Alternative titles; symbols
HGNC Approved Gene Symbol: TPH1
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38): 11:18,017,555-18,046,269 (from NCBI)
Tryptophan hydroxylase (TPH; EC 1.14.16.4) catalyzes the biopterin-dependent monooxygenation of tryptophan to 5-hydroxytryptophan (5HT), which is subsequently decarboxylated to form the neurotransmitter serotonin. It is thus the rate-limiting enzyme in the biosynthesis of serotonin. TPH expression is limited to a few specialized tissues: raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta-cells of the islets of Langerhans, and intestinal and pancreatic enterochromaffin cells.
Stoll et al. (1990) isolated a cDNA for tryptophan hydroxylase (Tph) from a library constructed from RNA prepared from a mouse mastocytoma cell line. Boularand et al. (1990) gave the sequence of a cDNA clone containing the complete coding sequence of TPH.
Matsuda et al. (2004) found that mouse mammary glands stimulated by prolactin (176760) expressed genes essential for serotonin biosynthesis, including Tph. Tph mRNA was elevated during pregnancy and lactation, and serotonin was detected in the mammary epithelium and in milk. Tph was induced by prolactin in mammosphere cultures and by milk stasis in nursing dams, suggesting that expression of TPH is controlled by milk filling in the alveoli. Serotonin suppressed beta-casein (115460) expression and caused shrinkage of mammary alveoli. Conversely, disruption of the Tph gene or antiserotonergic drugs enhanced secretory features and alveolar dilation. Matsuda et al. (2004) concluded that autocrine-paracrine serotonin signaling is an important regulator of mammary homeostasis and early involution.
The liver can regenerate its volume after major tissue loss. Lesurtel et al. (2006) showed that in a mouse model of liver regeneration, thrombocytopenia resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A (182135) and 2B (601122) subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking TPH1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. Lesurtel et al. (2006) concluded that platelet-derived serotonin is involved in the initiation of liver regeneration.
Loss- and gain-of-function mutations in mouse Lrp5 (603506) affect bone formation, causing osteoporosis and high bone mass, respectively. Yadav et al. (2008) identified Tph1 as the most highly overexpressed gene in Lrp5 -/- mice. Tph1 expression was also elevated in Lrp5 -/- duodenal cells, its primary site of expression. Decreasing serotonin blood levels normalized bone formation and bone mass in Lrp5 -/- mice, and gut-specific Lrp5 inactivation decreased bone formation in a beta-catenin (CTNNB1; 116806)-independent manner. Moreover, gut-specific activation of Lrp5 or inactivation of Tph1 increased bone mass and prevented ovariectomy-induced bone loss in mice. Yadav et al. (2008) showed that serotonin determined the extent of bone formation by binding its receptor, Htr1b (182131), on osteoblasts and limiting osteoblast proliferation by inhibiting Creb (see 123810)-mediated cyclin D1 (CCND1; 168461) expression. Yadav et al. (2008) concluded that LRP5 inhibits bone formation by inhibiting serotonin production.
To examine putative central and peripheral sources of embryonic brain 5-HT (serotonin), Bonnin et al. (2011) used Pet1 (FEV; 607150)-null mice in which most dorsal raphe neurons lack 5-HT. They detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, Bonnin et al. (2011) investigated the nature of this exogenous source and uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. The mouse placenta expresses both Tph1 and Aadc (608643) in the syncytiotrophoblastic cell layer at embryonic days 10.5 through 14.5. Human placental fetal villi at 11 weeks' gestation showed robust 5-HT neosynthesis, indicating that a placental source of 5-HT is important for human fetal development. Bonnin et al. (2011) concluded that their study revealed a new, direct role for placental metabolic pathways in modulating fetal brain development and indicated that maternal-placental-fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.
Gizatullin et al. (2006) noted that the TPH1 gene spans 29 kb and contains 11 exons.
Using a clone for rabbit tryptophan hydroxylase as a probe in the study of a panel of hamster-human somatic cell hybrids, Ledley et al. (1987) assigned the gene to chromosome 11. They discussed the evolution of the aromatic amino acid hydroxylase superfamily, which also includes TH (191290), located at 11p15.5, and phenylalanine hydroxylase (612349), located at 12q24.1. The locations of these genes and their evolutionary distance (as indicated by their sequences) suggested to Ledley et al. (1987) that at least 3 distinct genetic events have occurred during the evolution of this superfamily: 2 sequential gene duplications giving rise to 3 distinct loci, and a translocation which separated the tryptophan and tyrosine hydroxylase loci on chromosome 11 from the phenylalanine hydroxylase locus on chromosome 12. HGM9 regionalized the assignment to 11p15-p13. Craig et al. (1991) regionalized the assignment to 11p15.3-p14 by in situ hybridization.
