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SRD5A2  -  steroid-5-alpha-reductase, alpha...

Homo sapiens

Synonyms: 3-oxo-5-alpha-steroid 4-dehydrogenase 2, 5 alpha-SR2, S5AR 2, SR type 2, Steroid 5-alpha-reductase 2, ...
 
 
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Disease relevance of SRD5A2

 

Psychiatry related information on SRD5A2

 

High impact information on SRD5A2

 

Chemical compound and disease context of SRD5A2

 

Biological context of SRD5A2

  • We observed significant association for several SNPs in the AR gene (P = 0.004-0.02) and CYP17 (P = 0.009-0.05) and one SNP in SRD5A2 (P = 0.02) [1].
  • We selected 23 haplotype-tagging single-nucleotide polymorphisms (htSNP) that could uniquely describe >95% of the haplotypes (6 in AR, 6 in CYP17, and 11 in SRD5A2) [1].
  • METHODS: The expression differences of SRD5A2 in tissues representative of normal, benign, and malignant growth in the human prostate were examined in parallel by comparative analysis of relevant microarray gene expression data [15].
  • Specifically, we examined the hypothesis that DNA sequence (allelic) variations in the type II (or prostatic) steroid 5alpha-reductase (SRD5A2) gene contribute substantially to the risk and progression of prostate cancer particularly across racial/ethnic lines [16].
  • The "candidate gene", SRD5A2, was chosen because the reaction product [i.e. dihydrotestosterone (DHT)] of the enzyme encoded by this gene modulates directly cell division in the prostate [16].
 

Anatomical context of SRD5A2

  • Individuals carrying the mutated SRD5A2 A49T allele (5.3% of the total population) had larger prostates (54.1 vs. 39.3 ml), higher PSA levels (12.2 vs. 4.3 ng/ml), and a 35% reduction in prostatic stroma/epithelial cell ratio [17].
  • The compound heterozygote mutations in SRD5A2 gene explained an extremely low 5alpha-reductase enzyme activity in genital skin fibroblasts [18].
  • BACKGROUND: AND OBJECTIVE: Mutations of the steroid 5alpha-reductase type 2 (SRD5A2) gene in karyotypic males result in a spectrum of external genitalia phenotypes ranging from complete female to nearly complete male [19].
  • We have investigated a polymorphic (TA)n dinucleotide repeat in the 3' UTR (untranslated region) of the SRD5A2 gene in 30 matched samples of constitutional ("germline") DNA from peripheral blood lymphocytes and microdissected, pure tumor DNA [20].
  • The enzyme steroid 5alpha-reductase 2 (encoded by the SRD5A2 gene) catalyses the conversion of testosterone to dihydrotestosterone, which is required for normal differentiation of the external male genitalia [21].
 

Associations of SRD5A2 with chemical compounds

  • BACKGROUND: Steroid 5alpha-reductase 2 (SRD5A2) catalyzes the conversion of testosterone to the more potent androgen, DHT, in the prostate [15].
  • The SRD5A2 gene harbours two frequent polymorphic sites, one in the coding region, at codon 89 of exon 1, where valine is substituted by leucine (V89L) and the other in the 3' untranslated region (3' UTR) where a variable number of dinucleotide TA repeat lengths exists [22].
  • Thus, steroid 5alpha-reductase activity encoded by SRD5A2 variant alleles may be important in regulating intraprostatic DHT steady state levels by controlling its biosynthesis [16].
  • Several polymorphisms have been identified in the SRD5A2 gene, including a valine-to-leucine substitution (V89L) at codon 89, a variable number of TA dinucleotide repeats and a missense substitution at codon 49 resulting in an amino acid substitution of alanine with threonine (A49T) [11].
  • Testosterone enanthate therapy is effective and independent of SRD5A2 and AR gene polymorphisms in boys with micropenis [23].
 

