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SRD5A2 (steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2))

Identity

HGNC (Hugo) SRD5A2
LocusID (NCBI) 6716
Location 2p23.1
Location_base_pair Starts at 31749656 and ends at 31806040 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description Genomic DNA of SRD5A2 gene spans about 58.6 kbp on chromosome 2p23.
Transcription Five exons with a long 3' UTR.

Protein

Description SRD5A2 is a microsomal protein of 254 amino acids in length.
Expression Androgen sensitive tissues, such as prostate.
Localisation Microsome.
Function SRD5A2 protein is an enzyme that converts testosterone to 5-alpha dihydrotestosterone (DHT) and progesterone or corticosterone into 5-alpha-3-oxosteroids. It is active at acidic pH, and is inhibited by finasteride.
Homology 50% homology with human SRD5A1 isoenzyme and 46% homology with rat 5-alpha-reductase.

Mutations

Note There were over 29 mutations of SRD5A2 gene documented in literature, including 12 single amino acid missense substitutions (Makridakis et al., 2000; Vilchis et al., 2008; Nie et al., 2011). It has been suggested that exon 4 may be a mutation hotspot region on the SRD5A2 gene (Vilchis et al., 2008). Some of the more studied polymorphisms of SRD5A2 included V89L, A49T, and the (TA)n dinucleotide repeat.

Implicated in

Entity Prostate cancer
Note Various genetic studies from multiple ethnic populations have shown genetic variations in the SRD5A2 gene are associated with prostate cancer. Polymorphisms V89L, A29T, and the (TA)n repeat are some of well-known SRD5A2 variation that have been liked to prostate cancer risk. However, these associations are not always consistent. For example, the V89L (rs523349) variant is a missense single nucleotide polymorphism resulting in a valine to leucine substitution at condon 89 that reduced SRD5A2 enzyme activity. More than couple dozen of studies performed genetic association studies between V89L polymorphism and prostate cancer risk since 1997. Although the association has been found significant repeatedly, the results were inconsistent and conflicting (Nam et al., 2001; Salam et al., 2005, Hsing et al., 2001). Recently, a meta-analysis review (Wang et al., 2010) was conducted on 25 genetic studies of SRD5A2 V89L polymorphism and prostate cancer, which included additional subgroup analysis in Asian, African, European and age ≤ 65 group. In overall analysis, no significant association was found between V89L and prostate cancer risk. Subgroup analysis revealed a slight but significant increased risk in European men with at least one L-allele (LL+LV vs VV, OR=1.11; 95%CI=1.03-1.19; P<0.01), and in men younger than 65 with LL genotype when compared to those with VV genotype (OR=1.70; 95%CI=1.14-2.68; P=0.02). The interethnic discrepancy of the effect of V89L may have arisen from a variable influence of the risk allele due to the significantly varied allelic distribution of V89L between the ethnic groups (Zeigler-Johnson et al., 2002). It was concluded that the V89L polymorphism plays a low-penetrant role in the risk of prostate cancer among European and men younger than 65 years of age.
Oncogenesis Androgen levels have been suggested to play an important role in the etiology of prostate cancer. The same SRD5A2 genetic variations linked to prostate cancer has also been repeatedly shown to be associated with various circulating androgen level in the blood, including testosterone, dihydrotestosterone and various forms of their metabolites (Makridakis et al., 2000; Allen et al., 2001; Hsing et al., 2001). Therefore, it is possible that these risk-predisposing polymorphisms may cause changes in the SRD5A2 enzyme functional activity that results in the variation of circulating androgens, and ultimately leads to the development of prostate cancer.
  

