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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents



  history
ID: 334797.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Characterization of a Functional Promoter Polymorphism of the Human Tryptophan Hydroxylase 2 Gene in Serotonergic Raphe Neurons.
Authors:Scheuch, Kathrin; Lautenschlager, Marion; Grohmann, Maik; Stahlberg, Silke; Kirchheiner, Julia; Zill, Peter; Heinz, Andreas; Walthe, Diego J.; Priller, Josef
Language:English
Date of Publication (YYYY-MM-DD):2007-12-01
Title of Journal:Biological Psychiatry : A Journal of Psychiatric Neuroscience
Journal Abbrev.:Biol. Psychiatry
Volume:62
Issue / Number:11
Start Page:1288
End Page:1294
Copyright:© 2007 Society of Biological Psychiatry Published by Elsevier Inc.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Background
Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in brain serotonin (5-HT) biosynthesis. Although dysfunction of 5-HT neurotransmission has been implicated in a variety of neuropsychiatric conditions, the human TPH2 promoter has not been characterized in vitro.
Methods
The functional relevance of TPH2 promoter polymorphisms was determined with luciferase assays in primary serotonergic neurons from rat raphe nuclei and in human small cell lung carcinoma cells (SHP-77 cells). We also investigated transcription factor binding to the variant promoter sequence with electrophoretic mobility shift assay (EMSA).
Results
The polymorphism rs11178997 of the human TPH2 promoter significantly reduced TPH2 transcriptional activity by 22% and 7% in primary serotonergic neurons and in SHP-77 cells, respectively. In contrast, no significant differences in promoter activity were observed for the G- and T-alleles of rs4570625. The EMSA revealed reduced binding of the transcription factor POU3F2 (also known as Brn-2, N-Oct-3) to the A-allele of the polymorphism rs11178997. Overexpression of POU3F2 resulted in a robust activation of the TPH2 promoter (2.7-fold).
Conclusions
Our data suggest that the human TPH2 promoter polymorphism rs11178997 impacts on gene expression, which might have implications for the development and function of the serotonergic system in the brain.
Free Keywords:Brain-2; haplotype; POU transcription factor; serotonin; SHP-77 cells; single nucleotide polymorphism; TPH2
Comment of the Author/Creator:Address reprint requests to Josef Priller, M.D., Laboratory of Molecular Psychiatry, Department of Psychiatry and Psychotherapy CCM, Charité-Universitätsmedizin Berlin, Schumannstr. 20/21, 10117 Berlin, Germany
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany;
2.Department of Psychiatry and Psychotherapy CCM, Charité-Universitätsmedizin Berlin, Berlin, Germany;
3.Department of Pharmacology of Natural Products & Clinical Pharmacology, University of Ulm, Ulm, Germany;
4.Department of Psychiatry, Psychiatric Clinic, Ludwig-Maximilians-University, Munich, Germany.
Identifiers:ISSN:0006-3223
DOI:10.1016/j.biopsych.2007.01.015
URL:http://www.sciencedirect.com/science?_ob=ArticleUR...
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