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CYP11A1
cytochrome P450 family 11 subfamily A member 1
CYP11A1 is located on the long (q) arm of chromosome 15, at band 15q24.1. Arm ratio per GRCh38 - banding schematic.
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Overview
CYP11A1 encodes cholesterol side-chain cleavage enzyme, a mitochondrial cytochrome P450 enzyme that catalyses the rate-limiting step in steroid hormone biosynthesis. This enzyme converts cholesterol into pregnenolone, the precursor for all steroid hormones including cortisol, aldosterone, and sex steroids.
Pathogenic variants in CYP11A1 can disrupt this essential metabolic pathway, resulting in congenital adrenal insufficiency and impaired sex steroid production. The clinical severity varies depending on how much residual enzyme activity remains, ranging from life-threatening neonatal presentations to milder late-onset forms.
What the gene does
The CYP11A1 protein functions as a mitochondrial enzyme that initiates steroidogenesis by removing a six-carbon side chain from cholesterol to produce pregnenolone. This reaction occurs in three sequential oxidation steps, all catalysed by the same enzyme working in conjunction with adrenodoxin and adrenodoxin reductase as electron transfer partners.
The enzyme is expressed primarily in steroidogenic tissues including the adrenal cortex, gonads, and placenta. Pregnenolone serves as the common substrate for subsequent enzymes that synthesise glucocorticoids, mineralocorticoids, and sex hormones. Without functional CYP11A1 activity, cells cannot produce any of these essential steroid hormones, making this enzyme indispensable for normal endocrine function and development.
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Chromosome location
CYP11A1 is located on the long arm of chromosome 15 at position 24.1 (15q24.1). The gene spans approximately 30 kilobases of genomic DNA and contains nine exons that encode the mature protein. This chromosomal region does not harbour other genes directly involved in steroidogenesis, though the clustering of steroidogenic genes occurs elsewhere in the genome.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The CYP11A1 protein comprises 521 amino acids and belongs to the cytochrome P450 superfamily, characterised by a haem-containing active site that enables oxidation reactions. The enzyme includes an N-terminal mitochondrial targeting sequence that directs the protein to the inner mitochondrial membrane where steroidogenesis occurs.
Key variants
Pathogenic variants in CYP11A1 range from complete loss-of-function changes that abolish enzyme activity to hypomorphic variants that permit residual function. Null variants typically cause severe, early-onset adrenal insufficiency, whilst variants allowing partial activity may present later in childhood or adolescence with milder features.
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.1270C>T | p.Arg424Ter | Pathogenic | ★★☆☆ | Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency |
c.1351C>T | p.Arg451Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency |
c.202dup | p.Glu68fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency |
c.358C>T | p.Arg120Ter | Pathogenic | ★★☆☆ | Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency |
c.358del | p.Arg120fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency |
c.425+1G>A | - | Pathogenic | ★★☆☆ | not provided |
c.508_509del | p.Leu170fs | Pathogenic | ★★☆☆ | Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency |
c.566C>T | p.Ala189Val | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency |
c.694C>T | p.Arg232Ter | Pathogenic | ★★☆☆ | 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia |
c.835del | p.Ile279fs | Pathogenic | ★★☆☆ | Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency |
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
CYP11A1-related disorders present as a spectrum of adrenal insufficiency and gonadal dysfunction. The classical presentation involves congenital lipoid adrenal hyperplasia, characterised by deficient production of all steroid hormones. Affected individuals typically experience salt-wasting adrenal crises in infancy, alongside undervirilisation in 46,XY individuals due to impaired testicular androgen synthesis. Milder, non-classic forms may manifest as primary adrenal insufficiency without prominent genital differences.
No disease links recorded for this gene in our reference set.
UK clinical status
CYP11A1 appears on several NHS Genomic Medicine Service gene panels as a green-rated gene. It is included on the Congenital Adrenal Hypoplasia panel (R150), the Differences in Sex Development panel (R146), and the Fetal Anomalies panel (R21), reflecting its role in conditions that may be diagnosed prenatally or in early life through NHS genomic testing pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What happens if CYP11A1 is not working properly?
When CYP11A1 function is impaired, the body cannot initiate steroid hormone production from cholesterol. This typically results in deficiency of cortisol, aldosterone, and sex hormones, leading to adrenal insufficiency that requires lifelong hormone replacement therapy.
How is CYP11A1 deficiency inherited?
CYP11A1-related conditions follow an autosomal recessive inheritance pattern. An individual must inherit pathogenic variants from both parents to develop the condition. Carriers with one pathogenic variant typically have normal steroid hormone production.
Can CYP11A1 variants affect fertility?
Yes, severe CYP11A1 deficiency can affect gonadal function and fertility, particularly in individuals with 46,XY karyotype who may have undervirilisation. The impact varies depending on residual enzyme activity and the effectiveness of hormone replacement therapy.