External links

Nomenclature
HGNC (Hugo)SRD5A2   11285
Cards
AtlasSRD5A2ID42385ch2p23
Entrez_Gene (NCBI)SRD5A2  6716  steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)
GeneCards (Weizmann)SRD5A2
Ensembl (Hinxton) [Gene_View]  chr2:31749656-31806040 [Contig_View]  SRD5A2 [Vega]
AceView (NCBI)SRD5A2
Genatlas (Paris)SRD5A2
WikiGenes6716
SOURCE (Princeton)NM_000348
Genomic and cartography
GoldenPath (UCSC)SRD5A2  -  2p23.1   chr2:31749656-31806040 -  2p23.1   [Description]    (hg19-Feb_2009)
EnsemblSRD5A2 - 2p23.1 [CytoView]
Mapping of homologs : NCBISRD5A2 [Mapview]
OMIM264600   607306   
Gene and transcription
Genbank (Entrez)AK307235 AK316597 BC112252 BC113641 EF560740
RefSeq transcript (Entrez)NM_000348
RefSeq genomic (Entrez)AC_000134 NC_000002 NC_018913 NG_008365 NT_022184 NW_001838769 NW_004929300
Consensus coding sequences : CCDS (NCBI)SRD5A2
Cluster EST : UnigeneHs.458345 [ NCBI ]
CGAP (NCI)Hs.458345
Alternative Splicing : Fast-db (Paris)GSHG0017533
Gene ExpressionSRD5A2 [ NCBI-GEO ]     SRD5A2 [ SEEK ]   SRD5A2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP31213 (Uniprot)
NextProtP31213  [Medical]
With graphics : InterProP31213
Splice isoforms : SwissVarP31213 (Swissvar)
Catalytic activity : Enzyme1.3.1.22 [ Enzyme-Expasy ]   1.3.1.221.3.1.22 [ IntEnz-EBI ]   1.3.1.22 [ BRENDA ]   1.3.1.22 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)S5A_REDUCTASE (PS50244)   
Domains : Interpro (EBI)3-oxo-5-alpha-steroid_4-DH    3-oxo-5_a-steroid_4-DH_C   
Related proteins : CluSTrP31213
Domain families : Pfam (Sanger)Steroid_dh (PF02544)   
Domain families : Pfam (NCBI)pfam02544   
DMDM Disease mutations6716
Blocks (Seattle)P31213
Peptide AtlasP31213
HPRD07390
IPIIPI00010651   
Protein Interaction databases
DIP (DOE-UCLA)P31213
IntAct (EBI)P31213
BioGRIDSRD5A2
IntegromeDBSRD5A2
STRING (EMBL)SRD5A2
Ontologies - Pathways
QuickGOP31213
Ontology : AmiGO3-oxo-5-alpha-steroid 4-dehydrogenase activity  endoplasmic reticulum membrane  androgen biosynthetic process  cell-cell signaling  steroid metabolic process  androgen metabolic process  male gonad development  sterol 5-alpha reductase activity  integral component of membrane  cell differentiation  small molecule metabolic process  cholestenone 5-alpha-reductase activity  oxidation-reduction process  
Ontology : EGO-EBI3-oxo-5-alpha-steroid 4-dehydrogenase activity  endoplasmic reticulum membrane  androgen biosynthetic process  cell-cell signaling  steroid metabolic process  androgen metabolic process  male gonad development  sterol 5-alpha reductase activity  integral component of membrane  cell differentiation  small molecule metabolic process  cholestenone 5-alpha-reductase activity  oxidation-reduction process  
Pathways : KEGGSteroid hormone biosynthesis    Prostate cancer   
REACTOMEP31213 [protein]
REACTOME PathwaysREACT_111217 Metabolism [pathway]
REACTOME PathwaysREACT_15493 Steroid hormones [pathway]
Protein Interaction DatabaseSRD5A2
Wikipedia pathwaysSRD5A2
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)SRD5A2
SNP (GeneSNP Utah)SRD5A2
SNP : HGBaseSRD5A2
Genetic variants : HAPMAPSRD5A2
1000_GenomesSRD5A2 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Zhejiang University Center for Genetic and Genomic Medicine (ZJU-CGGM)
DECIPHER (Syndromes)2:31749656-31806040
Mutations and Diseases : HGMDSRD5A2
OMIM264600    607306   
MedgenSRD5A2
GENETestsSRD5A2
Disease Genetic AssociationSRD5A2
Huge Navigator SRD5A2 [HugePedia]  SRD5A2 [HugeCancerGEM]
Genomic VariantsSRD5A2  SRD5A2 [DGVbeta]
Exome VariantSRD5A2
dbVarSRD5A2
ClinVarSRD5A2
snp3D : Map Gene to Disease6716
General knowledge
Homologs : HomoloGeneSRD5A2
Homology/Alignments : Family Browser (UCSC)SRD5A2
Phylogenetic Trees/Animal Genes : TreeFamSRD5A2
Chemical/Protein Interactions : CTD6716
Chemical/Pharm GKB GenePA36113
Clinical trialSRD5A2
Other databases
Probes
Litterature
PubMed191 Pubmed reference(s) in Entrez
CoreMineSRD5A2
GoPubMedSRD5A2
iHOPSRD5A2

