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CYP21A2
cytochrome P450 family 21 subfamily A member 2
The CYP21A2 gene encodes the 21-hydroxylase enzyme, vital for producing essential adrenal hormones such as cortisol and aldosterone, which regulate stress response, blood sugar, and fluid balance. CYP21A2 provides instructions for the 21-hydroxylase enzyme, a key component in the cytochrome P450 family.
CYP21A2 is located on the short (p) arm of chromosome 6, at band 6p21.33. Arm ratio per GRCh38 - banding schematic.
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Overview
The CYP21A2 gene, also known as cytochrome P450 family 21 subfamily A member 2, is essential for the normal function of the adrenal glands. It directs the production of the 21-hydroxylase enzyme, which belongs to the cytochrome P450 enzyme family. These enzymes participate in various metabolic processes throughout the body, including the breakdown of drugs and the production of lipids and certain hormones.
The 21-hydroxylase enzyme specifically facilitates the synthesis of two vital steroid hormones: cortisol and aldosterone. Cortisol helps regulate blood sugar levels, supports the body's response to stress, and possesses anti-inflammatory properties. Aldosterone manages sodium balance in the kidneys, thereby influencing both body fluid levels and blood pressure.
What the gene does
The CYP21A2 gene directs the synthesis of 21-hydroxylase, an enzyme critical for steroidogenesis within the adrenal glands. This enzyme belongs to the cytochrome P450 superfamily, a group of proteins that assist in numerous metabolic transformations. Within the adrenal cortex, 21-hydroxylase facilitates key steps in the production of glucocorticoids and mineralocorticoids.
The enzyme's primary role involves supporting the biosynthesis of cortisol and aldosterone, two hormones that maintain physiological balance. Cortisol coordinates metabolic adjustments throughout the day, modulates inflammatory processes, and enables physiological adaptation to stressful conditions. Aldosterone, sometimes referred to as the salt-retaining hormone, governs how much sodium the kidneys reabsorb, which in turn affects the body's fluid volume and blood pressure regulation. When CYP21A2 variants reduce or eliminate enzyme activity, these essential hormone production pathways become disrupted.
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Chromosome location
The CYP21A2 gene is located on chromosome 6, specifically at band 6p21.33. This region is part of the short arm of chromosome 6. The gene provides instructions for a protein that is 495 amino acids in length. The CYP21A2 gene is found in close proximity to a similar, non-functional DNA sequence known as a pseudogene, which can sometimes lead to complex genetic rearrangements.
Key variants
More than 100 mutations in the CYP21A2 gene have been identified that cause 21-hydroxylase deficiency. These genetic alterations encompass point mutations, deletions, and gene conversions. Some variants arise from the exchange of genetic material between the functional CYP21A2 gene and its closely located pseudogene, a process referred to as gene conversion. These changes can impact the enzyme's activity, leading to reduced or absent function.
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 |
|---|---|---|---|---|
g.(?_32006191)_(32006402_32006498)del | - | Pathogenic | ★☆☆☆ | Congenital adrenal hyperplasia |
g.(?_32006191)_(32007026_32007132)del | - | Pathogenic | ★☆☆☆ | Congenital adrenal hyperplasia |
g.(?_32006191)_(32007983_32008182)del | - | Pathogenic | ★☆☆☆ | Congenital adrenal hyperplasia |
g.(?_32006208)_(32007983_32008182)del | - | Pathogenic | ★☆☆☆ | Congenital adrenal hyperplasia |
g.(32006589_32006870)_(32007026_32007132)del | - | Pathogenic | ★☆☆☆ | Congenital adrenal hyperplasia |
g.(32006589_32006870)_(32007983_32008182)del | - | Pathogenic | ★☆☆☆ | Congenital adrenal hyperplasia |
g.(32007026_32007132)_(32007235_32007322)del | - | Pathogenic | ★☆☆☆ | Congenital adrenal hyperplasia |
g.(32007026_32007132)_(32007983_32008182)del | - | Pathogenic | ★☆☆☆ | Congenital adrenal hyperplasia |
c.(?_1)_(*_?)del | - | Pathogenic | ★☆☆☆ | 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia |
c.*28698024_*28698031del8 | - | Pathogenic | - | 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia |
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
Variants in the CYP21A2 gene are primarily associated with congenital adrenal hyperplasia (21-hydroxylase). This is an autosomal recessive inherited condition where the adrenal glands are unable to produce sufficient amounts of certain steroid hormones. The severity of the condition depends on the specific genetic variants present and the resulting level of 21-hydroxylase enzyme deficiency. Manifestations can range from severe, life-threatening forms to milder, non-classic presentations.
UK clinical status
The CYP21A2 gene is recognised within several NHS Genomic Medicine Service national testing panels. It is included in panels for congenital adrenal hyperplasia, differences in sex development, and foetal anomalies, indicating its established role in these clinical areas within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the CYP21A2 gene do?
The CYP21A2 gene provides instructions for making the 21-hydroxylase enzyme. This enzyme is crucial for producing steroid hormones like cortisol and aldosterone in the adrenal glands, which are vital for stress response, blood sugar regulation, and fluid balance.
What condition is associated with CYP21A2 variants?
Variants in the CYP21A2 gene are primarily associated with congenital adrenal hyperplasia (21-hydroxylase). This is an inherited condition that affects the adrenal glands' ability to produce essential hormones.
How do genetic variants in CYP21A2 occur?
Genetic variants in CYP21A2 can occur in various ways, including point mutations, deletions, and a process called gene conversion. Gene conversion involves the exchange of genetic material between the CYP21A2 gene and a neighbouring, non-functional pseudogene.
References
- Huynh T, McGown I, Cowley D. The clinical and biochemical spectrum of congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. The Clinical biochemist. Reviews. 2009. PMID: 19565027
- Nimkarn S, Lin-Su K, New MI. Steroid 21 hydroxylase deficiency congenital adrenal hyperplasia. Endocrinology and metabolism clinics of North America. 2009. PMID: 19944288
- Krone N, Riepe FG, Grötzinger J. Functional characterization of two novel point mutations in the CYP21 gene causing simple virilizing forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The Journal of clinical endocrinology and metabolism. 2005. PMID: 15483094
- Lee HH. Diversity of the CYP21P-like gene in CYP21 deficiency. DNA and cell biology. 2005. PMID: 15684714
- Keen-Kim D, Redman JB, Alanes RU. Validation and clinical application of a locus-specific polymerase chain reaction- and minisequencing-based assay for congenital adrenal hyperplasia (21-hydroxylase deficiency). The Journal of molecular diagnostics : JMD. 2005. PMID: 15858147
- New MI. An update of congenital adrenal hyperplasia. Annals of the New York Academy of Sciences. 2004. PMID: 15838095
- Torres N, Mello MP, Germano CM. Phenotype and genotype correlation of the microconversion from the CYP21A1P to the CYP21A2 gene in congenital adrenal hyperplasia. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2003. PMID: 14502362
- Hughes IA. Congenital adrenal hyperplasia: 21-hydroxylase deficiency in the newborn and during infancy. Seminars in reproductive medicine. 2002. PMID: 12428203