On this page
CYP27A1
cytochrome P450 family 27 subfamily A member 1
The CYP27A1 gene provides instructions for an enzyme called sterol 27-hydroxylase, which is vital for the breakdown of cholesterol and the production of bile acids in the body. CYP27A1 is a gene within the cytochrome P450 family, crucial for lipid metabolism.
CYP27A1 is located on the long (q) arm of chromosome 2, at band 2q35. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 2 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The CYP27A1 gene, also known as cytochrome P450 family 27 subfamily A member 1, is an important component of the body's metabolic machinery. It is classified as an autosomal recessive gene, meaning that individuals typically need to inherit two affected copies to develop an associated condition. This gene is frequently included in cardiac screening panels due to its role in lipid metabolism and its association with conditions affecting cardiovascular health.
What the gene does
The CYP27A1 gene directs the synthesis of an enzyme called sterol 27-hydroxylase, which belongs to the cytochrome P450 enzyme family. This enzyme is primarily located in the mitochondria, the energy-producing organelles within cells. Its main function involves breaking down cholesterol to form bile acids, particularly chenodeoxycholic acid. This process represents the body's principal pathway for eliminating cholesterol, making sterol 27-hydroxylase essential for regulating cholesterol levels. By facilitating the conversion of cholesterol into bile acids, the CYP27A1 gene product plays a critical role in digestion and lipid homeostasis.
Video: Genetics 101
Chromosome location
The CYP27A1 gene is situated on chromosome 2 at position 2q35. This genomic location specifies where the gene can be found within the human genome, residing on the long arm (q arm) of chromosome 2. The protein encoded by this gene consists of 531 amino acids.
Protein structure
The sterol 27-hydroxylase protein, encoded by CYP27A1, contains a key functional region. One notable feature is a sterol-binding region, located between amino acids 384 and 398. This specific region is crucial for the enzyme's ability to bind with sterols, such as cholesterol, which is necessary for its enzymatic activity in bile acid synthesis.
Key variants
Variants within the CYP27A1 gene can influence the function of the sterol 27-hydroxylase enzyme. These genetic changes can range from single amino acid substitutions to larger alterations, potentially affecting the enzyme's ability to process cholesterol efficiently. The clinical impact of these variants varies, depending on their nature and location within the gene.
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.1170del | p.Lys391fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cholestanol storage disease |
c.1193del | p.Pro398fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cholestanol storage disease |
c.1468del | p.Leu490fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cholestanol storage disease |
c.1563dup | p.Val522fs | Pathogenic | ★★☆☆ | Cholestanol storage disease |
c.303del | p.Pro102fs | Pathogenic | ★★☆☆ | Cholestanol storage disease |
c.38del | p.Leu13fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cholestanol storage disease |
c.461G>A | p.Trp154Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cholestanol storage disease |
c.547del | p.Asp183fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cholestanol storage disease |
c.639del | p.Leu214fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cholestanol storage disease |
c.845-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cholestanol storage disease |
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 the CYP27A1 gene are primarily associated with Cerebrotendinous xanthomatosis. This condition is characterised by the abnormal accumulation of lipids, or fats, in various tissues throughout the body, including the brain and tendons. The impairment of the sterol 27-hydroxylase enzyme leads to a disruption in cholesterol metabolism, resulting in these lipid deposits.
Inheritance pattern
Conditions caused by pathogenic CYP27A1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
CYP27A1 is a gene of significant interest within the NHS Genomic Medicine Service, being featured in numerous PanelApp panels. It is listed as 'green' for conditions such as "Ataxia and cerebellar anomalies - childhood onset", "Bilateral congenital or childhood onset cataracts", "Cholestasis", and "Hereditary spastic paraplegia", indicating that there is strong evidence for its involvement in these conditions and that variants in this gene are considered medically actionable within these contexts. Other panels include "Familial hypercholesterolaemia" and "Inherited white matter disorders".
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the CYP27A1 gene?
The CYP27A1 gene is responsible for producing the sterol 27-hydroxylase enzyme. This enzyme's primary function is to break down cholesterol to form bile acids, which is a key process for eliminating cholesterol from the body and aiding in fat digestion.
What condition is primarily associated with CYP27A1 gene variants?
Variants in the CYP27A1 gene are most commonly associated with Cerebrotendinous xanthomatosis. This is a disorder where lipids abnormally accumulate in various parts of the body due to impaired cholesterol metabolism.
How does CYP27A1 affect cholesterol levels?
The enzyme produced by CYP27A1 plays a crucial role in maintaining normal cholesterol levels. It facilitates the conversion of cholesterol into bile acids, which is the body's main mechanism for removing excess cholesterol.
References
- Nie S, Chen G, Cao X. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet journal of rare diseases. 2014. PMID: 25424010
- Björkhem I. Cerebrotendinous xanthomatosis. Current opinion in lipidology. 2013. PMID: 23759795
- Björkhem I, Hansson M. Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge. Biochemical and biophysical research communications. 2010. PMID: 20494109
- Gallus GN, Dotti MT, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2006. PMID: 16816916
- Araya Z, Tang W, Wikvall K. Hormonal regulation of the human sterol 27-hydroxylase gene CYP27A1. The Biochemical journal. 2003. PMID: 12597773
- Norlin M, von Bahr S, Bjorkhem I. On the substrate specificity of human CYP27A1: implications for bile acid and cholestanol formation. Journal of lipid research. 2003. PMID: 12777473
- von Bahr S, Movin T, Papadogiannakis N. Mechanism of accumulation of cholesterol and cholestanol in tendons and the role of sterol 27-hydroxylase (CYP27A1). Arteriosclerosis, thrombosis, and vascular biology. 2002. PMID: 12117727