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TPH1 (tryptophan hydroxylase 1)

Written2020-03Rafig Gurbanov, Sevinç Karaçam
Bilecik Şeyh Edebali University, Department of Molecular Biology and Genetics Bilecik Şeyh Edebali University, Biotechnology Application and Research Center; rafig.gurbanov@bilecik.edu.tr (RG); Bilecik Şeyh Edebali University, Department of Biotechnology, Bilecik Şeyh Edebali University, Biotechnology Application and Research Center; karacamsevinc@gmail.com (SK)

Abstract Tryptophan hydroxylase 1 gene (TPH1) encodes a rate-limiting enzyme in the biosynthesis of the monoamine neurotransmitter serotonin. TPH1 is expressed in peripheral tissues such as the heart, lung, kidney, duodenum and adrenal gland, as well as in female reproductive tissues. The mutations in this gene have been associated with various diseases with high risk, including, schizophrenia, somatic anxiety, anger-related features, bipolar disorder, suicidal behavior, and several addictions.

Keywords Tryptophan hydroxylase 1, Alzheimer's Disease, Serotonin, Intestine, Inflammation, Suicide, Schizophrenia, Bipolar disorder

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Identity

Alias (NCBI)TRPH
TPH
TPRH
HGNC (Hugo) TPH1
HGNC Alias nametryptophan 5-monooxygenase
HGNC Previous nameTPRH
 TPH
HGNC Previous nametryptophan hydroxylase (tryptophan 5-monooxygenase)
LocusID (NCBI) 7166
Atlas_Id 51272
Location 11p15.1  [Link to chromosome band 11p15]
Location_base_pair Starts at 18017555 and ends at 18046269 bp from pter ( according to hg19-Feb_2009)  [Mapping TPH1.png]
Local_order shown in Chromosome 11 - NC_000011.10 Reference GRCh38.p13 Primary Assembly.
 
  Figure 1. Genomic location of TPH1 gene (Chromosome 11 - NC_000011.10 Reference GRCh38.p13 Primary Assembly)
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Description The gene spans a region of 29 kilobases (kb) and consists of 11 exons.
Transcription The gene has 4 transcripts (Table 1).
Table 1. Transcripts of the human TPH1 gene (Ensemble, GRCh38: CM000673.2).
NameTranscript IDbpProteinTranslation IDBiotypeCCDSUniProtRefSeq MatchFlags
TPH1-201ENST00000250018.65325444aaENSP00000250018.2Protein codingCCDS7829P17752-TSL:1GENCODE basicAPPRIS P1
TPH1-204ENST00000528338.1556165aaENSP00000436081.1Protein coding-E9PR49-CDS 3' incompleteTSL:3
TPH1-202ENST00000417164.51138206aaENSP00000403831.1Nonsense mediated decay-E7EMX4-TSL:1
TPH1-203ENST00000525406.1461No protein-lncRNA---TSL:5

Single nucleotide polymorphisms (SNPs) found in the human TPH1 gene were given in Table 2.
Table 2. Single nucleotide polymorphisms (SNPs) of the human TPH1 gene (Lai et al. 2005).
SNP name (Genomic localization)Position in the geneSNP IDPCR primers and short-extension probe
5'flankingSNP1 (T-1721G)5' flanking regionSNP000574351F: 5'-ctgttcttttggtgtcctc-3'
R:5'-gctcctggcacttaacata-3'
P: 5'-taatttctttcatgagtattttatagtt
5'flankingSNP2 (A-1067G)5' flanking regionSNP000574353F: 5'-ctgttcttttggtgtcctc-3'
R: 5'-gctcctggcacttaacata-3'
P: 5'-ttttttgctgagtatggatgtactttaaagctcagga
5'flankingSNP3 (G-347T)5' flanking regionSNP000574354F: 5'-cgataataggcgttatcttg-3'
R: 5'-ctcaatctctgcgtgtatct-3'
P: 5'-tcaggactgggctattaaatagcccagaagcacagaga
in1SNP1 (T3804A)Intron 1 (exon 1c)rs623580F: 5'-taattatcctccctccaagt-3' R: 5'-cttacccattcaattaccac-3'
P: 5'-agagtatgggcgacgttgtccta
in2SNP1 (G7465A)Intron 2rs684302F: 5'-tgctcttatatgtcttttcaagt-3'
R: 5'-gagagatggagcaaaacac-3'
P: 5'-ttaaataaaatacctgtatgtcttcttccatca
in3SNP1 (A12517C)Intron 3rs211105F: 5'-tcaggaaaacagaagggta-3'
R: 5'-ggtaaattgccctatttctaa-3'
P: 5'-aggtggcaaagacaaatgatttctaagatcttttccatcggc
in6SNP1 (C18626G)Intron 6rs2237907F: 5'-gggaagaaattatgtaagtgg-3'
R: 5'-gaaatgttccatatctgtgc-3'
P: 5'-ttgtaatgcacacaaaactgaaagctgatctcttagggtctggagc
in7SNP1 (A20004C)dIntron 7rs1800532CF: 5'-acccacctacactttcctc-3' CR: 5'-taattgacaacctattaggttc-3'
AR: 5'-agcacatgtgaagcatttag-3'
AF: 5'-cctatgctcagaatagcagctct-3'
3'UTRSNP1 (C27224T)3' UTRrs2108977F: 5'-cacttgaatatcacagtccatc-3'
R: 5'-gcttacagtagatttccttgc-3'
P: 5'-tacatttgatggtaaatagatgctagctaatct
3'UTRSNP2 (A27237G)3' UTRNewF: 5'-cacttgaatatcacagtccatc-3'
R: 5'-gcttacagtagatttccttgc-3'
P: 5'-aactataaatcagataatcaata

