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SRD5A2
steroid 5 alpha-reductase 2
SRD5A2 is located on the short (p) arm of chromosome 2, at band 2p23.1. Arm ratio per GRCh38 - banding schematic.
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Overview
SRD5A2 is located on chromosome 2 and encodes steroid 5-alpha reductase 2, an enzyme that plays a central role in androgen hormone processing. The enzyme facilitates a chemical reaction that transforms testosterone into dihydrotestosterone (DHT), a more potent form of androgen essential for the development of male external genitalia and the prostate gland. During foetal development, DHT directs the formation of the penis and scrotum, whilst testosterone guides the development of internal reproductive structures. At puberty, both hormones contribute to the emergence of secondary sex characteristics including facial and body hair growth, muscle development, and voice deepening. Pathogenic changes in SRD5A2 can reduce or eliminate enzyme activity, leading to atypical genital development in individuals with 46,XY chromosomes.
What the gene does
The steroid 5-alpha reductase 2 enzyme functions primarily in male reproductive tissues, where it catalyses the irreversible reduction of testosterone to dihydrotestosterone. This biochemical conversion involves the addition of hydrogen atoms to the testosterone molecule, creating a hormone with significantly greater binding affinity for androgen receptors. DHT exhibits approximately three to five times the potency of testosterone in activating these receptors, making it particularly important during critical developmental windows.
Before birth, the enzyme is active in genital tissues, where DHT signalling orchestrates the differentiation of external male anatomy. In adult tissues, steroid 5-alpha reductase 2 continues to operate in the prostate gland, skin, and other androgen-sensitive sites. The enzyme's substrate specificity extends beyond testosterone to include other steroid hormones, though testosterone conversion represents its most clinically significant function. The efficiency of this enzymatic reaction influences local androgen availability and cellular responses throughout reproductive development and adult physiology.
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Chromosome location
SRD5A2 is located on the short arm of chromosome 2 at position 23.1 (2p23.1). The gene spans approximately 40 kilobases of genomic DNA and contains five coding exons. The relatively compact structure of SRD5A2 facilitates complete sequencing in clinical diagnostic settings. The chromosomal region 2p23.1 contains several other genes involved in metabolic processes, though SRD5A2 represents the primary androgen-processing enzyme encoded in this vicinity.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The mature steroid 5-alpha reductase 2 polypeptide comprises 254 amino acids and functions as a membrane-bound enzyme embedded in the endoplasmic reticulum. The protein adopts a structure that allows it to interact with both steroid substrates and the cofactor NADPH, which provides the reducing power for the enzymatic reaction. Certain regions of the protein sequence are highly conserved across species, suggesting critical functional importance for substrate binding and catalytic activity.
Key variants
Approximately 50 pathogenic variants in SRD5A2 have been identified in individuals with 5-alpha reductase deficiency. Most pathogenic changes involve single amino acid substitutions that either completely abolish enzyme activity or substantially reduce catalytic efficiency. Missense variants are the most common class of pathogenic alteration, though small deletions and nonsense changes have also been documented. The severity of clinical features generally correlates with the degree of residual enzyme function, with complete loss-of-function variants typically producing more pronounced developmental differences than partial-activity variants.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic variants in SRD5A2 cause 5-alpha reductase deficiency, an autosomal recessive condition characterised by differences in sexual development in individuals with 46,XY chromosomes. Affected individuals are typically born with ambiguous or predominantly female external genitalia despite having internal male reproductive structures such as testes. At puberty, the influence of testosterone often leads to partial masculinisation, including voice deepening and increased muscle mass. Research has also examined potential associations between common SRD5A2 variants and prostate cancer risk, as well as polycystic ovary syndrome in individuals with 46,XX chromosomes, though these relationships remain areas of ongoing investigation.
UK clinical status
Within the NHS Genomic Medicine Service, SRD5A2 appears on clinical gene panels for differences in sex development and foetal anomalies, both holding green classification status. The gene's inclusion on the differences in sex development panel reflects its established role in atypical genital development, whilst its presence on the foetal anomalies panel acknowledges the potential for prenatal detection of associated features. These panel memberships indicate that SRD5A2 testing may be appropriate for individuals presenting with relevant clinical findings, subject to clinician assessment and genetic counselling.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between testosterone and dihydrotestosterone?
Testosterone and dihydrotestosterone are both androgen hormones, but dihydrotestosterone binds more strongly to androgen receptors and exerts more potent effects on target tissues. Testosterone primarily drives the development of internal male reproductive structures before birth, whilst dihydrotestosterone is essential for external genital formation and prostate development.
Can SRD5A2 variants affect fertility?
Individuals with 5-alpha reductase deficiency may have reduced fertility depending on the severity of their condition and the extent of genital development. Fertility potential varies considerably and depends on factors including hormone levels, surgical history, and anatomical considerations, requiring individualised clinical assessment.
Is SRD5A2 testing available through the NHS?
SRD5A2 genetic testing may be available through the NHS for individuals presenting with differences in sex development or related clinical features. Testing is typically arranged by specialist clinicians following clinical assessment and genetic counselling to determine appropriateness for each individual situation.
References
- Goodarzi MO, Shah NA, Antoine HJ. Variants in the 5alpha-reductase type 1 and type 2 genes are associated with polycystic ovary syndrome and the severity of hirsutism in affected women. The Journal of clinical endocrinology and metabolism. 2006. PMID: 16849416
- Salam MT, Ursin G, Skinner EC. Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyperplasia and prostate cancer. Urologic oncology. 2005. PMID: 16018939
- Cicek MS, Conti DV, Curran A. Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17, and the AR. The Prostate. 2004. PMID: 14991867
- Wang Y, Li Q, Xu J. Mutation analysis of five candidate genes in Chinese patients with hypospadias. European journal of human genetics : EJHG. 2004. PMID: 15266301
- Makridakis N, Akalu A, Reichardt JK. Identification and characterization of somatic steroid 5alpha-reductase (SRD5A2) mutations in human prostate cancer tissue. Oncogene. 2004. PMID: 15326487
- Sasaki G, Ogata T, Ishii T. Micropenis and the 5alpha-reductase-2 (SRD5A2) gene: mutation and V89L polymorphism analysis in 81 Japanese patients. The Journal of clinical endocrinology and metabolism. 2003. PMID: 12843198
- Ntais C, Polycarpou A, Ioannidis JP. SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2003. PMID: 12869400
- Kim KS, Liu W, Cunha GR. Expression of the androgen receptor and 5 alpha-reductase type 2 in the developing human fetal penis and urethra. Cell and tissue research. 2002. PMID: 11845321
- Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annual review of biochemistry. 1994. PMID: 7979239
- Wilson JD, Griffin JE, Russell DW. Steroid 5 alpha-reductase 2 deficiency. Endocrine reviews. 1993. PMID: 8262007