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Human Molecular Genetics Advance Access published online on December 22, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl468
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Human SULT1A1 Gene: Copy Number Differences and Functional Implications

Scott J. Hebbring1, Araba A. Adjei2, Janel L. Baer2, Gregory D. Jenkins3, Jianping Zhang2, Julie M. Cunningham1, Daniel J. Schaid3, Richard M. Weinshilboum2 and Stephen N. Thibodeau*,1

1 Department of Laboratory Medicine and Pathology 2 Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics 3 Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905 USA

Address correspondence to: Stephen N. Thibodeau, Ph.D. Mayo Clinic College of Medicine 200 First Street SW, 920 Hilton Building Rochester, MN 55905 Phone: 507-284-9185 Fax: 507-284-0670 E-mail: sthibodeau{at}mayo.edu

Received October 13, 2006; Revised December 11, 2006; Accepted December 11, 2006

SULT1A1, which catalyzes the sulfate-conjugation of a wide variety of natural and synthetic compounds, is genetically polymorphic. Biochemical and pharmacogenetic studies have demonstrated that individual variation in the level of enzyme activity is inherited. Common single nucleotide polymorphisms (SNPs) located in the open reading frame and in the 5'-flanking region (5'-FR) may account for a portion of this individual variation. In this study, we demonstrate the presence of SULT1A1 gene deletions and duplications, representing an additional source of variability in the metabolic activity of this enzyme. A quantitative multiplex PCR assay was used to measure the extent of copy number differences and the frequency of these events in different populations. An analysis of DNA from 362 Caucasian-American and 99 African-American showed the presence of 1 to ~5 copies of SULT1A1 in individual samples: 5% of Caucasian subjects contained a single copy of the gene and 26% had three or more copies, while 63% of African-American subjects had three or more copies. Analysis of the genomic region surrounding the SULT1A1 gene in 3 separate cases with a deletion demonstrated that the entire SULT1A1 gene was affected. Reporter assays, constructed for each of the various 5'-FR SNP haplotypes, suggest that these may also play a role in SULT1A1 activity. However, the variability in the level of enzyme activity among 23 human platelet and 267 human liver samples was best explained by gene copy number differences when all sources of genetic variability were considered (p<0.0001). Overall, these observations have obvious implications for the effectiveness of SULT1A1 as a drug and hormone metabolizing enzyme and its potential role as a risk factor for disease.


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