HGNC Approved Gene Symbol: SRD5A1
Cytogenetic location: 5p15.31 Genomic coordinates (GRCh38): 5:6,633,440-6,674,386 (from NCBI)
Steroid 5-alpha-reductase (EC 1.3.99.5) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT). Also see SRD5A2 (607306).
Andersson and Russell (1990) described the structure of a cDNA encoding human steroid 5-alpha-reductase. Sequence analysis indicated that the enzyme is a hydrophobic protein of 259 amino acids with a predicted molecular mass of 29,462 Da. The human and rat proteins share 60% sequence identity.
Using a cDNA isolated from a prostate cDNA library for analysis of Chinese hamster/human somatic cell hybrid lines, Hsieh et al. (1991) demonstrated that the steroid 5-alpha-reductase gene is located on chromosome 5 and on 5pter-q13 in a regional mapping panel. By in situ hybridization, the gene was localized to 5p15.
Hsieh et al. (1991) mapped the homologous gene (Srd5a-1) to mouse chromosome 13 in a panel of Chinese hamster or rat/mouse somatic cell hybrids and by study of recombinant inbred strains. A human pseudogene was found in the Xq24-qter region; no such gene was found in the mouse. Also see Jenkins et al. (1991).
By bioinformatic analysis of SRD5A gene family members, Cantagrel et al. (2010) showed that proteins with a steroid 5-alpha-reductase domain could be separated into 3 groups. SRD5A1 and SRD5A2 belonged to 1 group, whereas SRD5A3 (611715), which is a polyprenol reductase, and its yeast ortholog Dfg10, constituted a second group. The third group consisted of TECR (610057), which is an enoyl reductase, and TECRL (617242). The phylogenetic analysis supported the idea that different classes of lipids can be substrates for these enzymes and suggested that the substrate of the enzyme encoded by the common ancestral gene was potentially not a steroid.
Harris et al. (1992) concluded that SRD5A1 is a minor component of the reductase activity in prostate although the gene was originally cloned from prostate. On the other hand, SRD5A1 appears to be the predominant isozyme of steroid 5-alpha-reductase in the scalp and elsewhere in the skin. The possibility of scalp-selective inhibitors being useful in the treatment of male pattern baldness, acne, and hirsutism, all 'disorders' that appear to be dihydrotestosterone dependent, was raised.
Investigating by immunoblotting the tissue-specific and developmental expression patterns of the 5-alpha-reductase isozymes, Thigpen et al. (1993) showed that the type 1 isozyme is not detectable in the fetus, is transiently expressed in newborn skin and scalp, and is permanently expressed in skin from the time of puberty. There was no qualitative difference in 5-alpha-reductase type 1 expression between adult balding versus nonbalding scalp. The type 2 isozyme was transiently expressed in skin and scalp of newborns. Type 2 is the predominant isozyme detectable in fetal genital skin, in male accessory sex organs, and in the prostate, including benign prostatic hyperplasia and prostate adenocarcinoma tissues. These results were considered consistent with 5-alpha-reductase type 1 being responsible for the virilization in type 2-deficient subjects (see 264600) during puberty and suggested that the type 2 isozyme may be an initiating factor in the development of male pattern baldness.
From a population survey of 828 healthy families comprising 3,000 individuals, Ellis et al. (1998) identified 58 young bald men (aged 18 to 30 years) and 114 older nonbald men (aged 50 to 70 years) for a case-control comparison. No significant differences were found between cases and controls in allele, genotype, or haplotype frequencies for RFLPs related to either the SRD5A1 or the SRD5A2 gene. These findings suggested that the genes encoding these 5-alpha-reductase isoenzymes are not associated with male pattern baldness. Ellis et al. (1998) failed to find a clear inheritance pattern of male pattern baldness.
Jakimiuk et al. (1999) sought to determine if there is increased SRD5A activity or mRNA expression in polycystic ovaries. SRD5A1 and SRD5A2 mRNAs were measured in thecal (TC) and granulosa (GC) cells from individual follicles of 18 women with polycystic ovary syndrome (PCOS; 184700) and 26 regularly cycling control women. SRD5A1 and SRD5A2 mRNA expression was higher in GC than in TC, and SRD5A2 mRNA levels were approximately 3-fold higher than SRD5A1 mRNA. SRD5A1 and SRD5A2 mRNA expression was similar in GC from PCOS and control women, but SRD5A mRNA was decreased in TC from PCOS follicles. The total SRD5A activity was approximately 4-fold higher in PCOS follicles than in control follicles. These data demonstrated elevated SRD5A activity in polycystic ovaries and supported the hypothesis that 5-alpha-reduced androgens may play a role in the pathogenesis of PCOS.
