Abstracts

Genetic Bases of Biodiversity

Tryptophan 2,3-dioxygenase (TDO2, EC 1.13.11.11) is the rate-limiting enzyme in the oxidative degradation of tryptophan, the serotonin precursor, which therefore controls serotonin level in the body. Defects in serotonin metabolism and abnormal serotonin/tryptophan levels have been reported for many behavioural disorders. This suggests the TDO2 gene as a potential candidate gene in psychiatric genetics. Single base mutations G  A at position 663 and G  T at position 666 of intron 6 of the human tryptophan oxygenase gene (TDO2) are associated with a variety of psychiatric disorders (Tourette syndrome, attention deficit hyperactivity disorder, alcoholism, drug dependence, and others) [Comings D.E. et al., 1996]. We have demonstrated that to each allelic state of the region there corresponds a specific set of proteins that interacts with it. With the aid of computer analysis and using specific anti-YY-1 antibodies it has been shown that both mutations damage the YY-1 transcription factor binding site [Vasiliev G.V. et al., 1999]..

To search for new functional variants of TDO2 gene, associated with behavioral disorders, intron 6 of this gene was completely sequenced at alcohol-preferring C57Bl mice and control CBA and DBA/2 mice. No intrastrain polymorphism was found. It was shown that alcohol-preferring C57Bl mice differed from both CBA and DBA/2 mice by 5 SNPs and one microdeletion. It is in concordance with high basal level of tryptophane oxygenase activity in the livers of alcohol-preferring C57Bl mice and indicate to the possible role of the alterations in introne 6 sequence in TDO2 gene expression and behavioural disorders. The results of gel shift experiments demonstrated, that nucleotide substitutions found in C57BL mice caused a dramatic change in transcription factor binding patterns. With the aid of competitor oligonucleotide and using specific anti-GATA-6 antibodies it has been shown that substitution of G (CBA and DBA/2 mice) by A (C57BL mice) at position 1016 bp of intron 6 leads to the considerable decrease of this transcription factor binding.

1. Comings D.E., Gade R., Muchleman D., Chue C. Exon and intron variants in the humman TO gene: potentional association with Tourette sindrome, substans abuse and other disorders // Pharmacogenetics. 1996. V. 6. P. 307-318.
2. Vasiliev G. V., Merculov V. M., Kobzev V. F., T.I. Merkulova V. F., Ponomorenko M. P., Kolchanov N. A. Point mutations within 663 – 666 bp of intron 6 of the human TDO2 gene, associated with a number of psychiatric disorders, damage the YY – 1 transcription factor binding site // FEBS Letters. 1999. V. 462. P. 85-88.

Note. Abstracts are published in author's edition

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