The genotypic and allelic distribution of the TPH1 gene is listed in Table 3.
Table 3. The genotypic and allelic distribution of the TPH1 gene (Lai et al. 2005).
MarkerGroup (Total Number)Genotype (frequency)Allele (frequency)
1-11-22-2χ2p value12χ2p value
T-1721GN(94)54(.57)37(.39)3(.03)2.720.248145(.77)43(.23)0.360.548
 P(92)53(.58)31(.34)8(.09)  137(.75)47(.26)  
A-1067GN(90)53(.59)34(.38)3(.03)1.620.446140(.78)40(.22)0.740.389
 P(92)51(.55)34(.37)7(.08)  136(.74)48(.26)  
G-347TN(102)58(.57)43(.42)1(.01)0.0480.976159(.78)45(.22)0.0370.847
 P(94)52(.55)41(.44)1(.01)  145(.77)43(.23)  
T3804AN(101)56(.55)38(.38)7(.07)2.170.304152(.74)52(.26)0.0150.946
 P(96)49(.51)44(.46)3(.03)  142(.74)50(.26)  
G7465AN(100)31(.31)43(.43)26(.26)0.460.793105(.53)95(.48)0.4390.508
 P(74)25(.34)33(.45)16(.22)  83(.56)65(.44)  
A12517CN(101)58(.57)39(.39)4(.04)0.2320.890155(.77)47(.23)0.2070.649
 P(96)58(.60)35(.37)3(.03)  151(.79)41(.21)  
C18626GN(100)28(.28)47(.47)25(.25)1.240.538103(.52)97(.49)0.3920.531
 P(71)25(.35)28(.39)18(.25)  78(.55)64(.45)  
A20004CN(102)40(.39)45(.44)17(.17)1.7260.422125(.61)79(.39)1 7950.18
 P(89)29(.32)39(.44)21(.24)  97(.54)81(.46)  
C27224TN(95)31(.33)49(.52)15(.16)3.580.167111(.58)79(.42)2.130.144
 P(80)23(.29)35(.44)22(.28)  81(.51)79(.49)  
A27237GN(95)49(.52)40(.42)6(.06)0.570.751138(.73)52(.27)0.6770.411
 P(78)37(.47)34(.44)7(.09)  107(.69)49(.34)  

N indicates the matched normal controls, P indicates the bipolar patients.
1 represents the major allele and 2 the minor allele

Protein

Description Size: 444 amino acids; Molecular mass: 50985 Da; Cofactor: Fe (2+); Xref=ChEBI:CHEBI:29033; Quaternary structure: Homotetramer
Protein properties for TPH1 Gene: TPH1 is a rate-limiting enzyme in the biosynthesis of serotonin. It catalyzes the biotin-dependent monooxygenation of tryptophan to 5-hydroxytryptophan (5HTP), then decarboxylates to form the neurotransmitter serotonin. The gene is localized on the human chromosome 11p15.3-p14, is about 29 kb long and contains 11 exons (Craig et al. 1991). Jonsson et al. (1997) identified single nucleotide polymorphisms (SNPs) A218C (rs1800532) and A779C (rs1799913) in intron 7 of the TPH1 gene. Mutations in this gene have been associated with high risk for various diseases and disorders such as schizophrenia, somatic anxiety, anger-related features, bipolar disorder, suicidal behavior, and several addictions (https://www.ncbi.nlm.nih.gov/gene).
 
  Figure 2. The possible mechanisms for microbial regulation of tryptophan and 5HT release (Simplified from Gheorghe et al. 2019).
Expression TPH1 gene is expressed in peripheral tissues such as heart, lung, kidney, duodenum and adrenal gland and female reproductive tissues (http://www.proteinatlas.org).
Function Remarkably, about 90% of the total serotonin of the human body is found in neuroendocrine enterochromaffin cells (EC) in the human gastrointestinal (GI) tract, where it is used to regulate bowel movements (Lukiw and Rogaev, 2017). The mouse mammary glands stimulated by prolactin (176760) express the genes necessary for serotonin biosynthesis, including TPH1 (Matsuda et al. 2004). The TPH1 mRNA increased during pregnancy and lactation, and serotonin was detected in breast epithelium and milk. It has been observed that serotonin suppresses beta-casein (115460) expression and causes contraction of breast alveoli. Accordingly, Matsuda et al. (2004) concluded that autocrine-paracrine serotonin signaling is an important regulator of breast homeostasis and early evolution (Matsuda et al. 2004).
The liver is an organ that can regenerate its volume after major tissue loss. Lesurtel et al. (2006) showed that mouse thrombocytopenia leads to the inhibition of cellular proliferation in the liver (Lesurtel et al. 2006). Thrombocytes are the main carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist has been observed to regenerate liver proliferation (Gershon and Tack, 2007). The expression of HT2A (182135) and HT2B (601122) serotonin receptor subtypes has been observed to increase in the liver after hepatectomy. Antagonists of these receptors have been shown to inhibit liver regeneration. Liver regeneration has also been disrupted in mice lacking TPH1, the rate-limiting enzyme for the synthesis of peripheral serotonin. Since thrombocytes contain most of the circulating serotonin, and serotonin is released by thrombocyte aggregation, inactivation of TPH1 function is assumed to lead to severe blood clotting defects (Gershon and Tack, 2007).
Loss- and gain-of-function mutations in mouse low-density lipoprotein receptor-related protein 5 ( LRP5) gene affected bone formation, leading to osteoporosis and increased bone mass, respectively. Yadav et al. (2008) described the TPH1 as the most over-expressed gene in LRP5 - / - mice and concluded that LRP5 suppresses bone formation by inhibiting serotonin production (Yadav et al. 2008). Enterochromaffin cells (EC) synthesize intestinal serotonin (5HT). LRP5 controls 5HT synthesis by negatively regulating TPH1 expression in these cells. When 5HT is released in the blood, it negatively regulates bone formation during bone remodeling process (Ducy and Karsenty, 2010).
Since 5HT is produced in the gut, its effects on the intestinal microbiota are inevitable. There is a significant difference in the composition of the gut microbiota depending on whether the TPH1 is knocked out and whether the progenitors are heterozygous or homozygous for this gene. Besides, there is evidence that 5HT directly modulates the growth of commensal bacteria (Kwon et al. 2019). The combination of microbial and host gastrointestinal metabolism of tryptophan is likely an important factor in the systemic availability of tryptophan, as well as levels of indoles, kynurenine and local 5HT (Roager and Licht, 2018). The possible mechanisms for microbial regulation of tryptophan and 5HT release are shown in Figure 2 (Gheorghe et al. 2019).

