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-limi ting enzyme in the catabolism of tryptophan, the precursor of serotoni n. As such it is a potential major candidate gene in psychiatric genet ics. The regulatory, intron, and exon regions of the human TDO2 gene h ave been sequenced. Twelve exons were identified. The amino acid seque nce of the enzyme was 88% homologous to that of the rat. Compared to t he rat, the regulatory region of the human TDO2 gene had an insertion of approximately 1064 bp of random DNA beginning at -293 bp and extend ing to -1357 bp. This displaced the glucocorticoid response element (G RE) occurring at -1174 bp in the rat to -1500 in the human. The proxim al GRE at -419 in the rat was missing in the human. However, within th e DNA insert there was a GRE-like microsatellite region containing mul tiple 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 intr on 5 showed an extensive CCCCT pentanucleotide repeat that was markedl y polymorphic. These polymorphisms allow the TDO2 gene to be examined for a possible role in psychiatric disorders. (C) 1995 Academic Press, Inc.