/j.ymgme.2011.12.025. Epub 2012 Jan 12.
• Kostandyan N, Britschgi C, Matevosyan A, Oganezova A, Davtyan A, Blau N, Steinmann B, Thöny B. The spectrum of phenylketonuria genotypes in the Armenian population: identification of three novel mutant PAH alleles. Mol Genet Metab. 2011;104 Suppl:S93-6. doi: 10.1016/j.ymgme.2011.08.006. Epub 2011 Aug 12.
• Werner ER, Blau N, Thöny B. Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J. 2011 Sep 15;438(3):397-414. doi: 10.1042/BJ20110293. Review.

Selected Lectures, Seminars or Colloquia

Clinical-Biochemical Colloquium, BIO408 (Molekulare Humangenetik) and BIO708 (Gene Therapy)

Collaboration

Prof. Dr. Nenad Blau, Department of Pediatrics, Division of Clinical Chemistry and Biochemistry, University of Zurich; various national and international collaborations.

Funding

Swiss National Science Foundation (no. 3100A0-119982 and no. 310000.-122045-1), U.S.A. National Institute of Health (NIH R01 no. 1R01HD057033-01A1), University of Zurich and various private research foundations.

URL

http://www.bh4.org
http://www.folates.com
http://www.kispi.uzh.ch/af/ForschungLehre/ClinicalChem_de.html

Additional Links (research data bank of the University of Zurich):

http://www.research-projects.uzh.ch/p2588.htm

http://www.research-projects.uzh.ch/p4644.htm

http://www.research-projects.uzh.ch/p8178.htm

http://www.research-projects.uzh.ch/p339.htm