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CYP17A1
cytochrome P450 family 17 subfamily A member 1
CYP17A1 encodes an enzyme essential for producing sex hormones and cortisol, with variants causing hormone deficiencies that affect sexual development and blood pressure. The CYP17A1 gene provides instructions for a cytochrome P450 enzyme that catalyses critical steps in steroid hormone biosynthesis.
CYP17A1 is located on the long (q) arm of chromosome 10, at band 10q24.32. Arm ratio per GRCh38 - banding schematic.
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Overview
CYP17A1 encodes cytochrome P450 17A1, a dual-function enzyme that performs two sequential reactions in the adrenal glands and gonads during steroid hormone synthesis [PMID:28849161]. This enzyme is essential for producing cortisol, androgens, and oestrogens from cholesterol-derived precursors. Variants that reduce or eliminate enzyme activity prevent normal hormone production, resulting in congenital adrenal hyperplasia with characteristic features including elevated blood pressure, low potassium levels, and impaired sexual maturation. The gene is located on chromosome 10 and is expressed primarily in steroidogenic tissues.
What the gene does
As a member of the cytochrome P450 family, the CYP17A1 enzyme carries out two separate chemical transformations during the stepwise synthesis of steroid hormones. The protein's 17-alpha-hydroxylase function modifies pregnenolone, creating 17-hydroxypregnenolone, and converts progesterone into 17-hydroxyprogesterone [PMID:28849161]. Further processing of these modified intermediates generates glucocorticoids like cortisol. Through its second catalytic role, the enzyme cleaves 17-hydroxypregnenolone to produce dehydroepiandrosterone (DHEA), an androgen precursor required for synthesising testosterone and oestrogen. The broader steroid hormone family encompasses sex hormones necessary for reproductive development, mineralocorticoids that regulate salt and water homeostasis, and glucocorticoids involved in glucose metabolism and stress responses. CYP17A1's position at a metabolic branch point determines whether precursor molecules advance towards mineralocorticoid, glucocorticoid, or sex hormone end products. This enzyme depends on electron transfer from NADPH through cytochrome P450 oxidoreductase. Adrenocorticotrophic hormone controls its expression in the adrenal cortex, whilst luteinising hormone regulates production in gonadal tissue [PMID:28849161].
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Chromosome location
CYP17A1 is located on the long arm of chromosome 10 at position 24.32 (10q24.32). The gene spans approximately 6.6 kilobases of genomic DNA and contains eight exons. This chromosomal region contains several other genes involved in metabolic processes, though CYP17A1 itself functions independently of neighbouring loci.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The CYP17A1 enzyme comprises 508 amino acids and belongs to the cytochrome P450 superfamily, sharing the characteristic haem-binding fold common to these oxidative enzymes. Like other P450 proteins, it contains regions that coordinate the iron-containing haem prosthetic group and interact with the cytochrome P450 oxidoreductase partner protein. Structural studies have identified substrate-binding pockets that accommodate steroid precursors and determine the enzyme's dual catalytic specificity.
Key variants
Dozens of pathogenic variants have been identified throughout CYP17A1, including missense substitutions, small deletions, and splice-site alterations. Most pathogenic variants eliminate or severely reduce both enzymatic activities, though some selectively impair 17,20-lyase function while preserving partial 17-alpha-hydroxylase activity. These latter variants tend to cluster in regions affecting substrate positioning for the lyase reaction. The variant spectrum shows geographical clustering, with certain founder mutations observed in specific populations.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1246C>T | p.Arg416Cys | Pathogenic | ★★☆☆ | Deficiency of steroid 17-alpha-monooxygenase |
c.1304T>C | p.Phe435Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of steroid 17-alpha-monooxygenase |
c.1318C>T | p.Arg440Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of steroid 17-alpha-monooxygenase |
c.1371del | p.Trp458fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of steroid 17-alpha-monooxygenase |
c.1487G>A | p.Arg496His | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of steroid 17-alpha-monooxygenase |
c.245C>A | p.Ala82Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of steroid 17-alpha-monooxygenase |
c.336dup | p.Ala113fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of steroid 17-alpha-monooxygenase |
c.973AAG[2] | p.Lys327del | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital adrenal hyperplasia |
c.987C>G | p.Tyr329Ter | Pathogenic/Likely pathogenic | ★★☆☆ | 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia |
c.995T>C | p.Ile332Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of steroid 17-alpha-monooxygenase |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in CYP17A1 cause congenital adrenal hyperplasia (17-hydroxylase deficiency), inherited in an autosomal recessive pattern. Affected individuals typically present with hypertension, hypokalaemia, and absent or incomplete pubertal development. The condition exists on a spectrum: complete enzyme deficiency affects both glucocorticoid and sex hormone synthesis, whilst isolated 17,20-lyase deficiency selectively impairs androgen and oestrogen production without causing hypertension. Phenotypic severity correlates with residual enzyme activity, and presentation may differ between genetic males and females due to the differential importance of gonadal versus adrenal androgen production.
UK clinical status
CYP17A1 appears on multiple NHS Genomic Medicine Service gene panels with green (high evidence) classification. It is included in the Differences in Sex Development panel (R146), the Extreme Early-Onset Hypertension panel, the Fetal Anomalies panel (R21), and the Primary Ovarian Insufficiency panel. This multi-panel membership reflects the diverse clinical presentations of CYP17A1-related conditions across endocrinology, hypertension, and reproductive medicine services.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between 17-hydroxylase and 17,20-lyase deficiency?
Complete CYP17A1 deficiency eliminates both enzymatic activities, causing hypertension and absent sexual development. Isolated 17,20-lyase deficiency affects only sex hormone production through selective impairment of the lyase reaction, resulting in disorders of sexual development without hypertension or electrolyte disturbances.
Why does CYP17A1 deficiency cause high blood pressure?
Loss of 17-alpha-hydroxylase activity prevents cortisol synthesis, triggering compensatory overproduction of earlier pathway precursors. These precursors are shunted into mineralocorticoid synthesis, leading to excess production of hormones that retain sodium and water, elevating blood pressure and suppressing potassium levels.
How is CYP17A1-related adrenal hyperplasia diagnosed?
Diagnosis typically combines clinical features (hypertension, absent puberty, low potassium) with characteristic steroid hormone profiles showing elevated mineralocorticoid precursors, low cortisol, and absent or reduced sex hormones. Genetic testing confirms pathogenic CYP17A1 variants and distinguishes this form from other types of congenital adrenal hyperplasia.
References
- Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine reviews. 2011. PMID: 21051590
- Rosa S, Steigert M, Lang-Muritano M. Clinical, genetic and functional characteristics of three novel CYP17A1 mutations causing combined 17alpha-hydroxylase/17,20-lyase deficiency. Hormone research in paediatrics. 2010. PMID: 20197673
- Van Den Akker EL, Koper JW, Boehmer AL. Differential inhibition of 17alpha-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency. The Journal of clinical endocrinology and metabolism. 2002. PMID: 12466376
- Geller DH, Auchus RJ, Mendonça BB. The genetic and functional basis of isolated 17,20-lyase deficiency. Nature genetics. 1997. PMID: 9326943