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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
Alternative splicing and extensive RNA editing of human TPH2 transcripts.
Maik Grohmann1, Paul Hammer, Maria Walther
1Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Plos One
|February 4, 2010
Summary
Brain serotonin (5-HT) regulation is crucial for mood. Tryptophan hydroxylase 2 (TPH2) gene variants and its alternative splicing/RNA editing are implicated in psychiatric disorders, including suicidal behavior.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Brain serotonin (5-HT) neurotransmission regulates mood and is linked to neuropsychiatric disorders.
- Tryptophan hydroxylase (TPH) is essential for 5-HT biosynthesis, with TPH2 identified as the primary brain isoform.
- TPH2 is a candidate gene for 5-HT-related psychiatric conditions.
Purpose of the Study:
- To investigate the role of TPH2 gene variability in the etiology of psychiatric diseases.
- To analyze TPH2 alternative splicing and RNA editing in human postmortem brain samples.
Main Methods:
- cDNA sequence analysis of TPH2 transcripts from human postmortem amygdala samples.
- Kinetic studies using cell lines expressing recombinant TPH2 variants.
- Molecular and large-scale linkage analysis.
Main Results:
- TPH2 exists in two alternatively spliced variants (TPH2a and TPH2b) in the coding region.
- TPH2 pre-mRNAs undergo dynamic, mutually exclusive RNA editing.
- TPH2B protein exhibits higher activity than TPH2A; RNA editing inhibits the activity of both variants.
- Evidence suggests deregulated TPH2 alternative splicing and RNA editing are involved in psychiatric diseases like suicidal behavior.
Conclusions:
- TPH2 alternative splicing and RNA editing provide complex fine-tuning of central nervous system 5-HT biosynthesis.
- Aberrant TPH2 splicing and editing are implicated in the etiology of psychiatric disorders, particularly suicidal behavior.
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