TY - JOUR
T1 - Human 3β-hydroxysteroid dehydrogenase types 1 and 2
T2 - Gene sequence variation and functional genomics
AU - Wang, Liewei
AU - Salavaggione, Ezequiel
AU - Pelleymounter, Linda
AU - Eckloff, Bruce
AU - Wieben, Eric
AU - Weinshilboum, Richard
N1 - Funding Information:
This work was supported in part by National Institutes of Health (NIH) grants R01 GM28157, R01 GM35720 and U01 GM61388 (The Pharmacogenetics Research Network), as well as a PhRMA Foundation Center of Excellence in Clinical Pharmacology Award. We thank Mrs. Luanne Wussow for her assistance with the preparation of this manuscript.
PY - 2007/10
Y1 - 2007/10
N2 - The 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase isoenzymes 1 and 2 (HSD3B1 and HSD3B2) are membrane-bound enzymes that play essential roles in the biosynthesis of steroid hormones. Therefore, variation in the HSD3B1 and HSD3B2 genes might play a role in the pathophysiology of steroid hormone-related disease. We set out to systematically identify common polymorphisms and haplotypes in human HSD3B1 and HSD3B2. We identified 17 single nucleotide polymorphisms (SNPs) in HSD3B1 and 9 in HSD3B2 - the majority of which were not present in public databases - by resequencing human HSD3B1 and HSD3B2 using 240 DNA samples from four different ethnic groups (60 samples per group). Functional genomic studies of the five non-synonymous cSNPs in HSD3B1 and the one observed in HSD3B2 showed that two of these polymorphisms resulted in significant decreases in the quantity of enzyme protein expressed. However, none of the three non-synonymous SNPs located in areas encoding putative membrane-binding domains altered subcellular localization of the enzyme as determined by immunofluorescence microscopy. Finally, common variant haplotypes in the 5′-flanking regions of these genes showed significant cell line-dependent variation in their ability to drive transcription. In aggregate, these results provide a basis for study of the possible role in human disease of common genetic variation in HSD3B1 and HSD3B2.
AB - The 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase isoenzymes 1 and 2 (HSD3B1 and HSD3B2) are membrane-bound enzymes that play essential roles in the biosynthesis of steroid hormones. Therefore, variation in the HSD3B1 and HSD3B2 genes might play a role in the pathophysiology of steroid hormone-related disease. We set out to systematically identify common polymorphisms and haplotypes in human HSD3B1 and HSD3B2. We identified 17 single nucleotide polymorphisms (SNPs) in HSD3B1 and 9 in HSD3B2 - the majority of which were not present in public databases - by resequencing human HSD3B1 and HSD3B2 using 240 DNA samples from four different ethnic groups (60 samples per group). Functional genomic studies of the five non-synonymous cSNPs in HSD3B1 and the one observed in HSD3B2 showed that two of these polymorphisms resulted in significant decreases in the quantity of enzyme protein expressed. However, none of the three non-synonymous SNPs located in areas encoding putative membrane-binding domains altered subcellular localization of the enzyme as determined by immunofluorescence microscopy. Finally, common variant haplotypes in the 5′-flanking regions of these genes showed significant cell line-dependent variation in their ability to drive transcription. In aggregate, these results provide a basis for study of the possible role in human disease of common genetic variation in HSD3B1 and HSD3B2.
KW - 3β-Hydroxysteroid dehydrogenase 1
KW - 3β-Hydroxysteroid dehydrogenase 2
KW - Functional genomics
KW - Gene resequencing
KW - Genetic polymorphisms
KW - HSD3B1
KW - HSD3B2
KW - Haplotypes
KW - SNPs
KW - Single nucleotide polymorphisms
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U2 - 10.1016/j.jsbmb.2007.03.037
DO - 10.1016/j.jsbmb.2007.03.037
M3 - Article
C2 - 17689071
AN - SCOPUS:34548405588
SN - 0960-0760
VL - 107
SP - 88
EP - 99
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 1-2
ER -