Publications (2)8.94 Total impact
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Article: Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics.
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ABSTRACT: Inosine monophosphate dehydrogenases, encoded by IMPDH1 and IMPDH2, are targets for the important immunosuppressive drug, mycophenolic acid (MPA). Variation in MPA response may result, in part, from genetic variation in IMPDH1 and IMPDH2. We resequenced IMPDH1 and IMPDH2 using DNA from 288 individuals from three ethnic groups and performed functional genomic studies of the sequence variants observed. We identified 73 single nucleotide polymorphisms (SNPs) in IMPDH1, 59 novel, and 25 SNPs, 24 novel, in IMPDH2. One novel IMPDH1 allozyme (Leu275) had 10.2% of the wild-type activity as a result of accelerated protein degradation. Decreased activity of the previously reported IMPDH2 Phe263 allozyme was primarily due to decreased protein quantity, also with accelerated degradation. These observations with regard to the functional implications of variant allozymes were supported by the IMPDH1 and IMPDH2 X-ray crystal structures. A novel IMPDH2 intron 1 SNP, G > C IVS1(93), was associated with decreased mRNA quantity, possibly because of altered transcription. These results provide insight into the nature and extent of sequence variation in the IMPDH1 and IMPDH2 genes. They also describe the influence of gene sequence variation that alters the encoded amino acids on IMPDH function and provide a foundation for future translational studies designed to correlate sequence variation in these genes with outcomes in patients treated with MPA.British Journal of Pharmacology 12/2010; 161(7):1584-98. · 4.41 Impact Factor -
Article: Genetic diversity and function in the human cytosolic sulfotransferases.
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ABSTRACT: Amino-acid substitutions, which result from common nonsynonymous (NS) polymorphisms, may dramatically alter the function of the encoded protein. Gaining insight into how these substitutions alter function is a step toward acquiring predictability. In this study, we incorporated gene resequencing, functional genomics, amino-acid characterization and crystal structure analysis for the cytosolic sulfotransferases (SULTs) to attempt to gain predictability regarding the function of variant allozymes. Previously, four SULT genes were resequenced in 118 DNA samples. With additional resequencing of the remaining eight SULT family members in the same DNA samples, a total of 217 polymorphisms were revealed. Of 64 polymorphisms identified within 8785 bp of coding regions from SULT genes examined, 25 were synonymous and 39 were NS. Overall, the proportion of synonymous changes was greater than expected from a random distribution of mutations, suggesting the presence of a selective pressure against amino-acid substitutions. Functional data for common variants of five SULT genes have been previously published. These data, together with the SULT1A1 variant allozyme data presented in this paper, showed that the major mechanism by which amino acid changes altered function in a transient expression system was through decreases in immunoreactive protein rather than changes in enzyme kinetics. Additional insight with regard to mechanisms by which NS single nucleotide polymorphisms alter function was sought by analysis of evolutionary conservation, physicochemical properties of the amino-acid substitutions and crystal structure analysis. Neither individual amino-acid characteristics nor structural models were able to accurately and reliably predict the function of variant allozymes. These results suggest that common amino-acid substitutions may not dramatically alter the protein structure, but affect interactions with the cellular environment that are currently not well understood.The Pharmacogenomics Journal 05/2007; 7(2):133-43. · 4.54 Impact Factor