Bibliography

International trends and patterns of prostate cancer incidence and mortality.
Hsing AW, Tsao L, Devesa SS.
Int J Cancer. 2000 Jan 1;85(1):60-7.
PMID 10585584
 
Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II.
Makridakis NM, di Salle E, Reichardt JK.
Pharmacogenetics. 2000 Jul;10(5):407-13.
PMID 10898110
 
The association between polymorphisms in the CYP17 and 5alpha-reductase (SRD5A2) genes and serum androgen concentrations in men.
Allen NE, Forrest MS, Key TJ.
Cancer Epidemiol Biomarkers Prev. 2001 Mar;10(3):185-9.
PMID 11303586
 
Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case-control study.
Hsing AW, Chen C, Chokkalingam AP, Gao YT, Dightman DA, Nguyen HT, Deng J, Cheng J, Sesterhenn IA, Mostofi FK, Stanczyk FZ, Reichardt JK.
Cancer Epidemiol Biomarkers Prev. 2001 Oct;10(10):1077-82.
PMID 11588134
 
V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression.
Nam RK, Toi A, Vesprini D, Ho M, Chu W, Harvie S, Sweet J, Trachtenberg J, Jewett MA, Narod SA.
Urology. 2001 Jan;57(1):199-204.
PMID 11164181
 
Ethnic differences in the frequency of prostate cancer susceptibility alleles at SRD5A2 and CYP3A4.
Zeigler-Johnson CM, Walker AH, Mancke B, Spangler E, Jalloh M, McBride S, Deitz A, Malkowicz SB, Ofori-Adjei D, Gueye SM, Rebbeck TR.
Hum Hered. 2002;54(1):13-21.
PMID 12446983
 
Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyperplasia and prostate cancer.
Salam MT, Ursin G, Skinner EC, Dessissa T, Reichardt JK.
Urol Oncol. 2005 Jul-Aug;23(4):246-53.
PMID 16018939
 
Novel compound heterozygous mutations in the SRD5A2 gene from 46,XY infants with ambiguous external genitalia.
Vilchis F, Valdez E, Ramos L, Garcia R, Gomez R, Chavez B.
J Hum Genet. 2008;53(5):401-6. doi: 10.1007/s10038-008-0274-2. Epub 2008 Mar 19.
PMID 18350250
 
Association of SRD5A2 variants and serum androstane-3alpha,17beta-diol glucuronide concentration in Chinese elderly men.
Jiang J, Tang NL, Ohlsson C, Eriksson AL, Vandenput L, Liao C, Wang X, Chan FW, Kwok A, Orwoll E, Kwok TC, Woo J, Leung PC.
Clin Chem. 2010 Nov;56(11):1742-9. doi: 10.1373/clinchem.2010.150607. Epub 2010 Sep 20.
PMID 20855474
 
SRD5A2 V89L polymorphism and prostate cancer risk: a meta-analysis.
Wang C, Tao W, Chen Q, Hu H, Wen XY, Han R.
Prostate. 2010 Feb 1;70(2):170-8. doi: 10.1002/pros.21050.
PMID 19760631
 
Five novel mutations of SRD5A2 found in eight Chinese patients with 46,XY disorders of sex development.
Nie M, Zhou Q, Mao J, Lu S, Wu X.
Mol Hum Reprod. 2011 Jan;17(1):57-62. doi: 10.1093/molehr/gaq072. Epub 2010 Aug 24.
PMID 20736251
 
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Contributor(s)

Written05-2013Nelson LS Tang, Chen Di Liao
Department of Chemical Pathology, The Chinese University of Hong Kong, China

Citation

This paper should be referenced as such :
Tang, NLS ; Liao, CD
SRD5A2 (steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2))
Atlas Genet Cytogenet Oncol Haematol. 2013;17(11):757-758.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/SRD5A2ID42385ch2p23.html

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indexed on : Sat Nov 8 16:28:04 CET 2014

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