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



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ID: 533085.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Alternative Splicing and Extensive RNA Editing of Human TPH2 Transcripts.
Authors:Grohmann, Maik; Hammer, Paul; Walther, Maria; Paulmann, Nils; Büttner, Andreas; Eisenmenger, Wolfgang; Baghai, Thomas C.; Schüle, Cornelius; Rupprecht, Rainer; Bader, Michael; Bondy, Brigitta; Zill, Peter; Priller, Josef; Walther, Diego J.
Language:English
Research Context:The study was funded in part by grants of the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung and the Max Planck Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Date of Publication (YYYY-MM-DD):2010-01-29
Title of Journal:PLoS ONE
Volume:5
Issue / Number:1
Start Page:e8956
End Page:e8956
Full name of Issue-Editor(s):Lennart Randau, Yale University, United States of America
Copyright:© 2010 Grohmann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Brain serotonin (5-HT) neurotransmission plays a key role in the regulation of mood and has been implicated in a variety of neuropsychiatric conditions. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT. Recently, we discovered a second TPH isoform (TPH2) in vertebrates, including man, which is predominantly expressed in brain, while the previously known TPH isoform (TPH1) is primarly a non-neuronal enzyme. Overwhelming evidence now points to TPH2 as a candidate gene for 5-HT-related psychiatric disorders. To assess the role of TPH2 gene variability in the etiology of psychiatric diseases we performed cDNA sequence analysis of TPH2 transcripts from human post mortem amygdala samples obtained from individuals with psychiatric disorders (drug abuse, schizophrenia, suicide) and controls. Here we show that TPH2 exists in two alternatively spliced variants in the coding region, denoted TPH2a and TPH2b. Moreover, we found evidence that the pre-mRNAs of both splice variants are dynamically RNA-edited in a mutually exclusive manner. Kinetic studies with cell lines expressing recombinant TPH2 variants revealed a higher activity of the novel TPH2B protein compared with the previously known TPH2A, whereas RNA editing was shown to inhibit the enzymatic activity of both TPH2 splice variants. Therefore, our results strongly suggest a complex fine-tuning of central nervous system 5-HT biosynthesis by TPH2 alternative splicing and RNA editing. Finally, we present molecular and large-scale linkage data evidencing that deregulated alternative splicing and RNA editing is involved in the etiology of psychiatric diseases, such as suicidal behaviour.
Comment of the Author/Creator:E-mail: dwalther@molgen.mpg.de
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Berlin, Germany;
2.Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin, Berlin, Germany;
3.Institute for Legal Medicine, Ludwig Maximilians University, Munich, Germany;
4.Laboratory of Molecular Biology of Peptide Hormones, Max Delbrück Center for Molecular Medicine, Berlin, Germany;
5.Department of Psychiatry, Ludwig Maximilians University, Munich, Germany.
Identifiers:URL:http://www.plosone.org/article/info%3Adoi%2F10.137...
ISSN:1932-6203
DOI:10.1371/journal.pone.0008956
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