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Licensed Unlicensed Requires Authentication Published by De Gruyter August 1, 2010

Target deletion of the bifunctional type 12 17β-hydroxysteroid dehydrogenase in mice results in reduction of androgen and estrogen levels in heterozygotes and embryonic lethality in homozygotes

  • Véronique Bellemare , Daniel Phaneuf and Van Luu-The


17β-Hydroxysteroid dehydrogenases (17β-HSDs) are enzymes issued from convergent evolution of activity from various ancestral genes having different functions. Type 12 17β-HSD (17β-HSD12) was described as a bifunctional enzyme, involved in the biosynthesis of estradiol (E2) and the elongation of very long chain fatty acid (VLCFA). It catalyzes selectively the transformation of estrone (E1) into estradiol (E2) in human and primates, whereas in the mouse and Caenorhabditis elegans the enzyme catalyzes the 17β-reduction of both androgens and estrogens. It is also able to catalyze the reduction of 3-keto-acylCoA into 3-hydroxy-acylCoA in the elongation cycle of VLCFA biosynthesis. To further understand the physiological role of 17β-HSD12, we performed targeted disruption of the Hsd17b12 gene by substituting exons 8 and 9 that contain the active site with a neomycin cassette. The data indicate that heterozygous (HSD17B12+/–) mice are viable with reduced levels of sex steroids, whereas homozygous (HSD17B12–/–) mice show embryonic lethality. The present data are in agreement with the bifunctional activities of 17β-HSD12 suggesting that the VLCFA elongation activity, having its origin in the yeast, is most probably responsible for embryonic lethality in HSD17B12–/–, whereas the more recently acquired 17β-HSD12 activity is responsible for reduced sex steroid levels in HSD17B12+/–.

Corresponding author: Dr. Van Luu-The, Research Center in Molecular Endocrinology, Oncology and Human Genomics (CREMOGH) and Department of Molecular Medicine, Faculty of Medicine, Laval University and the Laval University Hospital Research Center (CRCHUL), 2705 Laurier Boulevard, T3–52 Quebec City, QC, G1V 4G2, Canada Phone: +1-418-654-2296, Fax: +1-418-654-2761,

Received: 2010-4-27
Accepted: 2010-7-20
Published Online: 2010-08-01
Published in Print: 2010-08-01

©2010 by Walter de Gruyter Berlin New York

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