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

Abstract

While classical 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase deficiency (3 beta-HSD) is a known cause of adrenal hyperplasia resulting in ambiguous genitalia and adrenal insufficiency at birth, nonclassical or late-onset 3 beta-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 3 beta-HSD, which represents the main species expressed in the placenta and skin. Recently, we isolated, sequenced, and expressed the functional cDNA encoding type II 3 beta-HSD, which is the predominant 3 beta-HSD expressed in human adrenals and gonads. The present study describes the isolation and complete sequence of the corresponding type II 3 beta-HSD gene, which is the form most likely responsible for human 3 beta-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 3 beta-HSD deficiency as well as of normal sex steroid biosynthesis.

The new biology of aldosterone

“…Two 3 -HSD isoenzymes have been identified in humans and several in the rat and mouse (Mason 1993, Simard et al 1993. HSD3B1 and HSD3B2 are encoded by the 3 -HSD1 and 3 -HSD2 genes, respectively, which lie in tandem on chromosome 1p13·1 (Berube et al 1989, Lachance et al 1991.…”

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

“…The full name of the enzyme is 3␤-hydroxysteroid dehydrogenase/ 5 -4 isomerase, because it catalyzes two reactions on separate active sites, located on a single protein: the dehydrogenation of 3␤-hydroxysteroids (3␤-HSD activity) and the subsequent isomerization of 5 -3-ketosteroids (double bond between C5 and C6) to 4 -3-ketosteroids (double bond between C4 and C5; ketosteroid isomerase (KSI) activity). The cDNAs of two human isoforms (types I and II) have been isolated, respectively, from placenta and adrenal glands and the corresponding genes, located on chromosome 1, have been cloned (Lachance et al, 1990(Lachance et al, , 1991. Mutations in the type II gene, which is predominantly expressed in the adrenal glands and gonads, have been related to different forms of congenital adrenal hyperplasia associated with pseudohermaphroditism (Simard et al, 1995).…”

Ovarian 3,β‐hydroxysteroid dehydrogenase/Δ5‐4‐isomerase of rainbow trout: Its cDNA cloning and properties of the enzyme expressed in a mammalian cell

“…3). The data indicate the presence of a single gene encoding 3fl-HSD in the rainbow trout, differing from the multiple related 3~-HSD isoenzymes in human [9,12,13,[25][26][27], rat [8,17,18], and mouse [16].…”