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This study tested the association between tardive dyskinesia (TD) and polymorphic variations in (a) 2 cytochrome P450 (CYP) genes (CYP2D6or CYP3A5), (b) 2 DRD2variants (Ser311Cys and -141C Ins/del) and the Ser9Gly DRD3variants, (c) 2 glutathione S-transferases (GSTT1and GSTM1), and (d) variations in the PgP gene, MDR1. The study sample included 516 severely mentally ill patients from Central Kentucky facilities. Logistic regression models that included clinical variables associated with TD were developed. Gene variants were added to these clinical models. The total sample included 31% (162/516) with TD where 30% (49/162) of those had severe TD. Polymorphisms in DRD2, MDR1, and GSTT1were never significant. Two gene variants appeared to be significant after adding them to the clinical regression models (1) Ser9Gly DRD3polymorphism was associated with severe TD (odds ratio for patients with 1 mutant allele when compared with individuals with 2 wild types was 2.5, 95% confidence interval 1.1-5.6, whereas the odds ratio for patients with 2 mutant alleles when compared with individuals with 1 mutant was 2.8, 95% confidence interval 1.0-7.4), and (2) GSTM1absence was associated with TD (odds ratio 1.7, 95% confidence interval 1.2-2.4) particularly in white women. The CYP2D6 and CYP3A5 absence showed potential for significant associations in larger samples, particularly in white men. New studies need to replicate whether these or other genes could be used conjointly with clinical variables to identify subjects at risk for TD in clinical settings.

The Escherichia coliRecA protein has at least three roles in SOS mutagenesis: (1) derepression of the SOS regulon by mediating LexA cleavage; (2) activation of the UmuD mutagenesis protein by mediating its cleavage; and (3) targeting the Umu-like mutagenesis proteins to DNA. Using a combined approach of molecular and physiological assays, it is now possible to determine which of the three defined steps has been altered in any recAmutant. In this study, we have focussed on the ability of six particular recAmutants (recA85, recA430, recA432, recA433, recA435and recA730) to perform these functions. Phenotypically, recA85and recA730were similar in that in lexA+and lexA(Def) backgrounds, they exhibited constitutive coprotease activity towards the UmuD mutagenesis protein. Somewhat surprisingly, in a lexA(Ind−) background, UmuD cleavage was damage inducible, suggesting that the repressed level of the RecA∗protein cannot spontaneously achieve a fully activated state. Although isolated in separate laboratories, the nucleotide sequence of the recA85and recA730mutants revealed that they were identical, with both alleles possessing a Glu38→ Lys change in the mutant protein. The recA430, recA433and recA435mutants were found to be defective for both λ mutagenesis and UmuD cleavage. λ mutagenesis was fully restored, however, to the recA433and recA435strains by a low copy plasmid expressing the mutagenically active UmuD′ protein. In contrast, λ mutagenesis was only partially restored to a recA430strain by a high copy UmuD′ plasmid, suggesting that RecA430 may also be additionally defective in targeting the Umu proteins to DNA. Sequence analysis of the recA433and recA435alleles revealed identical substitutions resulting in Arg243→ His. The recA432mutation had a complex phenotype in that its coprotease activity towards UmuD depended upon the lexAbackground: inducible in lexA+strains, inefficient in lexA(Ind−) cells and constitutive in a lexA(Def) background. The recA432mutant was found to carry a Pro119→ Ser substitution, a residue believed to be at the RecA subunit interface; thus this complex phenotype may result from alterations in the assembly of RecA multimers.