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

Abstract

Single base mutations GC CA at position 663 and GC CT at position 666 of intron 6 of the human tryptophan oxygenase gene (TDO2) are associated with a variety of psychiatric disorders [Comings, D.E. et al. (1996) Pharmacogenetics 6, 307^318]. Binding of rat liver nuclear extract proteins to synthetic double-strand oligonucleotides corresponding to three allelic states of the region between 651 bp and 680 bp of human TDO2 intron 6 has been studied by gel shift assay. It has been 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.z 1999 Federation of European Biochemical Societies.

Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12

“…Taken together, these two studies provide strong evidence for a potential bipolar susceptibility gene in this region. Potential candidate genes for consideration include: the tryptophan oxygenase gene (TDO2) 45 and potentially genes encoding a glycine receptor (GLRB) 46 and glutamate receptor (GRIA2). 47 We observed a second peak on chromosome 4 at marker D4S3051 on 4q35 (NPL ¼ 2.43, Po0.01).…”

Enzymology of NAD+ homeostasis in man

“…The rat TDO is a tetrameric protein and requires 2 mol of heme per mol of protein for its catalytic function [54]. Different polymorphisms of the human TDO gene have been identified, and the association of these functional variants with psychiatric disorders, characterized by abnormalities in tryptophan and serotonin levels, has been suggested [55,56].…”

rSNP_Guide: An integrated database-tools system for studying SNPs and site-directed mutations in transcription factor binding sites

“…As known, gene transcription is launched by interaction of transcription factors (TFs) with relevant binding sites (TF-sites) in regulatory gene regions. Depending on localization, an SNP in a regulatory region may cause either complete elimination of the natural TF site [Vasiliev et al, 1999;Boccia et al, 1996], formation of a novel spurious TF site [Knight et al, 1999;Piedrafita et al, 1996], or quantitative alteration in TF-binding efficiency [O'Neill et al, 1990;Matsuda et al, 1992;Moi et al, 1992;Tsutsumi-Ishii et al, 1995;Langdon and Kaufman, 1998]. Because gene expression in eukaryotes is mediated not only by individual transcription factors, but also through sophisticated transcriptosome machinery [Gall et al, 1999] and gene network relationships, very few SNPs or genome variations in regulatory gene regions may ultimately result in alteration of the expression patterns of many genes.…”

“…Besides, a single mutation may cause misbalance between several overlapping TF-sites, thus causing disease penetration due to re-arrangement of gene network functioning [O'Neill et al, 1990;Langdon and Kaufman, 1998]. In fact, many experiments [Bienvenu et al, 1995;Cowell et al, 1996;Nedelcheva Kristensen et al, 1999;Vasiliev et al, 1999] demonstrate that a mutation-altered TF site cannot be reliably recognized by only its textual similarity to the known TF site. All things considered, there is a need for designing novel approaches aimed at SNP analysis.…”