Alternative titles; symbols
HGNC Approved Gene Symbol: TDO2
Cytogenetic location: 4q32.1 Genomic coordinates (GRCh38): 4:155,903,696-155,920,406 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q32.1 | [?Hypertryptophanemia] | 600627 | Autosomal recessive | 3 |
Tryptophan 2,3-dioxygenase (EC 1.13.11.11) plays a role in catalyzing the first and rat-limiting step in the kynurenine pathway, the major pathway of tryptophan metabolism.
Comings et al. (1989, 1991) reported the identification of a human cDNA clone encoding tryptophan oxygenase. Comings et al. (1995) reported that the human TDO2 enzyme is 88% homologous to that of the rat.
Comings et al. (1995) reported the structure of the TDO2 gene. Twelve exons were identified. Compared to the rat, the regulatory region of the human TDO2 gene had an insertion of approximately 1,064 bp of random DNA beginning at -293 bp and extended to -1357 bp. This displaced the glucocorticoid response element (GRE) occurring at -1174 bp in the rat to -1500 in human. The proximal GRE at -419 in the rat was missing in the human. However, within the DNA insert there was a GRE-like microsatellite region containing multiple GTT repeats plus additional GT(n) sequences. The intronic regions 5-prime and 3-prime to each exon were sequenced.
By hybridization of a cloned rat TRPO cDNA to Chinese hamster/human hybrid cell DNAs, Comings et al. (1989) assigned the human TRPO gene to chromosome 4q25-q31. Donlon et al. (1989) used the same rat cDNA to identify a homologous human cDNA and used the latter for mapping by in situ hybridization. They concluded that the human TRPO gene is located at 4q31-q32. By in situ hybridization, Comings et al. (1991) localized the TRPO gene to 4q31.
Opitz et al. (2011) identified the tryptophan catabolite kynurenine (kyn) as an endogenous ligand of the human aryl hydrocarbon receptor (AHR; 600253) that is constitutively generated by human tumor cells via tryptophan 2,3-dioxygenase (TDO). TDO-derived kyn suppresses antitumor immune responses and promotes tumor cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumors and is associated with malignant progression and poor survival. Opitz et al. (2011) concluded that because kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, their results provided evidence for a previously unidentified pathophysiologic function of the AHR with profound implications for cancer and immune biology.
By analyzing TDO2 clones isolated from a human liver cDNA library, Comings et al. (1995) identified a his-to-val polymorphism in exon 7 of the TDO2 gene. They also identified 2 polymorphisms consisting of G-to-T and G-to-A 2 bp apart in intron 6. The 3-prime end of intron 5 showed an extensive CCCCT pentanucleotide repeat that was markedly polymorphic. The authors stated that these polymorphisms should be useful for examining the possible role of TDO2 in psychiatric disorders.
Hypertryptophanemia
In a 28-year-old woman with congenital hypertryptophanemia (HYPTRP; 600627), Ferreira et al. (2017) identified compound heterozygosity for a 1-bp duplication (191070.0001) and a missense mutation (M108I; 191070.0002) in the TDO2 gene. Analysis of the variants showed that the frameshift mutation does not produce soluble protein, whereas the M108I mutant enzyme is catalytically less efficient and prone to proteolytic degradation.
Too et al. (2016) generated mice lacking Tdo2, Ido1 (147435), or Ido2 (612129) and assessed their behavior and cognitive function during 2 periods separated by 1 month. Ido1 -/- mice displayed reductions of early diurnal exploration in both periods. In contrast, Ido2 -/- mice showed early diurnal hyperactivity in both periods. Tdo2 -/- mice displayed increased diurnal and nocturnal activity, but only in the second period. Ido2 -/- mice appeared to have enhanced reference memory in a complex patrolling task, and Tdo2 -/- mice exhibited enhanced performance in complex patrolling and discrimination reversal tasks. Neurochemical measurements revealed attenuated serotonin levels in Ido1 -/- mice, augmented tryptophan and serotonin levels in Tdo2 -/- mice, and no neurochemical alterations in Ido2 -/- mice. Too et al. (2016) concluded that Ido1, Ido2, and Tdo2 deficiencies differentially affect exploratory behavior and learning performance, as well as metabolism of kyn, serotonin, and dopamine, in mice.