Mutations

Note The main mutations in the human TPH1 gene were given in Table 4.
Table 4. Mutations of the human TPH1 gene (http://www.hgmd.cf.ac.uk).
Missense/nonsense mutation
AccessionHGMD codon changeHGMD amino acid changeHGVS (nucleotide)HGVS (protein)Variant classPhenotypeReferenceSource
CM109141AAA-CAALys54Glnc.160A>Cp.K54QDisease-causing mutations (DM)Attention deficit hyperactivity disorderHalmøy (2010) Arch Gen Psychiatry 67:1033PubMed 20921119
CM109142CGT-TGTArg142Cysc.424C>Tp.R142CDisease-causing mutations (DM)Attention deficit hyperactivity disorderHalmøy (2010) Arch Gen Psychiatry 67:1033PubMed 20921119
CM109143CGA-TGAArg145Termc.433C>Tp.R145*Disease-causing mutations (DM)Attention deficit hyperactivity disorderHalmøy (2010) Arch Gen Psychiatry 67:1033PubMed 20921119
CM109149GTA-ATAVal177Ilec.529G>Ap.V177IDisease-causing mutations (DM) ?Attention deficit hyperactivity disorderHalmøy (2010) Arch Gen Psychiatry 67:1033PubMed 20921119
CM109145CTC-ATCLeu274Ilec.820C>Ap.L274IDisease-causing mutations (DM)Attention deficit hyperactivity disorderHalmøy (2010) Arch Gen Psychiatry 67:1033PubMed 20921119
CM109146GCT-ACTAla300Thrc.898G>Ap.A300TDisease-causing mutations (DM)Attention deficit hyperactivity disorderHalmøy (2010) Arch Gen Psychiatry 67:1033PubMed 20921119
CM187494CGT-CATArg395Hisc.1184G>Ap.R395HDisease-causing mutations (DM) ?Mood dysregulation disorderUngar (2018) Am J Med Genet A 176:1432PubMed 29696773
CM109144ATC-AACIle410Asnc.1229T>Ap.I410NDisease-causing mutations (DM)Attention deficit hyperactivity disorderHalmøy (2010) Arch Gen Psychiatry 67:1033PubMed 20921119
Splicing mutation
AccessionHGMD codon changeHGMD amino acid changeHGVS(nucleotide)HGVS (dbSNP number)Variant classPhenotypeReferenceSource
CS034323IVS6 ds C-A +221 not yet availablec.803+221C>Ars1800532Disease-associated polymorphisms  (DP)Depression, association withTsai (1999) Neuroreport 10:3773PubMed 10716208
Regulatory mutation
AccessionHGMD codon changeHGMD amino acid changeHGVS (nucleotide)HGVS (dbSNP number)Variant classPhenotypeReferenceSource
CR1314899GGGCTATTAAATAGCCCA
GAAGCACAGAGA(T-G)GT
GTGGGAGGTGGGGGGATT
CTTGCTTTGG 
-5854 relative to initiation codon
 not yet available not yet availablers7130929Disease-associated polymorphisms  (DP)Irritable bowel syndrome, diarrhoea predominant, association withGrasberger(2013) Am J Gastroenterol 108:1766PubMed 24060757
Small deletion
AccessionHGMD codon changeHGMD amino acid changeHGVSHGVS (dbSNP number)Variant classPhenotypeReferenceSource
CD166898CAGATACATGactTCAGTTCTTA non-coding region not yet availablec.*1342_*1344delACTrs60273374Disease-causing mutations (DM) ?Attention deficit hyperactivity disorder, persistentDemontis (2016) J Am Acad Child Adolesc Psychiatry 55:521PubMed 27238071

Implicated in

  
Entity Breast Cancer
Note TPH1 was analyzed in histological samples to learn about the possible relationship between changing 5HT synthesis and human breast cancer progression. TPH1 is evenly distributed in the epithelial stroma in normal breast tissue and epithelial TPH1 is markedly stained. Compared to healthy breast cell lines, TPH1 staining intensity increased significantly in cancerous cell lines (Pai et al. 2009).
  
