Alternative titles; symbols
HGNC Approved Gene Symbol: HSD17B1
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:42,552,923-42,555,214 (from NCBI)
The enzyme that is responsible for the interconversion of estrone (E1) and estradiol (E2) as well as the interconversion of androstenedione and testosterone is known as either 17-beta-hydroxysteroid dehydrogenase or 17-ketosteroid reductase (Migeon, 1990). Harkness et al. (1979) concluded that there are at least 2 forms of 17-beta-hydroxysteroid oxidoreductase (EC 1.1.1.64) under independent genetic control and that only 1 of these is localized to the testis. Luu-The et al. (1990) isolated, sequenced, and characterized 2 in-tandem 17-beta-hydroxysteroid dehydrogenase genes that reside within a 13-kb genomic DNA fragment. In addition to being found in ovary, testis, and placenta, appreciable levels of 17-beta-HSD mRNAs were found in peripheral tissues such as uterus, breast, prostate, and fat.
Green et al. (1999) investigated HSD17B1, -2 (109685), -3 (605573), and -4 (601860) gene expression and HSD17B estrogenic activity in human anterior pituitary adenomas. HSD17B mRNA expression was studied by RT-PCR in 42 pituitary tumors and 3 normal pituitaries, HSD17B activity was studied in 11 tumors, and HSD17B1 was immunolocalized in vitro in 6 tumors. HSD17B1 gene expression was detected in 34 of 42 (81%) adenomas in all tumor subtypes; HSD17B2 mRNA was detected in 18 of 42 (43%) adenomas but not in prolactinomas; HSD17B3 mRNA was detected in 12 of 42 (29%) adenomas but not in corticotropinomas; and HSD17B4 was expressed in 20 of 42 (48%) adenomas by all adenoma subtypes. All 4 HSD17B isoforms were variably expressed in human anterior pituitary adenomas, which also showed HSD17B enzyme activity, suggesting that HSD17B may play an important role in regulating the local cellular levels of estradiol.
Normand et al. (1993) determined the complete nucleotide sequence of the EDH17B2 gene in 4 unrelated individuals. Direct sequencing of PCR fragments that spanned the complete gene revealed a total of 11 allelic variants that were due to single-base substitutions. Studies in 26 unrelated persons demonstrated that 9 of these variants were frequent polymorphisms and 2 of them rare variants. Complete linkage disequilibrium was demonstrated for 7 of the 11 polymorphisms. They suggested that these polymorphisms could be used for further mapping of the gene and for establishing whether EDH17B2 is a candidate gene for hereditary breast-ovarian cancer. The second EDH17B2 gene that was mapped to chromosome 17 is, in fact, a pseudogene (Russell, 1994), EDH17BP1.
Human estrogenic HSD17B1 is an NADP(H)-preferring enzyme. It possesses 11- and 4-fold higher specificity toward NADP(H) over NAD(H) for oxidation and reduction, respectively, as demonstrated by kinetic studies. To elucidate the roles of the amino acids involved, Huang et al. (2001) generated variants by site-directed mutagenesis. The results showed that introducing a positively charged residue, lysine, at the ser12 position increased the enzyme's preference for NADP(H) more than 20-fold. Substitution of a negatively charged residue, aspartic acid, into the leu36 position switched the enzyme's cofactor preference from NADPH to NAD with a 220-fold change in the ratio of the specificity toward the 2 cofactors in the case of oxidation. The substrate-binding pocket was also studied with 4 variants: ser142 to gly, ser142 to cys, his221 to ala, and glu282 to ala. The ser142-to-gly variant abolished most of the enzyme's oxidation and reduction activities. His221 variation weakened the apparent affinity for estrone, as demonstrated by a 30-fold increase in Michaelis-Menten constant, supporting its important role in substrate binding.
