Gene modifiers

The intracellular distribution of steroid hormone receptors has long been the object of controversy. The first theoretical formulation on the intracellular location of the ERs was elaborated by Jensen in 1968 and is known as the two-step theory. Its execution was based entirely on biochemical observations obtained by means of tritium-marked estradiol. The ERs, in cells not exposed to hormones, are found abundantly in the soluble cell fraction, or cytosol (Fig. 1.1). Treatment with hormones confines the receptors to the particulated or nuclear fraction and causes their disappearance from the cytosol. The two-step theory established that the receptor is found in the cytoplasm naturally and upon the arrival of a hormone it is transformed into a complex hormone-receptor (first step) capable of translocating itself to the nucleus and of modifying gene expression (second step). 

More than 50 polymorphisms, three insertions/deletions, and several promoter alterations that modify gene transcription have been described in the ABCBl gene. There are three single-nucleotide polymorphisms (SNPs) that are common in most racial populations and demonstrate strong linkage disequilibrium the synonymous... 

Addition of the modified gene to a cell-free system containing the appropriate RNA polymerase and semi-synthetic suppressor tRNA. 

Figure 15.4 Four compounds that are methylated either by SAM or methyl FH4 (CH3 FH4). The processes are (i) cytidine bases in DNA (11) methylatlon of deoxyUMP to produce deoxythymidine monophosphate (111) formation of phosphatidylcholine from phos-phatldylethanolamlne (Chapter 17) (Iv) methylatlon of a protein In myelin. The base cytidine Is methylated In DNA to produce methylcytidine which. If deamlnated, produces methylthymidine In DNA. Methylatlon of the bases can modify gene transcription (see text). (PR 5 -phosphor1bose).

Lomvardas, S. and Thanos, D. (2002) Modifying gene expression programs by altering core promoter architecture. Cell 110, 261-271. 

While certain behavioral and nonbehavioral diseases are believed to be monogenic, diseases such as Huntington s, cystic fibrosis, Marfan, and Hirschsprung result in the specified disease, and the outward appearance or result (phenotype) of the disease varies between individuals. For instance, for Marfan syndrome, there is a level below which the mutant protein does not exhibit itself in an outward manner. Most of these diseases have modifier genes that cause modifications in the outward demonstration of the disease and play a key role in the clinical symptoms. Further, the particular metabolic pathways are often varied, with several of the steps being important and the importance of each mechanistic pathway may differ with every individual. 

Dixon SJ, Stockwell BR (2009) Identifying druggable disease-modifying gene products. Curr Opinion Chem Biol 13 549-555... 

It is an acetylenic retinoid prodrug which is hydrolysed to active metabolite tazarotenic acid, binds to retinoic acid receptors resulting in modified gene expression. 

Thus in man and a number of other species, the basis for the acetylator polymorphism is qualitative differences in NAT2 and to some extent NAT1, resulting from mutations. There may also be post translational modifications of the primary gene product. In mice, there is evidence that other factors such as modifier genes may also affect the expression of a cetyl transferase activity. 

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