  
Entity Alzheimer's disease (AD)
Note It was observed that the amount of serotonin increased 4 times in raphe cell bodies and decreased 0.4-fold in amygdala synaptic ends in Alzheimer's disease (AD) cases compared to controls. As a result of the accumulation of oxidative metabolites of serotonin and reduced transport of TPH to the axon terminals, TPH and its products are accumulated in the perikarya of raphe neurons, which may lead to the degeneration of serotonergic neurons in AD (Lukiw and Rogaev, 2017). In one study, fifty percent of patients showed agitation/aggression in response to the NPI screening question. A significant relationship was observed between agitation/aggression in male subjects carrying the C allele of the TPH1 gene. A218C polymorphism in this gene is linked to aggression and irritability in men. Given this, it was concluded that the agitated and aggressive behavior in AD is associated with the polymorphic variation in the TPH1 gene in men. According to these results, TPH (TPH1, chr11p15.1, and TPH2, chr12q21.1) gene is considered as one of the six genes frequently seen in AD and aggression (Lukiw and Rogaev, 2017).
  
  
Entity Suicidal behavior (SB)
Note Three polymorphisms of the TPH1 gene, a potential GATA transcription factor binding site A218C, A779C located in intron 7, and A6526G located in the promoter region, were studied in patients with suicide attempts (Mirkovic et al. 2016). The A allele of A218C was found to be more common in suicide attempts than in patients who did not attempt suicide (Mirkovic et al. 2016). AA genotypes in the intron 7 and promoter region were associated with increased suicide attempts (Galfalvy et al. 2009). A relationship between the C allele of A218C and suicidal behavior (SB) was found only in people over 65 years of age (Stefulj et al. 2006). A significant relationship between suicide risk and AA218C SNP allele has been reported in Caucasian populations (Bellivier et al. 2004). There is a strong relationship between SB and A779C / A218C polymorphisms in both European and Asian populations (Mirkovic et al. 2016). The prevalence of TPH1 A218C polymorphism was evaluated in a Turkish population and a significant relationship was found between the A allele and SB (Beden et al. 2016). It was shown that not only the AA genotype but also the CC genotype was significantly associated with suicide risk and depression (Zalsman et al. 2001). On the other hand, some studies have reported that A218C genotypes are not related to the suicide attempt. A multi-center case-control study and meta-analysis showed that the A218/A779 locus increased sensitivity to schizophrenia and contributed to psychiatric disorders characterized by high suicide rates rather than affecting suicide (Beden et al. 2016). Although it was not associated with SB, there was a significant relationship between bipolar disorder (BPD) and small alleles of A218C in individuals with psychiatric disorders (Beden et al. 2016).
  
  
Entity Schizophrenia
Note A study conducted with 837 Scandinavian schizophrenic patients and 1473 healthy individuals revealed that three of the five SNPs tested are associated with schizophrenia sensitivity including A218C and A779C polymorphisms (Saetre et al. 2010). However, it has been shown that there is no difference in the allele frequencies of these loci among people who have attempted suicide at least once and have no history of a suicide attempt (Saetre et al. 2010). Although TPH1 is expressed mainly in peripheral tissues, its variants have been reported to be frequently associated with psychiatric disorders. The TPH1 gene, shown in Figure 3, is a strong candidate gene for schizophrenia (Halmøy et al. 2010).
 
Figure 3. Representation of TPH1 and other Schizophrenia-associated candidate genes (green-colored) located on Chromosome 11 (http://www.szgene.org/chromo.asp?c=11).
  
  
Entity Aggressive Behavior
Note The A218C and A779C SNPs (usually called U/top and L/bottom alleles) found in the intron of the TPH1 gene are associated with different aggression evaluated by interview and self-reporting questionnaires (Rujescu et al. 2002). Lower cerebrospinal fluid (CSF) 5-Hydroxyindoleacetic acid (5-HIAA) levels were observed in healthy men with the U allele (Jonsson et al. 1997), while the lowest CSF 5-HIAA levels were observed in LL carriers diagnosed with antisocial alcoholism (Nielsen et al. 1994). Both U and L alleles were thought to be associated with different types of aggressiveness (Quadros et al. 2010). Individuals with a UU allele have been shown to have more aggressive hostility but slightly lower neurotic hostility (New et al. 1998). Individuals with a UU allele have been shown to have more aggressive hostility but slightly lower neurotic hostility (New et al. 1998). A higher level of impulsivity was found in tests that focused on neurotic hostility for LL homozygous individuals (Hennig et al. 2005). Genetic studies show that the polymorphism in both alleles (L and U) of the TPH1 gene is associated with human aggression, but each allele is associated with a different type of aggression (Quadros et al. 2010).
  