By examining introns of the human TPH gene by PCR amplification and analysis by the single-strand conformational polymorphism (SSCP) technique, Nielsen et al. (1992) identified an informative intronic polymorphism useful in linkage studies. Using this polymorphism in 24 informative CEPH families, they showed that TPH lies between D11S151 and D11S134.
Stoll et al. (1990) mapped the mouse Tph gene by Southern blot analysis of somatic cell hybrids and by an interspecific backcross to a position in the proximal half of chromosome 7. Thus, this is another example of homology of synteny between human chromosome 11 and mouse chromosome 7.
Bellivier et al. (2004) conducted a metaanalysis of 9 association studies (961 patients and 1,485 controls) of the relationship between the A218C polymorphism of the TPH gene and suicidal behavior. A significant association was observed between this polymorphism and suicidal behavior using the fixed effect method (odds ratio, 1.62; 95% CI, 1.26; 2.07) and in the random effect method (odds ratio = 1.61; CI, 1.11; 2.35). When 2 of the studies that deviated from the calculated global effect were removed, significant association remained. A dose-dependent effect of the A allele on the risk for suicidal behavior was observed.
Stefulj et al. (2006) studied the TPH1 A218C polymorphism in 247 male victims of violent suicide and 320 controls of Slavic (Croatian) origin, with specific relation to age. The frequency of the CC genotype was increased in victims aged 65 and older as compared to controls (p = 0.0126 and 0.0008, for comparison with age-specific and integral control samples, respectively), while there was no difference between victims under age 65 and controls. The authors suggested a possible combined effect of the genetic factor and physiologic changes due to aging on the predisposition to violent suicide.
In a metaanalysis of 34 case-control studies from 21 published articles and an unpublished paper, Li and He (2006) found an overall association between suicidal behavior and the TPH A779C/A218C polymorphisms. The A allele was the risk allele for both polymorphisms, yielding an odds ratio of 1.12 overall for carriers of both A alleles. Sand (2007) commented that the report of Li and He (2006) used pooled populations, pooled SNP frequencies, imprecise phenotypes, and redundant reports, and questioned the finding of allelic association.
Gizatullin et al. (2006) screened TPH1 SNPs spanning over 23 kb (promoter to exon 8) in 228 patients with major depression (608516) and 253 healthy control subjects. Several haplotypes were associated with depression, and the 6-SNP haplotypes that occurred in less than 5% of both groups were associated with the disease (31.6% vs 18.0% in controls, p less than 0.00005). A sliding window analysis attributed the strongest disease association to a 2-SNP haplotype comprising rs1799913 (A779C) and rs7933505 localized between intron 7 and 8 (p less than 0.00005). Gizatullin et al. (2006) concluded that the most common variants appear not to carry risk while some less frequent variants might contribute to major depression.
Li et al. (2006) examined the relationship between the A218C and A-6526G polymorphisms of the TPH1 gene and attention deficit-hyperactivity disorder (ADHD; 143465) in the Chinese Han population; 362 unrelated ADHD probands and their biologic parents were studied. No biased transmission of any allele of the 2 polymorphisms was associated by transmission disequilibrium test (TDT) analysis. However, haplotype analysis showed that the rare 218A/-6526G haplotype was significantly not transmitted to probands with ADHD (chi square = 4.4995, p = 0.034), regardless of subtype.
Allen et al. (2008) performed a metaanalysis across all ancestries comparing 829 patients with schizophrenia with 1,268 controls and found that the A versus C allele at position 218 in intron 7 (rs1800532) of the TPH1 gene was associated with susceptibility to schizophrenia (OR, 1.31; 95% CI, 1.15-1.51; p less than 8(-5)). According to the Venice guidelines for the assessment of cumulative evidence in genetic association studies (Ioannidis et al., 2008), the TPH1 association showed a 'strong' degree of epidemiologic credibility.
