Disease relevance of TPH1

• Analysis of mouse tissues confirms that TPH1 is the predominant form expressed in pineal gland and in P815 mastocytoma cells with a molecular weight of 51 kDa [1].
• Mice deficient in peripheral tryptophan hydroxylase (TPH1) and serotonin exhibit a reduced risk of thrombosis and thromboembolism [2].
• This study elucidates that TPH1, VMAT1, and Survivin should be further investigated as potential target antigens for T cell-mediated immunotherapy of midgut carcinoids [3].
• In this report we demonstrate, using a series of truncation mutants of the 14-3-3 eta isoform expressed in Escherichia coli, that the COOH-terminal region, especially restricted in amino acids 171-213, binds indeed with the phosphorylated TPH [4].
• TPH reactivity was the best predictor for autoimmune hepatitis, with an OR of 27 [5].

Psychiatry related information on TPH1

• TPH2, rather than TPH1, has now become a candidate gene for 5-HT-related affective disorders [6].
• With respect to TPH1 and TPH2, the majority of studies did not provide evidence for an association between these genes and bipolar disorder [7].
• RESULTS: The TPH A779 allele was more common in deliberate self-harm subjects than in controls (OR 1.38, 95% CI 1.02-1.88; P = 0.03) [8].
• We observed a 62% decrease in brainstem TPH activity (p = 0.009) in 4-week-old R6/2 mice, well before the onset of behavioral symptoms [9].
• Interaction between TPH1 and GNB3 genotypes and electroconvulsive therapy in major depression [10].

High impact information on TPH1

• The crystal structure of a complex containing deoxy CpG and a terpyridine platinum compound (TPH) shows a DNA double helical fragment with TPH intercalated between two Watson-Crick GC base pairs [11].
• BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin [12].
• RESULTS: There was a significant association between TPH genotypes and manic-depressive illness [13].
• Among patients with bipolar disorder, no association was found between TPH alleles and suicidal behavior [13].
• RESULTS: In the behaviorally extreme impulsive group, we observed a significant association between TPH genotype and cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) concentration [14].

Chemical compound and disease context of TPH1

• Deliberate self-harm is associated with allelic variation in the tryptophan hydroxylase gene (TPH A779C), but not with polymorphisms in five other serotonergic genes [8].
• In our sample of 814 patients comprising 114 with schizophrenia, 416 with bipolar affective disorder and 284 with unipolar affective disorder, we studied interactions between the tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR), and the dopamine receptor (DRD4) genes in relation to five major psychiatric symptomatology scores [15].
• We showed in human melanoma cells tryptophan hydroxylase (TPH) and hydroxyindole methyltransferase genes expression with the sequential enzymatic activities of TPH, serotonin (Ser) N-acetyltransferase and hydroxyindole methyltransferase [16].
• The aim of this study was to investigate the possible association between the tryptophan hydroxylase (TPH) gene and prophylactic efficacy of lithium in mood disorders [17].

Biological context of TPH1

• Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04) [18].
• Both enzymes are phosphorylated by cAMP-dependent protein kinase A. TPH2 was phosphorylated at Ser19, a phosphorylation site not present in TPH1 [19].
• In humans, two different TPH genes exist, located on chromosomes 11 and 12, respectively, and encoding two enzymes (TPH1 and TPH2) with an overall sequence identity of 71% [19].
• METHODS: DNA from the Taiwanese Han and Bunun was subjected to sequence for screening genetic variation in the coding and promoter regions of the TPH1 locus [20].
• RESULTS: Three variants in the TPH1 promoter region were identified, and the markers are in complete linkage disequilibrium in both populations [20].

Anatomical context of TPH1

• This gene is preferentially expressed in the central nervous system, while the original TPH1 is the peripheral gene [21].
• This gene is predominantly expressed in the brain stem, while the classical TPH gene, now called TPH1, is expressed in the gut, pineal gland, spleen, and thymus [22].
• 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) [23].
• 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) [23].
• Here we show that a mesencephalic neural cell line, mes-c-myc A1 (A1) produces 5-HT and expresses SERT and both peripheral (TPH1) and CNS-specific (TPH2) form of tryptophan hydroxylase, the limiting enzyme in 5-HT biosynthesis [24].

Associations of TPH1 with chemical compounds

• TPH2 is more soluble than TPH1, has a higher molecular weight and different kinetic properties, including a lower catalytic efficiency towards phenylalanine than TPH1 [19].
• Since tryptophan hydroxylase (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, its role in the pathophysiology of these psychiatric diseases has been intensively studied [25].
• Two isoforms (TPH1 and TPH2) having tryptophan hydroxylating activity were identified [26].
• The positive heterosis effects with respect to nicotine addiction and personality support the idea that the TPH1 gene exerts pleiotropic effects [27].
• Tyrosine-, tryptophan- and phenylalanine hydroxylase (TH, TPH and PAH, respectively) were transiently activated at low urea concentrations and rapidly inactivated in >3 M urea [28].

Other interactions of TPH1

• Our study did not support the involvement of 5-HTTLPR, TPH, MAO-A, or DRD4 polymorphisms in mood disorders [29].
• HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction [30].
• Thus, we have prepared a model of the structure of TPH based on the crystal structures of TH and PAH [31].
• In vitro binding showed that TPH does not bind to exon 1 of huntingtin in a polyglutamine-dependent manner [9].
• The frequencies of COMT Val158Met, 5-HTTLPR, and TPH IVS7+218C>A polymorphisms were determined [32].

Analytical, diagnostic and therapeutic context of TPH1

• These antibodies allow the differentiation of TPH1 and TPH2 upon immunoblotting, immunoprecipitation, and immunocytochemical staining of tissue sections from brain and gut [1].
• The presymptomatic inhibition of TPH activity in the R6/2 mice may help explain the functional consequences of HD and provide insights into new targets for pharmacotherapy [9].
• Because the antibody does not cross react with tyrosine hydroxylase as defined in Western blotting or brain sections, these positive structures may contain TPH [33].
• By examining introns of the human TPH gene by PCR amplification and analysis by the single-strand conformational polymorphism (SSCP) technique, an SSCP was revealed with two alleles that occur with frequencies of .40 and .60 in unrelated Caucasians [34].
• Four TPH mRNA species were detected by Northern blot with pineal gland and carcinoid tumor RNAs [35].

References