Jenkins et al. (1992) used RFLPs of the SRD5A1 gene to exclude the gene as the site of the mutation in classic 5-alpha-reductase deficiency (pseudovaginal perineoscrotal hypospadias; 264600). They further showed that in contrast to the major steroid 5-alpha-reductase in the prostate and cultured skin fibroblasts, which was designated SRD5A2, the cDNA-encoded enzyme, representing SRD5A1, exhibited a neutral to basic pH optimum and was much less sensitive to inhibition by the 4-aza steroid finasteride.
Goodarzi et al. (2006) tested the hypothesis that haplotypes in the SRD5A1 and SRD5A2 genes are risk factors for PCOS and the severity of hirsutism in affected women. A total of 287 white women with PCOS and 187 controls participated. Haplotypes within both genes were associated with PCOS risk. Haplotypes in SRD5A1 but not SRD5A2 were also associated with the degree of hirsutism in affected women. That only SRD5A1 haplotypes were associated with hirsutism suggested to Goodarzi et al. (2006) that only this isoform is important in the hair follicle.
Andersson, S., Russell, D. W. Structural and biochemical properties of cloned and expressed human and rat steroid 5-alpha-reductases. Proc. Nat. Acad. Sci. 87: 3640-3644, 1990. [PubMed: 2339109] [Full Text: https://doi.org/10.1073/pnas.87.10.3640]
Cantagrel, V., Lefeber, D. J., Ng, B. G., Guan, Z., Silhavy, J. L., Bielas, S. L., Lehle, L., Hombauer, H., Adamowicz, M., Swiezewska, E., De Brouwer, A. P., Blumel, P., and 13 others. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell 142: 203-217, 2010. [PubMed: 20637498] [Full Text: https://doi.org/10.1016/j.cell.2010.06.001]
Ellis, J. A., Stebbing, M., Harrap, S. B. Genetic analysis of male pattern baldness and the 5-alpha-reductase genes. J. Invest. Derm. 110: 849-853, 1998. [PubMed: 9620288] [Full Text: https://doi.org/10.1046/j.1523-1747.1998.00224.x]
Goodarzi, M. O., Shah, N. A., Antoine, H. J., Pall, M., Guo, X., Azziz, R. Variants in the 5-alpha-reductase type 1 and type 2 genes are associated with polycystic ovary syndrome and the severity of hirsutism in affected women. J. Clin. Endocr. Metab. 91: 4085-4091, 2006. [PubMed: 16849416] [Full Text: https://doi.org/10.1210/jc.2006-0227]
Harris, G., Azzolina, B., Baginsky, W., Cimis, G., Rasmusson, G. H., Tolman, R. L., Raetz, C. R. H., Ellsworth, K. Identification and selective inhibition of an isozyme of steroid 5-alpha-reductase in human scalp. Proc. Nat. Acad. Sci. 89: 10787-10791, 1992. [PubMed: 1438277] [Full Text: https://doi.org/10.1073/pnas.89.22.10787]
Hsieh, C.-L., Milatovich, A., Russell, D., Francke, U. Chromosomal mapping of human steroid 5 alpha-reductase gene (SRD5A1) and pseudogene (SRD5AP1) in human and mouse. (Abstract) Cytogenet. Cell Genet. 58: 1897 only, 1991.
Jakimiuk, A. J., Weitsman, S. R., Magoffin, D. A. 5-alpha-reductase activity in women with polycystic ovary syndrome. J. Clin. Endocr. Metab. 84: 2414-2418, 1999. [PubMed: 10404813] [Full Text: https://doi.org/10.1210/jcem.84.7.5863]
Jenkins, E. P., Andersson, S., Imperato-McGinley, J., Wilson, J. D., Russell, D. W. Genetic and pharmacological evidence for more than one human steroid 5-alpha-reductase. J. Clin. Invest. 89: 293-300, 1992. [PubMed: 1345916] [Full Text: https://doi.org/10.1172/JCI115574]
Jenkins, E. P., Hsieh, C.-L., Milatovich, A., Normington, K., Berman, D. M., Francke, U., Russell, D. W. Characterization and chromosomal mapping of a human steroid 5-alpha-reductase gene and pseudogene and mapping of the mouse homologue. Genomics 11: 1102-1112, 1991. [PubMed: 1686016] [Full Text: https://doi.org/10.1016/0888-7543(91)90038-g]
Thigpen, A. E., Silver, R. I., Guileyardo, J. M., Casey, M. L., McConnell, J. D., Russell, D. W. Tissue distribution and ontogeny of steroid 5-alpha-reductase isozyme expression. J. Clin. Invest. 92: 903-910, 1993. [PubMed: 7688765] [Full Text: https://doi.org/10.1172/JCI116665]