Walther et al. (2003) developed Tph-null mice. Mutant mice showed no significant differences in 5HT-related behaviors and expressed normal amounts of 5HT in classical serotonergic brain regions. However, Tph-null mice lacked 5HT in the periphery, except for the duodenum. Using RNAse protection assays, they determined that Tph2 (607478) is the predominant isoform expressed in mouse brain.
Walther et al. (2003) found that mice selectively deficient in peripheral Tph and serotonin exhibited impaired hemostasis, resulting in a reduced risk of thrombosis and thromboembolism, although platelet ultrastructure was not affected. While the aggregation of serotonin-deficient platelets in vitro was apparently normal, their adhesion in vivo was reduced due to reduced secretion of adhesive alpha-granular proteins. Walther et al. (2003) showed that serotonin was transamidated to small GTPases by transglutaminases (see TGM2; 190196) during activation and aggregation of platelets, rendering these GTPases constitutively active.
Using lymphocytic choriomeningitis virus in a Cd8 (see 186910)-positive T cell-dependent mouse model of immunopathologic hepatitis, Lang et al. (2008) showed that Tph1-deficient mice, but not wildtype mice, normalized hepatic microcirculatory dysfunction, accelerated clearance of virus from liver, and reduced Cd8-positive T cell-dependent liver cell damage. In contrast, serotonin treatment of infected wildtype mice delayed entry to liver of Cd8-positive T cells, delayed viral clearance, and aggravated liver immunopathology. Lang et al. (2008) concluded that vasoactive serotonin supports virus persistence in liver and aggravates virus-induced immunopathology.
Allen, N. C., Bagade, S., McQueen, M. B., Ioannidis, J. P. A., Kavvoura, F. K., Khoury, M. J., Tanzi, R. E., Bertram, L. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature Genet. 40: 827-834, 2008. [PubMed: 18583979] [Full Text: https://doi.org/10.1038/ng.171]
Bellivier, F., Chaste, P., Malafosse, A. Association between the TPH gene A218C polymorphism and suicidal behavior: a meta-analysis. Am. J. Med. Genet. 124B: 87-91, 2004. [PubMed: 14681922] [Full Text: https://doi.org/10.1002/ajmg.b.20015]
Bonnin, A., Goeden, N., Chen, K., Wilson, M. L., King, J., Shih, J. C., Blakely, R. D., Deneris, E. S., Levitt, P. A transient placental source of serotonin for the fetal forebrain. Nature 472: 347-350, 2011. [PubMed: 21512572] [Full Text: https://doi.org/10.1038/nature09972]
Boularand, S., Darmon, M. C., Ganem, Y., Launay, J.-M., Mallet, J. Complete coding sequence of human tryptophan hydroxylase. Nucleic Acids Res. 18: 4257 only, 1990. [PubMed: 2377472] [Full Text: https://doi.org/10.1093/nar/18.14.4257]
Craig, S. P., Boularand, S., Darmon, M. C., Mallet, J., Craig, I. W. Localization of human tryptophan hydroxylase (TPH) to chromosome 11p15.3-p14 by in situ hybridization. Cytogenet. Cell Genet. 56: 157-159, 1991. [PubMed: 2055111] [Full Text: https://doi.org/10.1159/000133075]
Gizatullin, R., Zaboli, G., Jonsson, E. G., Asberg, M., Leopardi, R. Haplotype analysis reveals tryptophan hydroxylase (TPH) 1 gene variants associated with major depression. Biol. Psychiat. 59: 295-300, 2006. [PubMed: 16165107] [Full Text: https://doi.org/10.1016/j.biopsych.2005.07.034]
Ioannidis, J. P., Boffetta, P., Little, J., O'Brien, T. R., Uitterlinden, A. G., Vineis, P., Balding, D. J., Chokkalingam, A., Dolan, S. M., Flanders, W. D., Higgins, J. P., McCarthy, M. I., McDermott, D. H., Page, G. P., Rebbeck, T. R., Seminara, D., Khoury, M. J. Assessment of cumulative evidence on genetic associations: interim guidelines. Int. J. Epidemiol. 37: 120-132, 2008. [PubMed: 17898028] [Full Text: https://doi.org/10.1093/ije/dym159]
