Characterization of a Human GlutathioneS-Transferase μ Cluster Containing a DuplicatedGSTM1 Gene that Causes Ultrarapid Enzyme Activity

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Abstract
The μ class glutathione S-transferase geneGSTM1 is polymorphic in humans, with approximately half of the Caucasian population being homozygous deleted for this gene. GSTM1 enzyme deficiency has been suggested to predispose people to lung and bladder cancer. Some people in a Saudi Arabian population, however, have been described previously with ultrarapid GSTM1 enzyme activity. Here we have evaluated the molecular genetic basis for this observation. Genomic DNA from two Saudi Arabian subjects exhibiting ultrarapid enzyme activity and from 13 Swedish subjects having null, one, or two GSTM1 genes were subjected to restriction fragment length polymorphism analysis using the restriction enzymesEcoRI, EcoRV, and HindIII and combinations thereof. Hybridization was carried out using a full-length GSTM1 cDNA or the 5′ and 3′ parts of the cDNA. The restriction mapping data revealed the presence of a GSTμ cluster with two GSTM1 genes in tandem situated between the GSTM2 and GSTM5 genes. A quantitative multiplex polymerase chain reaction method, which simultaneously amplified a fragment of the GSTM1 gene and the β-globin gene, was developed, and the genomicGSTM1 copy number was determined from theGSTM1/β-globin ratio. This method clearly separatedGSTM1 +/− subjects (ratios between 0.4 and 0.7) fromGSTM1 +/+ subjects (ratios between 0.8 and 1.2). The two Saudi Arabians with ultrarapid GSTM1 activities had ratios of approximately 1.5, indicating that they carried threeGSTM1 genes. These results demonstrate the existence of a novel μ class GST cluster containing a duplicated active GSTM1 gene causing ultrarapid enzyme activity.

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