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POR
cytochrome p450 oxidoreductase
The *POR* gene provides instructions for producing cytochrome P450 oxidoreductase, an enzyme crucial for the function of many cytochrome P450 enzymes involved in metabolism and hormone synthesis. The *POR* gene is responsible for encoding cytochrome P450 oxidoreductase, a key enzyme that facilitates the activity of over 50 other cytochrome P450 enzymes.
POR is located on the long (q) arm of chromosome 7, at band 7q11.23. Arm ratio per GRCh38 - banding schematic.
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Overview
The *POR* gene, also known as cytochrome P450 oxidoreductase, provides the genetic blueprint for an enzyme of the same name. This enzyme is indispensable for the proper functioning of numerous other enzymes within the cytochrome P450 family. These cytochrome P450 enzymes are widely involved in both the creation and degradation of various molecules and chemicals within the body's cells.
Its functions are particularly important for the synthesis of cholesterol and various steroid hormones. Additionally, the cytochrome P450 oxidoreductase enzyme supports the metabolism of ingested substances, such as medications, predominantly in the liver. Variations within the *POR* gene are thought to influence an individual's response to certain drugs.
What the gene does
The enzyme encoded by the *POR* gene, cytochrome P450 oxidoreductase, is a critical component for the activity of over 50 cytochrome P450 enzymes. These enzymes are central to various cellular processes, including the biosynthesis and metabolism of different compounds. For instance, they are essential for the production of cholesterol and steroid hormones, which include oestrogen and testosterone vital for sexual development, corticosteroids involved in stress response, and aldosterone for regulating salt and water balance.
Beyond hormone synthesis, cytochrome P450 enzymes also play a significant role in the liver's detoxification processes, breaking down various substances, including medications. The cytochrome P450 oxidoreductase enzyme acts as a facilitator, ensuring these diverse cytochrome P450 enzymes can perform their catalytic functions efficiently. Therefore, its proper function is fundamental to maintaining metabolic homeostasis and influencing drug responses.
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Chromosome location
The *POR* gene is situated on the long arm of chromosome 7 at band 7q11.23. This specific location on the human genome dictates where the genetic instructions for the cytochrome P450 oxidoreductase enzyme are found.
Protein structure
The cytochrome P450 oxidoreductase protein is composed of 677 amino acids. It features distinct functional regions, including a Flavodoxin-like domain spanning amino acids 80-224, and a FAD-binding FR-type domain located between amino acids 279-521. These domains are crucial for the protein's ability to interact with cofactors and facilitate electron transfer.
Key variants
Genetic variations within the *POR* gene can lead to changes in the cytochrome P450 oxidoreductase enzyme. Some variants may alter the enzyme's structure or reduce its activity, potentially impacting the function of other cytochrome P450 enzymes. These changes can affect various metabolic pathways, including those involved in hormone synthesis and drug metabolism.
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.1103_1109del | p.Arg368fs | Pathogenic/Likely pathogenic | ★★☆☆ | Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis |
c.115del | p.Thr39fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency |
c.1434C>G | p.Tyr478Ter | Pathogenic/Likely pathogenic | ★★☆☆ | POR-related disorder |
c.1676_1679dup | p.Leu561fs | Pathogenic | ★★☆☆ | Congenital adrenal hyperplasia |
c.1718dup | p.Tyr573Ter | Pathogenic | ★★☆☆ | Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency |
c.1837C>T | p.Arg613Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency |
c.253G>A | p.Gly85Ser | Pathogenic/Likely pathogenic | ★★☆☆ | POR-related disorder |
c.40G>T | p.Glu14Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency |
c.64_65del | p.Leu22fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency |
c.658C>T | p.Arg220Ter | Pathogenic | ★★☆☆ | Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase 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
Variations in the *POR* gene are associated with cytochrome P450 oxidoreductase deficiency. This condition results in hormonal imbalances that can influence the development of the reproductive system, skeleton, and other bodily systems. It typically affects sexual development both before birth and during puberty, and severe cases may also present with skeletal abnormalities.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic POR 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
The *POR* gene is included in several NHS Genomic Medicine Service national panels. These include panels for Arthrogryposis (R83), Differences in sex development (R146), Foetal anomalies (R21), Likely inborn error of metabolism (R98), Rare syndromic craniosynostosis or isolated multisuture synostosis (R100), Skeletal dysplasia (R104), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the POR gene?
The *POR* gene provides instructions for making cytochrome P450 oxidoreductase, an enzyme that is essential for the function of over 50 other cytochrome P450 enzymes. These enzymes are involved in critical processes like steroid hormone synthesis and drug metabolism.
What happens if there are variations in the POR gene?
Variations in the *POR* gene can lead to a condition called cytochrome P450 oxidoreductase deficiency. This can result in hormonal imbalances affecting reproductive and skeletal development, as well as influencing how the body metabolises certain drugs.
How does the POR gene affect drug metabolism?
The enzyme produced by the *POR* gene helps regulate the activity of many cytochrome P450 enzymes, which are primarily responsible for breaking down medications in the liver. Therefore, variations in the *POR* gene can influence how an individual processes and responds to certain drugs.
References
- Miller WL, Huang N, Agrawal V. Genetic variation in human P450 oxidoreductase. Molecular and cellular endocrinology. 2009. PMID: 18930113
- Sim SC, Miller WL, Zhong XB. Nomenclature for alleles of the cytochrome P450 oxidoreductase gene. Pharmacogenetics and genomics. 2009. PMID: 19535965
- Huang N, Agrawal V, Giacomini KM. Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proceedings of the National Academy of Sciences of the United States of America. 2008. PMID: 18230729
- Hart SN, Zhong XB. P450 oxidoreductase: genetic polymorphisms and implications for drug metabolism and toxicity. Expert opinion on drug metabolism & toxicology. 2008. PMID: 18433346
- Fukami M, Horikawa R, Nagai T. Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. The Journal of clinical endocrinology and metabolism. 2005. PMID: 15483095
- Huang N, Pandey AV, Agrawal V. Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. American journal of human genetics. 2005. PMID: 15793702
- Flück CE, Tajima T, Pandey AV. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nature genetics. 2004. PMID: 14758361
- Arlt W, Walker EA, Draper N. Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet (London, England). 2004. PMID: 15220035