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