Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder

Abstract

The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] controls a broad range of biological functions that are disturbed in affective disorder. In the brain, 5-HT production is controlled by tryptophan hydroxylase 2 (TPH2). In order to assess the possible contribution of TPH2 genetic variability to the aetiology of bipolar affective disorder (BPAD), we systematically investigated common and rare genetic variation in the TPH2 gene through a sequential sequencing and SNP-based genotyping approach. Our study sample comprised two cohorts of BPAD from Germany and Russia, totalling 883 patients and 1300 controls. SNPs located in a haplotype block covering the 5' region of the gene as well as a rare, non-synonymous SNP, resulting in a Pro206Ser substitution, showed significant association with bipolar disorder. The odds ratio for the minor allele in the pooled sample was 1.5 (95% CI 1.2-1.9) for rs11178997 (in the 5'-associated haplotype block) and 4.8 (95% CI 1.6-14.8) for rs17110563 encoding the Pro206Ser substitution. Examination of the functional effects of TPH2 Pro206Ser provided evidence for a reduced thermal stability and solubility of the mutated enzyme, suggesting reduced 5-HT production in the brain as a pathophysiological mechanism in BPAD.

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

“…Furthermore, several naturally occurring functional polymorphisms in the Tph2 gene have also been identified in mice (15), rhesus monkeys (42), chimpanzees (43), and humans (17)(18)(19). The existence of multiple rare variants in a single gene leading to the development of human pathologies is not a rare occurrence.…”

“…This enzyme catalyzes the conversion of the amino acid tryptophan to 5-hydroxytryptophan (5-HTP) that is subsequently decarboxylated to 5-HT by L-aromatic amino acid decarboxylase. Recent investigations of naturally occurring genetic polymorphisms in humans and mice have identified functional mutations in Tph2 that lead to pronounced reduction in enzyme activity (15,(17)(18)(19). A rare R441H TPH2 variant has been identified in individuals from a small cohort of elderly patients with major unipolar depression.…”

Mutations in human monoamine-related neurotransmitter pathway genes

“…Recently, it was found that the pure enzyme had intact kinetic properties, but decreased thermal stability and an increased rate of aggregation in vitro, supporting a role of this mutation in the clinical phenotype [Winge et al, 2007]. More recently, another rare missense mutation (p.P206S) has been reported to be associated with unipolar and bipolar depression in different populations [Cichon et al, 2008;Zhou et al, 2005b]. Molecular characterization of this mutation revealed that the enzyme behaved similar to the wild type, but had a moderately reduced thermal stability and increased rate of aggregation in vitro [Cichon et al, 2008].…”

“…More recently, another rare missense mutation (p.P206S) has been reported to be associated with unipolar and bipolar depression in different populations [Cichon et al, 2008;Zhou et al, 2005b]. Molecular characterization of this mutation revealed that the enzyme behaved similar to the wild type, but had a moderately reduced thermal stability and increased rate of aggregation in vitro [Cichon et al, 2008]. The other coding nonsynonymous SNPs and synonymous SNPs in TPH2 have so far not been associated with any particular phenotype (see Supplementary Table S3 and Fig.…”

“…In TPH1, the common intronic SNPs A218C and A779C have been studied the most, while in the TPH2 gene several different 5 0 -UTR or intronic variants have been reported to be associated with various psychiatric symptoms [Cichon et al, 2008;Scheuch et al, 2007;Van Den Bogaert et al, 2006;Zhou et al, 2005b]. There is also evidence that polymorphisms in the 5 0 regulatory regions of these genes affect gene expression both in vivo and in vitro, but these results should be considered as preliminary, as the mechanisms underlying the findings are not known and the promoter regions of the TPH1 and TPH2 genes are only superficially characterized.…”