Structure of the Human Type II 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4Isomerase (3β-HSD) Gene: Adrenal and Gonadal Specificity

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Abstract
While classical 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase deficiency (3β-HSD) is a known cause of adrenal hyperplasia resulting in ambiguous genitalia and adrenal insufficiency at birth, nonclassical or late-onset 3β-HSD deficiency is found in an important proportion of women with androgen excess. We have previously isolated and sequenced the cDNA and gene for the human type I 3β-HSD, which represents the main species expressed in the placenta and skin. Recently, we isolated, sequenced, and expressed the functional cDNA encoding type II 3β-HSD, which is the predominant 3β-HSD expressed in human adrenals and gonads. The present study describes the isolation and complete sequence of the corresponding type II 3β-HSD gene, which is the form most likely responsible for human 3β-HSD deficiency. The structural gene contains four exons of 57, 231, 165, and 1,214 bp, respectively, separated by introns of 128, 3,383, and 2,162 bp. DNA sequence analysis of the 5′-flanking region reveals the existence of two putative TATA boxes situated 28 and 140 nucleotides upstream from the transcription start site whereas two putative CAAT boxes are located 57 and 38 nucleotides upstream from the TATA boxes, respectively. A restriction fragment length pattern specific for each gene has been characterized. The present findings should provide the tools required for detailed analysis of the molecular basis of 3β-HSD deficiency as well as of normal sex steroid biosynthesis.

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