Disease relevance of TPH2

• We have expressed human tryptophan hydroxylase 2 (hTPH2) and two deletion mutants (NDelta150 and NDelta150/CDelta24) using isopropyl beta-d-thiogalactopyranoside-free autoinduction in Escherichia coli [1].

Psychiatry related information on TPH2

• Recently, a second TPH gene, designated TPH2, was detected, located on human chromosome 12, a susceptibility region for affective disorders [2].
• Analysis of the novel TPH2 gene in bipolar disorder and suicidality [3].
• Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes [4].
• In the present case-control genetic association study we investigated whether panic disorder (PD) phenotypes are related to two single nucleotide polymorphisms (SNP) of TPH2, rs1386494 A/G and rs1386483 C/T [5].
• The results of this first study of TPH2 in panic disorder argue against an importance of allelic variation of TPH2 in the pathogenesis of panic disorder with or without agoraphobia [6].

High impact information on TPH2

• The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells [7].
• Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2) [7].
• Association of Brain-Specific Tryptophan Hydroxylase, TPH2, With Unipolar and Bipolar Disorder in a Northern Swedish, Isolated Population [8].
• CONCLUSIONS: Haplotype-based analysis of TPH2 in patients with UP and BP disorder and controls from northern Swedish descent provides preliminary evidence for protective association in both disorders and thus supports a central role for TPH2 in the pathogenesis of affective disorders [8].
• The 15-locus panel defined and maximized information content from 2 haplotype blocks in whites, 3 haplotype blocks in African Americans, and the single haplotype block spanning TPH2 in southwestern American Indians [9].

Chemical compound and disease context of TPH2

• TPH2, rather than TPH1, has now become a candidate gene for 5-HT-related affective disorders [2].

Biological context of TPH2

• We examined eight single nucleotide polymorphisms (SNP) in the TPH2 gene for association with ADHD in 179 Irish nuclear families [10].
• This led us to the detection of a second TPH gene in the genome of humans, mice, and rats, called TPH2 [11].
• Antibody specificity against TPH1 and TPH2 is retained across mouse, rat, rabbit, primate, and human tissues [12].
• We compared TPH2 mRNA levels in postmortem parietal cortex of unipolar-depressed, bipolar, and schizophrenic patients vs control subjects, using real-time reverse transcription polymerase chain reaction [2].
• We performed single-nucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene [13].

Anatomical context of TPH2

• Previously, we reported elevated levels of TPH protein in the dorsal raphe nucleus (DRN) of depressed suicides and now examine expression of neuronal TPH2 mRNA in a cohort of matched controls and depressed suicides (n = 11 pairs) [14].
• TPH2 is the predominant enzyme form expressed in brain extracts from mesencephalic tegmentum, striatum, and hippocampus with a molecular weight of 56 kDa [12].
• Due to the lack of data about its anatomic expression in humans we performed a mRNA expression analysis comparing TPH1 and TPH2 mRNA in several regions of the human brain (cortex, thalamus, hypothalamus, hippocampus, amygdala, cerebellum and raphe nuclei) [15].
• TPH2 and beta-actin mRNA levels in postmortem brain were quantified using real-time PCR. mRNA samples provided by the Stanley Foundation Array Collection were derived from the dorsolateral prefrontal cortex (Brodmann Area 46) of 35 bipolar, 35 schizophrenic, and 35 control subjects [16].
• OBJECTIVE: To determine the association of TPH2 with suicide attempt, major depression, and a neurochemical intermediate phenotype, cerebrospinal fluid 5-hydroxyindoleacetic acid [9].

Associations of TPH2 with chemical compounds

• Recent studies have indicated that a newly identified second isoform of the tryptophan hydroxylase gene (TPH2) is preferentially involved in the rate-limiting synthesis of neuronal serotonin [17].
• TPH2 is more soluble than TPH1, has a higher molecular weight and different kinetic properties, including a lower catalytic efficiency towards phenylalanine than TPH1 [18].
• OBJECTIVE: We screened the complete protein coding sequence of the newly identified neuronal form of tryptophan hydroxylase (TPH2) for genetic variants [19].
• Two-week fluoxetine treatment also significantly reduced expression of tryptophan hydroxylase-2 (TPH2) and 5-HT transporter mRNAs as determined by RT-PCR in the brainstem [20].
• The results indicate that none of the SNPs in the TPH2 gene examined in this study associate with the cocaine-dependent phenotype [21].

Regulatory relationships of TPH2

• Serotonin signaling has long been implicated in both BPAD and suicide, and the gene encoding the brain-expressed isoform of tryptophan hydroxlyase (TPH2) has been described [22].

Other interactions of TPH2

• The major finding of this study was the high expression level of TPH2 mRNA in the raphe nuclei ( approximately 4-fold more abundant than that of TPH1) [15].
• Further confirmation, preferably from different ethnic groups, is required to firmly implicate TPH2 in the pathophysiology of ADHD [10].
• In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P=0.02-0.04) were positively associated and one SNP in the HTR2A gene (P=0.02) was negatively associated [23].
• This study was designed to examine whether the -473T > A and -8396G > C polymorphisms of the TPH2 gene may be associated with completed suicide in subjects with major psychoses from the Stanley Foundation Brain Bank sample [24].
• We conclude that TPH2 may play a modest role in autism susceptibility, perhaps relating specifically to repetitive behaviors, pending replication of this result [25].

Analytical, diagnostic and therapeutic context of TPH2

• DRN TPH2 mRNA was measured by densitometric analysis of autoradiograms from in situ hybridization histochemistry experiments [14].
• These antibodies allow the differentiation of TPH1 and TPH2 upon immunoblotting, immunoprecipitation, and immunocytochemical staining of tissue sections from brain and gut [12].
• The wild type hTPH2, like other members of the aromatic amino acid hydroxylase superfamily, exists as a homotetramer (236 kDa on size exclusion chromatography) [1].
• Here, we used functional magnetic resonance imaging (fMRI) to demonstrate that a potentially functional variant of TPH2 modulates amygdala responsiveness to emotional stimuli of both negative and positive valence [26].
• To examine this hypothesis, we used a case-control study design in which the genotype and allele distributions for six single nucleotide polymorphisms (SNPs) in the TPH2 gene were compared between cocaine-dependent (n = 299) and control individuals (n = 208) of African descent [21].

References