Disrupting genes

The generation of mice with disrupted genes should allow the evaluation of the pharmacokinetic and pharmacodynamic consequences of the complete, specific inhibition of particular drug enzymes, transporters or receptors. 

Transposon integration mutagenesis can be used to allow the selection of metalloid-resistant mutants with enhanced MICs.147 Ledgham et al.148 found a transposon-disrupted gene in a mutant - with a three-fold increase in Se-resistance - that encoded a protein from a member of the DedA family of membrane proteins that was implicated in the uptake of selenite through cell membranes. This is a reasonable hypothesis for how metalloid resistance occurs in some microorganisms. 

Sanchez Alvarado, A. and Newmark, P.A. (1 999) Double-stranded RNA specifically disrupts gene expression during planarian regeneration. Proceedings of the National Academy of Sciences USA 96, 5049-5054. 

Examine how developmental exposure of rodents to toxicants such as 2,3,7,8-TCDD disrupt gene expression and produce cellular defects... 

Mutations in each of the three domains mentioned above can potentially disrupt gene transcription and lead to hormone resistance or other hormonally related disorders (Table 4). Information about glucocorticoid, mineralocorticoids, androgens, estrogens, retinoic acid, vitamin D, and the AH receptor is summarized in Table 4. Mineralocorticoid, estrogen, and AH receptors are discussed in greater detail below. 

Rohrer DK, Bernstein D, Chruscinski A, Desai KH, Schauble E, Kobilka BK. The developmental and physiological consequences of disrupting genes encoding P and p2 adrenoceptors. Adv Pharmacol 1998 42 499-501. 

RNA Interference Provides an Additional Tool for Disrupting Gene Expression... 

An extremely powerful tool for disrupting gene expression was serendipi-tously discovered in the course of studies that required the introduction of RNA into a cell. The introduction of a specific double-stranded RNA molecule into a cell was found to suppress the transcription of genes that contained sequences present in the double-stranded RNA molecule. Thus, the introduction of a specific RNA molecule can interfere with the expression of a specific gene. 

If the disrupted gene is essential, these spores will be nonviable... 

Researchers are exploiting a recently discovered phenomenon known as RNA interference (RNAi) to inhibit the function of specific genes. This approach is technically simpler than the methods described above for disrupting genes. First observed in the roundworm C. elegans, RNAl refers to the ability of a double-stranded (ds) RNA to block expression of its corresponding single-stranded mRNA but not that of mRNAs with a different sequence. 

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