Berube et al. (1989) mapped the gene for this enzyme to 17q11-q12 by in situ hybridization. By Southern blotting studies, Tremblay et al. (1989) concluded that the mRNA for estrogenic 17-KSR is encoded by 2 similar genes, which they localized to 17cen-q25 by analysis of DNA from mouse/human somatic hybrid cell lines. Winqvist et al. (1990) assigned the 17-HSD gene to chromosome 17 by Southern blot analysis of human/rodent somatic cell hybrids and independently to 17q12-q21 by chromosomal in situ hybridization. Male pseudohermaphroditism (264300) is caused by mutations in the testicular isoform, 17-beta-hydroxysteroid dehydrogenase-3 (605573) (Geissler et al., 1994).
Berube, D., Luu-The, V., Simard, J., Gagne, R., Labrie, F. Localization of the beta-estradiol dehydrogenase genes to q11-q12 of chromosome 17. (Abstract) Cytogenet. Cell Genet. 51: 962 only, 1989.
Geissler, W. M., Davis, D. L., Wu, L., Bradshaw, K. D., Patel, S., Mendonca, B. B., Elliston, K. O., Wilson, J. D., Russell, D. W., Andersson, S. Male pseudohermaphroditism caused by mutations of testicular 17-beta-hydroxysteroid dehydrogenase 3. Nature Genet. 7: 34-39, 1994. [PubMed: 8075637] [Full Text: https://doi.org/10.1038/ng0594-34]
Green, V. L., Speirs, V., Landolt, A. M., Foy, P. M., Atkin, S. L. 17-beta-hydroxysteroid dehydrogenase type 1, 2, 3, and 4 expression and enzyme activity in human anterior pituitary adenomas. J. Clin. Endocr. Metab. 84: 1340-1345, 1999. [PubMed: 10199776] [Full Text: https://doi.org/10.1210/jcem.84.4.5619]
Harkness, R. A., Thistlethwaite, D., Darling, J. A. B., Skakkebaek, N. E., Corker, C. S. Neutral 17-beta-hydroxysteroid oxidoreductase deficiency in testes causing male pseudohermaphroditism in an infant. J. Inherit. Metab. Dis. 2: 51-54, 1979.
Huang, Y.-W., Pineau, I., Chang, H.-J., Azzi, A., Bellemare, V., Laberge, S., Lin, S.-X. Critical residues for the specificity of cofactors and substrates in human estrogenic 17-beta-hydroxysteroid dehydrogenase 1: variants designed from the three-dimensional structure of the enzyme. Molec. Endocr. 15: 2010-2020, 2001. [PubMed: 11682630] [Full Text: https://doi.org/10.1210/mend.15.11.0730]
Luu-The, V., Labrie, C., Simard, J., Lachance, Y., Zhao, H.-F., Couet, J., Leblanc, G., Labrie, F. Structure of two in tandem human 17-beta-hydroxysteroid dehydrogenase genes. Molec. Endocr. 4: 268-275, 1990. [PubMed: 2330005] [Full Text: https://doi.org/10.1210/mend-4-2-268]
Migeon, C. J. Personal Communication. Baltimore, Md. 10/29/1990.
Normand, T., Narod, S., Labrie, F., Simard, J. Detection of polymorphisms in the estradiol 17-beta-hydroxysteroid dehydrogenase II gene at the EDH17B2 locus on 17q11-q21. Hum. Molec. Genet. 2: 479-483, 1993. [PubMed: 8389226] [Full Text: https://doi.org/10.1093/hmg/2.4.479]
Russell, D. W. Personal Communication. Dallas, Texas 5/9/1994.
Tremblay, Y., Ringler, G. E., Morel, Y., Mohandas, T. K., Labrie, F., Strauss, J. F., III, Miller, W. L. Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen-q25. J. Biol. Chem. 264: 20458-20462, 1989. [PubMed: 2584224]
Winqvist, R., Peltoketo, H., Isomaa, V., Grzeschik, K. H., Mannermaa, A., Vihko, R. The gene for 17-beta-hydroxysteroid dehydrogenase maps to human chromosome 17, bands q12-q21, and shows an RFLP with ScaI. Hum. Genet. 85: 473-476, 1990. [PubMed: 1977681] [Full Text: https://doi.org/10.1007/BF00194219]