Human SULT1A3 pharmacogenetics: gene duplication and functional genomic studies.
Sulfotransferase (SULT) 1A3 catalyzes the sulfate conjugation of catecholamines. Inheritance is an important factor responsible for individual variation in SULT1A3 activity, and gene resequencing studies have shown the presence of one functionally significant SULT1A3 nonsynonymous cSNP. However, following completion of the Human Genome Project, it appeared that SULT1A3 might be duplicated. We used specific PCR-based assays and fluorescence in situ hybridization to verify that 2 SULT1A3 genes-SULT1A3 and SULT1A4-were present on chromosome 16 in all human DNA samples studied. Furthermore, reanalysis of previous gene resequencing data confirmed the presence of the SULT1A3 SNPs identified previously, but also revealed 11 novel polymorphisms, including 3 nonsynonymous cSNPs. Functional genomic studies showed that two of those cSNPs, C302T, and C302A, resulted in decreased enzyme activity without striking changes in substrate kinetics but with parallel changes in levels of immunoreactive protein. In addition, RT-PCR revealed that both SULT1A3 and SULT1A4 can be transcriptionally active. The duplication of SULT1A3 will have to be taken into account in future efforts to understand individual variation in SULT1A3 activity or properties.
Hildebrandt
Michelle A T
MA
Department of Molecular Pharmacology, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, MN 55905, USA.
Salavaggione
Oreste E
OE
Martin
Yvette N
YN
Flynn
Heather C
HC
Jalal
Syed
S
Wieben
Eric D
ED
Weinshilboum
Richard M
RM
D015239:Arylsulfotransferase; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D005091:Exons; D020440:Gene Duplication; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D007438:Introns; D007700:Kinetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism
D015238:Sulfotransferases; D015239:Arylsulfotransferase; C403170:monoamine-sulfating phenol sulfotransferase