  
Entity Major depressive disorder (MDD)
Note The frequency of TPH1 C allele and CC homozygous in patients with Major depressive disorder (MDD) was higher than healthy individuals with the same genotype. According to the results of the verbal aggression and aggression questionnaire, TPH1 CC homozygotes in the MDD group scored significantly higher than the A carrier genotypes. It has been revealed that there is a relationship between the frequency of this polymorphism, aggression, and MDD (Frodl, 2016).
Vitamin D activates a series of processes that are critical for maintaining normal healthy neurons, also preventing the onset of depression. Where vitamin D enters the nucleus, it joins with the retinoid X receptor (RXR) and then binds to the vitamin D response element (VDRE) found on a large number of genes. Eventually, Ca2+ homeostasis is maintained by inducing the expression of the calcium-binding proteins (calbindin and parvalbumin), SLC8A1 (Na2+/Ca2+ exchanger1 NCX1) and cell membrane Ca2+ ATPase (PMCA) pump (ATP2B1 to 4 genes). Besides, vitamin D regulates Ca2+ levels by reducing the expression of the voltage-dependent calcium channel CaV1.2. In this case, TPH1 is suppressed and serotonin formation is controlled by increasing the TPH2 level. Reduced expression of inflammatory cytokines diminishes inflammation as well (Figure 4). By binding to its receptor ( VDR), vitamin D also regulates the expression of many mitochondrial proteins that maintain mitochondrial respiration (Berridge, 2017).
 
Figure 4. Vitamin D signaling affecting TPH1 expression in depression (Simplified from https://www.wikipathways.org/index.php/Pathway:WP4698).
  
  
Entity Somatoform Disorders
Note Genes in the serotonergic hypofunction and serotonergic pathway were thought to be associated with symptoms of somatoform disorders (Frodl, 2016). This hypothesis has been studied using a variety of serotonin-related gene polymorphisms to determine whether the undifferentiated somatoform disorder is associated with specific serotonin-related gene pathways. 102 patients with the undifferentiated somatoform disorder and 133 healthy individuals were examined. It was emphasized that patients with undifferentiated somatoform disorder had a higher frequency of TPH1 (A218C) C-allele than healthy controls, but this difference was not significant after Bonferroni correction. These findings indicate that serotonin-related gene pathways are unlikely to be genetic risk factors for the undifferentiated somatoform disorder (Frodl, 2016).
  
  
Entity Middle Insomnia
Note A study found a relationship between TPH1 and middle insomnia. The serotonergic pathway plays an important role in the regulation of circadian rhythm, sleep, and wakefulness. Serotonergic axon release is high during wakefulness, decreases during non-rapid eye movement (NREM) sleep, and is absent during rapid eye movement (REM) sleep (Ursin R, 2002). TPH activity is most abundant in brain raphe, gut, and pineal gland where N-acetyltransferase converts serotonin to melatonin (Patel et al. 2004). Therefore, the polymorphism of TPH1 may affect the synthesis of serotonin and melatonin, so that depressed patients with this polymorphism are more prone to middle insomnia (Myung et al. 2012).
  
  
Entity Bipolar Disorder (BPD)
Note Emotional disorders (MDD and BPD) and alcohol dependence are common psychiatric disorders. Nine studies involving 1951 cases and 2161 control subjects were conducted to investigate the relationship between TPH1 A218C polymorphism and BPD risk (Chen et al. 2012). Of these, 4 studies with 416 cases and 596 control subjects were conducted in Asians, whereas 5 studies with 1535 cases and 1565 controls were conducted in Caucasians. A nominally significant relationship was observed in the homozygous model of Asian populations and homozygous and recessive models of Caucasian populations. It was found that the relationship between this polymorphism and the risk of BPD and alcohol dependence varies according to ethnicity, and the 218A variant homozygous genotype is an important risk factor for BPD and alcohol dependence in the Caucasians (Chen et al. 2012). A significant relationship has been reported between A218C polymorphism of TPH1 intron 7 and BPD in the French population (Lai et al. 2005). There was a positive relationship between BD and TPH1 polymorphism (rs1800532) in CC genotype, but no relation was found between other genotypes and alleles (Hormozi et al. 2019).
  
  
Entity Inflammation, Crohn's Disease (CD), and Inflammatory Bowel Disease (IBD)
Note TPH1 catalyzes serotonin biosynthesis in EC, the main source of 5HT (Shajib et al. 2019). The secreted 5HT regulates gut functions through a variety of 5HT receptor (5HTR) families. In inflammatory bowel disease (IBD), the mucosal 5HT signal is altered, including upregulated EC cell numbers and 5HT levels. The two major forms of IBD are Crohn's disease (CD) and ulcerative colitis (UC) which are described by long-lasting and recurrent inflammatory lesions throughout the digestive tract (Shajib et al. 2019). Through TPH1, EC produces 5HT from dietary tryptophan (Shajib and Khan et al. 2015). This 5HT can then be released into the intestinal lumen and surrounding tissue that can enter the bloodstream through the dense capillary bed of lamina propria (Shajib et al. 2019).
5HT has been evaluated in IBD and animal colitis models. TPH1-deficient mice have reduced 5HT content in the gut and low inflammatory cytokine production has been observed (Ghia et al. 2009). Besides, pharmacological blocking of peripheral 5HT synthesis reduced the severity of both chemical and infection-related gut inflammation. In colon biopsy samples from CD patients, TPH1, HTR3A, mucosal HTR4, and HTR7 expressions were upregulated, whereas serotonin transporter (5HTT) expression was downregulated in inflammation. Besides, colonic TPH1 expression was found to be significantly higher in inflamed areas compared to non-inflamed areas and controls (Shajib et al. 2019). Other important factors such as gut microbiota, may also affect host 5HT production in IBD. The role of gut microbiota in 5-HT production, via the regulation of TPH1, has been shown (Yano et al. 2015). The increase in TPH1 expression was thought to be associated with dysbiosis observed in IBD. In particular, a study showed that a 5HT increase due to 5HTT deficiency was associated with dysbiosis. As a result, CD and inflammation are associated with increasing the mucosal 5HT signal, characterized by the upregulation of TPH1 expression and downregulation of 5HTT expression (Shajib et al. 2019). Furthermore, high expression of IL13, a cytokine associated with increased 5HT production, is noteworthy. Increased 5HT availability due to its increased production and impaired clearance is thought to play an important role in maintaining intestinal inflammation and associated symptoms (Shajib et al. 2019).
  