Regulatory relationships of SRD5A2

 

Other interactions of SRD5A2

  • No aberrant expression of AKR1C4 expression or significant differences in SRD5A2 gene expression were found [25].
  • Polymorphisms in SRD5A2 were not associated with severity of BPH; however, SRD5A1 polymorphisms were associated with severity of BPH [26].
  • Conversely, it is possible that an individual carries both a high- and a low-risk marker (e.g., CYP17 A2 allele and V89L in SRD5A2) resulting in no overall difference in risk observed across the population [27].
  • I summarize the significant findings, particularly of allelic variants in the HSD3B2 and SRD5A2 genes and discuss how they by themselves, in combination and through interactions with the environment may play a role in prostate cancer predisposition and its progression [16].
  • No differences were observed for SRD5A2 and COMT gene polymorphisms [28].
 

Analytical, diagnostic and therapeutic context of SRD5A2

References

  1. Germ-Line Genetic Variation in the Key Androgen-Regulating Genes Androgen Receptor, Cytochrome P450, and Steroid-5-{alpha}-Reductase Type 2 Is Important for Prostate Cancer Development. Lindstr??m, S., Wiklund, F., Adami, H.O., B??lter, K.A., Adolfsson, J., Gr??nberg, H. Cancer Res. (2006) [Pubmed]
  2. Uniparental disomy in steroid 5alpha-reductase 2 deficiency. Chávez, B., Valdez, E., Vilchis, F. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  3. 5alpha-reductase 2 polymorphisms as risk factors in prostate cancer. Söderström, T., Wadelius, M., Andersson, S.O., Johansson, J.E., Johansson, S., Granath, F., Rane, A. Pharmacogenetics (2002) [Pubmed]
  4. Mutation analysis of five candidate genes in Chinese patients with hypospadias. Wang, Y., Li, Q., Xu, J., Liu, Q., Wang, W., Lin, Y., Ma, F., Chen, T., Li, S., Shen, Y. Eur. J. Hum. Genet. (2004) [Pubmed]
  5. A novel homozygous disruptive mutation in the SRD5A2-gene in a partially virilized patient with 5alpha-reductase deficiency. Hiort, O., Schütt, S.M., Bals-Pratsch, M., Holterhus, P.M., Marschke, C., Struve, D. Int. J. Androl. (2002) [Pubmed]
  6. Steroid 5 alpha-reductase 2 deficiency. Wilson, J.D., Griffin, J.E., Russell, D.W. Endocr. Rev. (1993) [Pubmed]
  7. Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism. Andersson, S., Berman, D.M., Jenkins, E.P., Russell, D.W. Nature (1991) [Pubmed]
  8. Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men. Yu, M.W., Yang, Y.C., Yang, S.Y., Cheng, S.W., Liaw, Y.F., Lin, S.M., Chen, C.J. J. Natl. Cancer Inst. (2001) [Pubmed]
  9. Molecular genetics of steroid 5 alpha-reductase 2 deficiency. Thigpen, A.E., Davis, D.L., Milatovich, A., Mendonca, B.B., Imperato-McGinley, J., Griffin, J.E., Francke, U., Wilson, J.D., Russell, D.W. J. Clin. Invest. (1992) [Pubmed]
  10. Identification and characterization of somatic steroid 5alpha-reductase (SRD5A2) mutations in human prostate cancer tissue. Makridakis, N., Akalu, A., Reichardt, J.K. Oncogene (2004) [Pubmed]
  11. Polymorphic markers in the 5alpha-reductase type II gene and the incidence of prostate cancer. Lamharzi, N., Johnson, M.M., Goodman, G., Etzioni, R., Weiss, N.S., Dightman, D.A., Barnett, M., DiTommaso, D., Chen, C. Int. J. Cancer (2003) [Pubmed]
  12. Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17, and the AR. Cicek, M.S., Conti, D.V., Curran, A., Neville, P.J., Paris, P.L., Casey, G., Witte, J.S. Prostate (2004) [Pubmed]
  13. Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyperplasia and prostate cancer. Salam, M.T., Ursin, G., Skinner, E.C., Dessissa, T., Reichardt, J.K. Urol. Oncol. (2005) [Pubmed]