In a 28-year-old woman with congenital hypertryptophanemia (HYPTRP; 600627), Ferreira et al. (2017) identified compound heterozygosity for a 1-bp duplication (c.491dup) in the TDO2 gene, causing a frameshift predicted to result in a premature termination codon (Ile165AspfsTer12) and a protein only 43% of its normal length, and a c.324G-C transversion, resulting in a met108-to-ile (M108I; 191070.0002) substitution at a highly conserved residue. The proband's unaffected parents were each heterozygous for 1 of the mutations. The duplication was reported in 1 of 121,218 ExAC chromosomes, and the M108I mutation was not found in the ExAC database. The frameshift variant did not express soluble protein. Analysis of the M108I variant demonstrated reduced catalytic efficiency compared to wildtype, as well as reduced affinity for L-tryptophan at the high-affinity noncatalytic exo L-trp binding site, which was predicted to result in a greatly accelerated rate of degradation.
For discussion of the c.324G-C transversion in the TDO2 gene, resulting in a met108-to-ile (M108I) substitution, that was found in compound heterozygous state in a patient with hypertryptophanemia (HYPTRP; 600627) by Ferreira et al. (2017), see 191070.0001.
Comings, D. E., Comings, B. G., Dietz, G., Muhleman, D. Localization of human tryptophan oxygenase to 4q31: possible relevance to alcoholism, depression and Tourette syndrome. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A135 only, 1989.
Comings, D. E., Dietz, G., Muhlman, D. Localization of human tryptophan oxygenase to 4q25-q31. (Abstract) Cytogenet. Cell Genet. 51: 979 only, 1989.
Comings, D. E., Muhleman, D., Dietz, G., Sherman, M., Forest, G. L. Sequence of human tryptophan 2,3-dioxygenase (TDO2): presence of a glucocorticoid response-like element composed of a GTT repeat and an intronic CCCCT repeat. Genomics 29: 390-396, 1995. [PubMed: 8666386] [Full Text: https://doi.org/10.1006/geno.1995.9990]
Comings, D. E., Muhleman, D., Dietz, G. W., Jr., Donlon, T. Human tryptophan oxygenase localized to 4q31: possible implications for alcoholism and other behavioral disorders. Genomics 9: 301-308, 1991. [PubMed: 2004780] [Full Text: https://doi.org/10.1016/0888-7543(91)90257-f]
Donlon, T. A., Muhleman, D., Dietz, G., Comings, D. E., Spak, D. K. Localization of human tryptophan oxygenase to 4q31-q32 by in situ hybridization. (Abstract) Cytogenet. Cell Genet. 51: 992 only, 1989.
Ferreira, P., Shin, I., Sosova, I., Dornevil, K., Jain, S., Dewey, D., Liu, F., Liu, A. Hypertryptophanemia due to tryptophan 2,3-dioxygenase deficiency. Molec. Genet. Metab. 120: 317-324, 2017. [PubMed: 28285122] [Full Text: https://doi.org/10.1016/j.ymgme.2017.02.009]
Opitz, C. A., Litzenburger, U. M., Sahm, F., Ott, M., Tritschler, I., Trump, S., Schumacher, T., Jestaedt, L., Schrenk, D., Weller, M., Jugold, M., Guillemin, G. J., Miller, C. L., Lutz, C., Radlwimmer, B., Lehmann, I., von Deimling, A., Wick, W., Platten, M. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478: 197-203, 2011. [PubMed: 21976023] [Full Text: https://doi.org/10.1038/nature10491]
Too, L. K., Li, K. M., Suarna, C., Maghzal, G. J., Stocker, R., McGregor, I. S., Hunt, N. H. Deletion of TDO2, IDO-1 and IDO-2 differentially affects mouse behavior and cognitive function. Behav. Brain Res. 312: 102-117, 2016. [PubMed: 27316339] [Full Text: https://doi.org/10.1016/j.bbr.2016.06.018]