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Gastroenterology 2009 Nov;137(5):1649-60
PMID 19706294
 
Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes
Grasberger H, Chang L, Shih W, Presson AP, Sayuk GS, Newberry RD, Karagiannides I, Pothoulakis C, Mayer E, Merchant JL
Am J Gastroenterol 2013 Nov;108(11):1766-74
PMID 24060757
 
Attention-deficit/hyperactivity disorder symptoms in offspring of mothers with impaired serotonin production
Halmøy A, Johansson S, Winge I, McKinney JA, Knappskog PM, Haavik J
Arch Gen Psychiatry 2010 Oct;67(10):1033-43
PMID 20921119
 
Two types of aggression are differentially related to serotonergic activity and the A779C TPH polymorphism
Hennig J, Reuter M, Netter P, Burk C, Landt O
Behav Neurosci 2005 Feb;119(1):16-25
PMID 15727508
 
Association study of TPH1 (rs1800532) and TPH2 (rs4570625) Polymorphisms in Type 1 Bipolar Disorder in Iran
Hormozi M, Zarei F, Rasouli A, Salimi S, Taji O, Narooie-Nejad M.
Gene Cell Tissue. In Press(In Press):e86109.
 
Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers
Jönsson EG, Goldman D, Spurlock G, Gustavsson JP, Nielsen DA, Linnoila M, Owen MJ, Sedvall GC
Eur Arch Psychiatry Clin Neurosci 1997;247(6):297-302
PMID 9477008
 
Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis
Kwon YH, Wang H, Denou E, Ghia JE, Rossi L, Fontes ME, Bernier SP, Shajib MS, Banskota S, Collins SM, Surette MG, Khan WI
Cell Mol Gastroenterol Hepatol 2019;7(4):709-728
PMID 30716420
 
Polymorphism screening and haplotype analysis of the tryptophan hydroxylase gene (TPH1) and association with bipolar affective disorder in Taiwan
Lai TJ, Wu CY, Tsai HW, Lin YM, Sun HS
BMC Med Genet 2005 Mar 31;6:14
PMID 15799788
 
Platelet-derived serotonin mediates liver regeneration
Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA
Science 2006 Apr 7;312(5770):104-7
PMID 16601191
 
Genetics of Aggression in Alzheimer's Disease (AD)
Lukiw WJ, Rogaev EI
Front Aging Neurosci 2017 Apr 10;9:87
PMID 28443016
 
Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients
Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J
Am J Psychiatry 1997 Oct;154(10):1451-3
PMID 9326831
 
Serotonin regulates mammary gland development via an autocrine-paracrine loop
Matsuda M, Imaoka T, Vomachka AJ, Gudelsky GA, Hou Z, Mistry M, Bailey JP, Nieport KM, Walther DJ, Bader M, Horseman ND
Dev Cell 2004 Feb;6(2):193-203
PMID 14960274
 
Genetic Association Studies of Suicidal Behavior: A Review of the Past 10Years, Progress, Limitations, and Future Directions
Mirkovic B, Laurent C, Podlipski MA, Frebourg T, Cohen D, Gerardin P
Front Psychiatry 2016 Sep 23;7:158
PMID 27721799
 
Genetic association study of individual symptoms in depression
Myung W, Song J, Lim SW, Won HH, Kim S, Lee Y, Kang HS, Lee H, Kim JW, Carroll BJ, Kim DK
Psychiatry Res 2012 Aug 15;198(3):400-6
PMID 22429480
 
Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study
New AS, Gelernter J, Yovell Y, Trestman RL, Nielsen DA, Silverman J, Mitropoulou V, Siever LJ
Am J Med Genet 1998 Feb 7;81(1):13-7
PMID 9514581
 
Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism
Nielsen DA, Goldman D, Virkkunen M, Tokola R, Rawlings R, Linnoila M
Arch Gen Psychiatry 1994 Jan;51(1):34-8
PMID 7506517
 
Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival
Pai VP, Marshall AM, Hernandez LL, Buckley AR, Horseman ND
Breast Cancer Res 2009;11(6):R81
PMID 19903352
 
Robust and tissue-specific expression of TPH2 versus TPH1 in rat raphe and pineal gland
Patel PD, Pontrello C, Burke S
Biol Psychiatry 2004 Feb 15;55(4):428-33
PMID 14960297
 
Serotonin and Aggression
Quadros M I, Aki Takahashi A, Miczek K A.
Handbook of Behavioral Neurobiology of Serotonin Copyright 2010 Elsevier B.V. All rights reserved ISBN 978-0-12-374634-4
 
Microbial tryptophan catabolites in health and disease
Roager HM, Licht TR
Nat Commun 2018 Aug 17;9(1):3294
PMID 30120222
 