  14. Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2). Lunn, R.M., Bell, D.A., Mohler, J.L., Taylor, J.A. Carcinogenesis (1999) [Pubmed]
  15. Decreased gene expression of steroid 5 alpha-reductase 2 in human prostate cancer: implications for finasteride therapy of prostate carcinoma. Luo, J., Dunn, T.A., Ewing, C.M., Walsh, P.C., Isaacs, W.B. Prostate (2003) [Pubmed]
  16. GEN GEN: the genomic genetic analysis of androgen-metabolic genes and prostate cancer as a paradigm for the dissection of complex phenotypes. Reichardt, J.K. Front. Biosci. (1999) [Pubmed]
  17. Association of polymorphisms within androgen receptor, 5alpha-reductase, and PSA genes with prostate volume, clinical parameters, and endocrine status in elderly men. Schatzl, G., Madersbacher, S., Gsur, A., Preyer, M., Haidinger, G., Haitel, A., Vutuc, C., Micksche, M., Marberger, M. Prostate (2002) [Pubmed]
  18. Clinical, biochemical and morphologic diagnostic markers in an infant male pseudohermaphrodite patient with compound heterozygous mutations (G115D/R246W) in SRD5A2 gene. Fernández-Cancio, M., Rodó, J., Andaluz, P., Martínez de Osaba, M.J., Rodríguez-Hierro, F., Esteban, C., Carrascosa, A., Audí, L. Horm. Res. (2004) [Pubmed]
  19. Identification of missense mutations in the SRD5A2 gene from patients with steroid 5alpha-reductase 2 deficiency. Vilchis, F., Méndez, J.P., Canto, P., Lieberman, E., Chávez, B. Clin. Endocrinol. (Oxf) (2000) [Pubmed]
  20. Somatic mutations at the SRD5A2 locus encoding prostatic steroid 5alpha-reductase during prostate cancer progression. Akalu, A., Dlmajian, D.A., Highshaw, R.A., Nichols, P.W., Reichardt, J.K. J. Urol. (1999) [Pubmed]
  21. New frameshift mutation in the 5alpha-reductase type 2 gene in a Brazilian patient with 5alpha-reductase deficiency. Ferraz, L.F., Mathias Baptista, M.T., Maciel-Guerra, A.T., Júnior, G.G., Hackel, C. Am. J. Med. Genet. (1999) [Pubmed]
  22. Codon 89 polymorphism in the human 5 alpha-reductase gene in primary breast cancer. Scorilas, A., Bharaj, B., Giai, M., Diamandis, E.P. Br. J. Cancer (2001) [Pubmed]
  23. Testosterone enanthate therapy is effective and independent of SRD5A2 and AR gene polymorphisms in boys with micropenis. Ishii, T., Sasaki, G., Hasegawa, T., Sato, S., Matsuo, N., Ogata, T. J. Urol. (2004) [Pubmed]
  24. The relationship between a polymorphism in CYP17 with plasma hormone levels and prostate cancer. Haiman, C.A., Stampfer, M.J., Giovannucci, E., Ma, J., Decalo, N.E., Kantoff, P.W., Hunter, D.J. Cancer Epidemiol. Biomarkers Prev. (2001) [Pubmed]
  25. Selective reduction of AKR1C2 in prostate cancer and its role in DHT metabolism. Ji, Q., Chang, L., VanDenBerg, D., Stanczyk, F.Z., Stolz, A. Prostate (2003) [Pubmed]
  26. A case-based evaluation of SRD5A1, SRD5A2, AR, and ADRA1A as candidate genes for severity of BPH. Klotsman, M., Weinberg, C.R., Davis, K., Binnie, C.G., Hartmann, K.E. Pharmacogenomics J. (2004) [Pubmed]
  27. Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways. Latil, A.G., Azzouzi, R., Cancel, G.S., Guillaume, E.C., Cochan-Priollet, B., Berthon, P.L., Cussenot, O. Cancer (2001) [Pubmed]
  28. Genetic polymorphisms of steroid hormone metabolizing enzymes and risk of liver cancer in hepatitis C-infected patients. Rossi, L., Leveri, M., Gritti, C., De Silvestri, A., Zavaglia, C., Sonzogni, L., Silvestri, L., Civardi, E., Mondelli, M.U., Silini, E.M. J. Hepatol. (2003) [Pubmed]
  29. Genetic linkage mapping of the human steroid 5 alpha-reductase type 2 gene (SRD5A2) close to D2S352 on chromosome region 2p23-->p22. Morissette, J., Durocher, F., Leblanc, J.F., Normand, T., Labrie, F., Simard, J. Cytogenet. Cell Genet. (1996) [Pubmed]
 
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