title: Human 3beta-hydroxysteroid dehydrogenase types 1 and 2: Gene sequence variation and functional genomics.
abstract: The 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) 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.
authors: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. wang.liewei@mayo.edu
authors: Liewei
authors: L
authors: Wang
authors: Ezequiel
authors: E
authors: Salavaggione
authors: Linda
authors: L
authors: Pelleymounter
authors: Bruce
authors: B
authors: Eckloff
authors: Eric
authors: E
authors: Wieben
authors: Richard
authors: R
authors: Weinshilboum
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D024506:5' Flanking Region; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017930:Genes, Reporter; D014644:Genetic Variation; D023281:Genomics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D018613:Microscopy, Confocal; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015096:3-Hydroxysteroid Dehydrogenases
references: Am J Hum Genet. 2002 Feb;70(2):425-34
references: 11791212
references: Drug Metab Dispos. 2006 Jul;34(7):1237-46
references: 16638819
references: J Neurochem. 2005 Dec;95(6):1766-76
references: 16277617
references: Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9394-9
references: 15967990
references: Genome Res. 1998 Mar;8(3):195-202
references: 9521923
references: Mol Endocrinol. 1990 Dec;4(12):1850-5
references: 2082186
references: Endocr Rev. 2005 Jun;26(4):525-82
references: 15632317
references: J Biol Chem. 1992 Feb 15;267(5):3551
references: 1737804
references: J Biol Chem. 1997 Mar 21;272(12):7960-7
references: 9065466
references: Endocrinology. 1999 Oct;140(10):4573-84
references: 10499513
references: Endocr Rev. 2004 Dec;25(6):947-70
references: 15583024
references: Pharmacogenet Genomics. 2005 May;15(5):267-75
references: 15864127
references: Steroids. 1997 Jan;62(1):176-84
references: 9029734
references: Mol Endocrinol. 1999 Jan;13(1):66-81
references: 9892013
references: DNA Cell Biol. 1991 Dec;10(10):701-11
references: 1741954
references: J Steroid Biochem Mol Biol. 1993 Dec;46(6):773-9
references: 8274411
references: Endocrinology. 1994 Feb;134(2):751-9
references: 8299570
references: J Endocrinol. 1996 Sep;150 Suppl:S189-207
references: 8943802
references: Steroids. 1997 Jan;62(1):164-8
references: 9029732
references: Clin Pharmacol Ther. 2004 Apr;75(4):253-8
references: 15080131
references: Pharmacogenetics. 2003 Sep;13(9):555-64
references: 12972954
references: Endocrinology. 1994 Mar;134(3):1358-64
references: 8119176
references: Semin Reprod Med. 2002 Aug;20(3):255-76
references: 12428206
references: Oncogene. 2006 Mar 13;25(11):1629-38
references: 16550163
references: Nat Genet. 1999 May;22(1):78-81
references: 10319866
references: J Biol Chem. 1993 Sep 5;268(25):18507-12
references: 8360152
references: Genome Res. 2005 Nov;15(11):1592-3
references: 16251469
references: Mol Endocrinol. 1995 Nov;9(11):1598-609
references: 8584036
references: J Mol Endocrinol. 2001 Aug;27(1):77-83
references: 11463578
references: Mol Endocrinol. 1999 Jul;13(7):1084-93
references: 10406460
references: J Mol Endocrinol. 1999 Oct;23(2):231-9
references: 10514560
references: J Biol Chem. 2002 Nov 8;277(45):42795-801
references: 12205101
references: Nucleic Acids Res. 1997 Jul 15;25(14):2745-51
references: 9207020
references: Arch Fr Pediatr. 1985 Mar;42(3):175-9
references: 3873926
references: Endocr Res. 1998 Aug-Nov;24(3-4):549-57
references: 9888536
references: Am J Hum Genet. 2000 Oct;67(4):881-900
references: 10986041
references: Genetics. 1989 Nov;123(3):585-95
references: 2513255
references: Prostate. 2006 Mar 1;66(4):392-404
references: 16302261
references: Pharmacogenet Genomics. 2006 Apr;16(4):265-77
references: 16538173
references: Acta Paediatr Scand. 1990 Feb;79(2):168-75
references: 2321478
references: J Biol Chem. 1990 Nov 25;265(33):20469-75
references: 2243100
references: Steroids. 1997 Jan;62(1):169-75
references: 9029733
references: Cancer Res. 2005 Dec 1;65(23):11071-82
references: 16322257
references: J Biol Chem. 2006 Mar 17;281(11):7364-73
references: 16407288