Association of anger-related traits with SNPs in the TPH gene
Rujescu D, Giegling I, Bondy B, Gietl A, Zill P, Möller HJ
Mol Psychiatry 2002;7(9):1023-9
PMID 12399958
 
The tryptophan hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: a multi-centre case-control study and meta-analysis
Saetre P, Lundmark P, Wang A, Hansen T, Rasmussen HB, Djurovic S, Melle I, Andreassen OA, Werge T, Agartz I, Hall H, Terenius L, Jönsson EG
Am J Med Genet B Neuropsychiatr Genet 2010 Mar 5;153B(2):387-396
PMID 19526457
 
Characterization of Serotonin Signaling Components in Patients with Inflammatory Bowel Disease
Shajib MS, Chauhan U, Adeeb S, Chetty Y, Armstrong D, Halder SLS, Marshall JK, Khan WI
J Can Assoc Gastroenterol 2019 Aug;2(3):132-140
PMID 31294376
 
The role of serotonin and its receptors in activation of immune responses and inflammation
Shajib MS, Khan WI
Acta Physiol (Oxf) 2015 Mar;213(3):561-74
PMID 25439045
 
TPH gene polymorphism and aging: indication of combined effect on the predisposition to violent suicide
Stefulj J, Kubat M, Balija M, Jernej B
Am J Med Genet B Neuropsychiatr Genet 2006 Mar 5;141B(2):139-41
PMID 16389591
 
Tryptophan hydroxylase gene polymorphism (A218C) and suicidal behaviors
Tsai SJ, Hong CJ, Wang YC
Neuroreport 1999 Dec 16;10(18):3773-5
PMID 10716208
 
Complex phenotype of dyskeratosis congenita and mood dysregulation with novel homozygous RTEL1 and TPH1 variants
Ungar RA, Giri N, Pao M, Khincha PP, Zhou W, Alter BP, Savage SA
Am J Med Genet A 2018 Jun;176(6):1432-1437
PMID 29696773
 
Serotonin and sleep
Ursin R
Sleep Med Rev 2002 Feb;6(1):55-69
PMID 12531142
 
Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum
Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G
Cell 2008 Nov 28;135(5):825-37
PMID 19041748
 
Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis
Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY
Cell 2015 Apr 9;161(2):264-76
PMID 25860609
 
Case control and family-based studies of tryptophan hydroxylase gene A218C polymorphism and suicidality in adolescents
Zalsman G, Frisch A, King RA, Pauls DL, Grice DE, Gelernter J, Alsobrook J, Michaelovsky E, Apter A, Tyano S, Weizman A, Leckman JF
Am J Med Genet 2001 Jul 8;105(5):451-7
PMID 11449398
 

Citation

This paper should be referenced as such :
Rafig Gurbanov, Sevin Karaam
TPH1 (tryptophan hydroxylase 1)
Atlas Genet Cytogenet Oncol Haematol. 2020;24(11):414-423.
Free journal version : [ pdf ]   [ DOI ]


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(3;11)(p14;p15) TPH1/ARL6IP5


