Human 3′-phosphoadenosine-5′-phosphosulfate synthetase2 (PAPSS2) pharmacogenetics: Gene cloning, resequencing and single nucleotide polymorphisms, (SNPs)

PAPS is the co-substrate for all sulfotransferase (SULT) enzymes. These enzymes catalyze the sulfate conjugation of many endogenous and exogenous compounds, including drugs and other xenobiotics. In humans, PAPS is synthesized from ATP and SO₄^2- by two bifunctional PAPSS isoforms. A rare inactivating mutation within PAPSS2 results in major skeletal deformity in humans. To determine whether less striking "pharmacogenomic" variations in the PAPSS2 gene might be one factor responsible for individual differences in sulfate conjugation, we cloned PAPSS2 and "resequenced" all exons and splice junctions, as well as the core promoter using 90 Coriell Polymorphism Discovery Resource DNA samples. A total of 1 Mb of sequence was analyzed. Twenty-two SNPs were seen, including 4 non-synonymous cSNPs which altered the following amino acids: Glu10Lys, Met281Leu, Val291Met, and Arg432Lys. We also observed 4 insertions/deletions, and one sample was homozygous for an 81 bp deletion in the core promoter region. The functional significance of these polymorphisms will now be assessed by site-directed mutagenesis and transient expression.