Lang, P. A., Contaldo, C., Georgiev, P., El-Badry, A. M., Recher, M., Kurrer, M., Cervantes-Barragan, L., Ludewig, B., Calzascia, T., Bolinger, B., Merkler, D., Odermatt, B., and 10 others. Aggravation of viral hepatitis by platelet-derived serotonin. Nature Med. 14: 756-761, 2008. [PubMed: 18516052] [Full Text: https://doi.org/10.1038/nm1780]
Ledley, F. D., Grenett, H. E., Bartos, D. P., van Tuinen, P., Ledbetter, D. H., Woo, S. L. C. Assignment of human tryptophan hydroxylase locus to chromosome 11: gene duplication and translocation in evolution of aromatic amino acid hydroxylases. Somat. Cell Molec. Genet. 13: 575-580, 1987. [PubMed: 2889273] [Full Text: https://doi.org/10.1007/BF01534499]
Lesurtel, M., Graf, R., Aleil, B., Walther, D. J., Tian, Y., Jochum, W., Gachet, C., Bader, M., Clavien, P.-A. Platelet-derived serotonin mediates liver regeneration. Science 312: 104-107, 2006. [PubMed: 16601191] [Full Text: https://doi.org/10.1126/science.1123842]
Li, D., He, L. Further clarification of the contribution of the tryptophan hydroxylase (TPH) gene to suicidal behavior using systematic allelic and genotypic meta-analyses. Hum. Genet. 119: 233-240, 2006. [PubMed: 16450114] [Full Text: https://doi.org/10.1007/s00439-005-0113-x]
Li, J., Wang, Y., Zhou, R., Zhang, H., Yang, L., Wang, B., Faraone, S. V. Association between tryptophan hydroxylase gene polymorphisms and attention deficit hyperactivity disorder in Chinese Han population. Am. J. Med. Genet. 141B: 126-129, 2006. [PubMed: 16389593] [Full Text: https://doi.org/10.1002/ajmg.b.30260]
Matsuda, M., Imaoka, T., Vomachka, A. J., Gudelsky, G. A., Hou, Z., Mistry, M., Bailey, J. P., Nieport, K. M., Walther, D. J., Bader, M., Horseman, N. D. Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev. Cell 6: 193-203, 2004. [PubMed: 14960274] [Full Text: https://doi.org/10.1016/s1534-5807(04)00022-x]
Nielsen, D. A., Dean, M., Goldman, D. Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism. Am. J. Hum. Genet. 51: 1366-1371, 1992. [PubMed: 1463016]
Sand, P. G. Comments on the paper by D. Li and L. He: meta-analysis showed association between the tryptophan hydroxylase (TPH) gene and schizophrenia. (Letter) Hum. Genet. 122: 409-411, 2007. [PubMed: 17653577] [Full Text: https://doi.org/10.1007/s00439-007-0383-6]
Stefulj, J., Kubat, M., Balija, M., Jernej, B. TPH gene polymorphism and aging: indication of combined effect on the predisposition to violent suicide. Am. J. Med. Genet. 141B: 139-141, 2006. [PubMed: 16389591] [Full Text: https://doi.org/10.1002/ajmg.b.30271]
Stoll, J., Kozak, C. A., Goldman, D. Characterization and chromosomal mapping of a cDNA encoding tryptophan hydroxylase from a mouse mastocytoma cell line. Genomics 7: 88-96, 1990. [PubMed: 2110547] [Full Text: https://doi.org/10.1016/0888-7543(90)90522-v]
Walther, D. J., Peter, J.-U., Bashammakh, S., Hortnagl, H., Voits, M., Fink, H., Bader, M. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299: 76 only, 2003. [PubMed: 12511643] [Full Text: https://doi.org/10.1126/science.1078197]
Walther, D. J., Peter, J.-U., Winter, S., Holtje, M., Paulmann, N., Grohmann, M., Vowinckel, J., Alamo-Bethencourt, V., Wilhelm, C. S., Ahnert-Hilger, G., Bader, M. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell 115: 851-862, 2003. [PubMed: 14697203] [Full Text: https://doi.org/10.1016/s0092-8674(03)01014-6]
Yadav, V. K., Ryu, J.-H., Suda, N., Tanaka, K. F., Gingrich, J. A., Schutz, G., Glorieux, F. H., Chiang, C. Y., Zajac, J. D., Insogna, K. L., Mann, J. J., Hen, R., Ducy, P., Karsenty, G. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135: 825-837, 2008. [PubMed: 19041748] [Full Text: https://doi.org/10.1016/j.cell.2008.09.059]