External links

Nomenclature
HGNC (Hugo)TPH1   12008
Cards
AtlasTPH1ID51272ch11p15
Entrez_Gene (NCBI)TPH1  7166  tryptophan hydroxylase 1
AliasesTPRH; TRPH
GeneCards (Weizmann)TPH1
Ensembl hg19 (Hinxton)ENSG00000129167 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000129167 [Gene_View]  ENSG00000129167 [Sequence]  chr11:18017555-18046269 [Contig_View]  TPH1 [Vega]
ICGC DataPortalENSG00000129167
TCGA cBioPortalTPH1
AceView (NCBI)TPH1
Genatlas (Paris)TPH1
WikiGenes7166
SOURCE (Princeton)TPH1
Genetics Home Reference (NIH)TPH1
Genomic and cartography
GoldenPath hg38 (UCSC)TPH1  -     chr11:18017555-18046269 -  11p15.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)TPH1  -     11p15.1   [Description]    (hg19-Feb_2009)
GoldenPathTPH1 - 11p15.1 [CytoView hg19]  TPH1 - 11p15.1 [CytoView hg38]
ImmunoBaseENSG00000129167
genome Data Viewer NCBITPH1 [Mapview hg19]  
OMIM191060   
Gene and transcription
Genbank (Entrez)AH012638 AH012638 AY196346 BC106739 BC106740
RefSeq transcript (Entrez)NM_004179
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)TPH1
Alternative Splicing GalleryENSG00000129167
Gene ExpressionTPH1 [ NCBI-GEO ]   TPH1 [ EBI - ARRAY_EXPRESS ]   TPH1 [ SEEK ]   TPH1 [ MEM ]
Gene Expression Viewer (FireBrowse)TPH1 [ Firebrowse - Broad ]
GenevisibleExpression of TPH1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7166
GTEX Portal (Tissue expression)TPH1
Human Protein AtlasENSG00000129167-TPH1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP17752   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP17752  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP17752
Splice isoforms : SwissVarP17752
Catalytic activity : Enzyme1.14.16.4 [ Enzyme-Expasy ]   1.14.16.41.14.16.4 [ IntEnz-EBI ]   1.14.16.4 [ BRENDA ]   1.14.16.4 [ KEGG ]   [ MEROPS ]
PhosPhoSitePlusP17752
Domaine pattern : Prosite (Expaxy)ACT (PS51671)    BH4_AAA_HYDROXYL_1 (PS00367)    BH4_AAA_HYDROXYL_2 (PS51410)   
Domains : Interpro (EBI)ACT_dom    ArAA_hydroxylase    ArAA_hydroxylase_Fe/CU_BS    ArAA_hydroxylase_sf    Aro-AA_hydroxylase_C_sf    Aromatic-AA_hydroxylase_C    Trp_5_mOase    TrpOH_cat    Tyrosine_3-monooxygenase-like   
Domain families : Pfam (Sanger)Biopterin_H (PF00351)   
Domain families : Pfam (NCBI)pfam00351   
Conserved Domain (NCBI)TPH1
DMDM Disease mutations7166
Blocks (Seattle)TPH1
PDB (RSDB)1IN9    1MLW    3HF6    3HF8    3HFB    5J6D    5L01    5TPG   
PDB Europe1IN9    1MLW    3HF6    3HF8    3HFB    5J6D    5L01    5TPG   
PDB (PDBSum)1IN9    1MLW    3HF6    3HF8    3HFB    5J6D    5L01    5TPG   
PDB (IMB)1IN9    1MLW    3HF6    3HF8    3HFB    5J6D    5L01    5TPG   
Structural Biology KnowledgeBase1IN9    1MLW    3HF6    3HF8    3HFB    5J6D    5L01    5TPG   
SCOP (Structural Classification of Proteins)1IN9    1MLW    3HF6    3HF8    3HFB    5J6D    5L01    5TPG   
CATH (Classification of proteins structures)1IN9    1MLW    3HF6    3HF8    3HFB    5J6D    5L01    5TPG   
SuperfamilyP17752
Human Protein Atlas [tissue]ENSG00000129167-TPH1 [tissue]
Peptide AtlasP17752
HPRD01846
IPIIPI00016810   IPI00216828   IPI00794674   IPI00979783   
Protein Interaction databases
DIP (DOE-UCLA)P17752
IntAct (EBI)P17752
BioGRIDTPH1
STRING (EMBL)TPH1
ZODIACTPH1
Ontologies - Pathways
QuickGOP17752
Ontology : AmiGOtryptophan 5-monooxygenase activity  iron ion binding  cytosol  circadian rhythm  aromatic amino acid family metabolic process  negative regulation of ossification  response to immobilization stress  serotonin biosynthetic process  neuron projection  positive regulation of fat cell differentiation  indolalkylamine biosynthetic process  bone remodeling  oxidation-reduction process  mammary gland alveolus development  
Ontology : EGO-EBItryptophan 5-monooxygenase activity  iron ion binding  cytosol  circadian rhythm  aromatic amino acid family metabolic process  negative regulation of ossification  response to immobilization stress  serotonin biosynthetic process  neuron projection  positive regulation of fat cell differentiation  indolalkylamine biosynthetic process  bone remodeling  oxidation-reduction process  mammary gland alveolus development  
Pathways : KEGGTryptophan metabolism    Serotonergic synapse   
REACTOMEP17752 [protein]
REACTOME PathwaysR-HSA-209931 [pathway]   
NDEx NetworkTPH1
Atlas of Cancer Signalling NetworkTPH1
Wikipedia pathwaysTPH1
Orthology - Evolution
OrthoDB7166
GeneTree (enSembl)ENSG00000129167
Phylogenetic Trees/Animal Genes : TreeFamTPH1
HOGENOMP17752
Homologs : HomoloGeneTPH1
Homology/Alignments : Family Browser (UCSC)TPH1
Gene fusions - Rearrangements
Fusion : FusionGDB1.14.16.4   
Fusion : Fusion_HubKIAA1429--TPH1    SDHAF2--TPH1    TPH1--ARL6IP5    TPH1--SERGEF   
Fusion : QuiverTPH1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerTPH1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)TPH1
dbVarTPH1
ClinVarTPH1
MonarchTPH1
1000_GenomesTPH1 
Exome Variant ServerTPH1
GNOMAD BrowserENSG00000129167
Varsome BrowserTPH1
Genetic variants : HAPMAP7166
Genomic Variants (DGV)TPH1 [DGVbeta]
DECIPHERTPH1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisTPH1 
Mutations
ICGC Data PortalTPH1 
TCGA Data PortalTPH1 
Broad Tumor PortalTPH1
OASIS PortalTPH1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICTPH1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DTPH1
Mutations and Diseases : HGMDTPH1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch TPH1
DgiDB (Drug Gene Interaction Database)TPH1
DoCM (Curated mutations)TPH1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)TPH1 (select a term)
intoGenTPH1
NCG6 (London) select TPH1
Cancer3DTPH1(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM191060   
Orphanet
DisGeNETTPH1
MedgenTPH1
Genetic Testing Registry TPH1
NextProtP17752 [Medical]
TSGene7166
GENETestsTPH1
Target ValidationTPH1
Huge Navigator TPH1 [HugePedia]
snp3D : Map Gene to Disease7166
BioCentury BCIQTPH1
ClinGenTPH1
Clinical trials, drugs, therapy
Protein Interactions : CTD7166
Pharm GKB GenePA355
Pharm GKB PathwaysPA161749006   
Clinical trialTPH1
Miscellaneous
canSAR (ICR)TPH1 (select the gene name)
HarmonizomeTPH1
DataMed IndexTPH1
Probes
Litterature
PubMed230 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineTPH1
EVEXTPH1
GoPubMedTPH1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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