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

Abnormalities in serotonin levels have been implicated in a wide range of psychiatric disorders. Tryptophan 2,3-dioxygenase is the rate-limiting enzyme in the catabolism of tryptophan, the precursor of serotonin. As such it is a potential major candidate gene in psychiatric genetics. The regulatory, intron, and exon regions of the human TDO2 gene have been sequenced. Twelve exons were identified. The amino acid sequence of the enzyme was 88% homologous to that of the rat. Compared to the rat, the regulatory region of the human TDO2 gene had an insertion of approximately 1064 bp of random DNA beginning at -293 bp and extending to -1357 bp. This displaced the glucocorticoid response element (GRE) occurring at -1174 bp in the rat to -1500 in the 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. This could produce several staggered regions of the sequence TGTTGTnnnTGTTGT similar to a GRE consensus sequence of TGTTCAnnnTGTTCT. The intron regions 5' and 3' to each exon were sequenced. This allowed each exon to be screened for mutations. This showed a His --> Val mutation polymorphism in exon 7. Three introns, 1, 5, and 6, were completely sequenced and examined for polymorphisms. This identified two polymorphisms consisting of G --> T and G --> A mutations 2 bp apart in intron 6. The 3' end of intron 5 showed an extensive CCCCT pentanucleotide repeat that was markedly polymorphic. These polymorphisms allow the TDO2 gene to be examined for a possible role in psychiatric disorders. (C) 1995 Academic Press, Inc.