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PCSK9
proprotein convertase subtilisin/kexin type 9
The PCSK9 gene provides instructions for a protein that plays a crucial role in regulating cholesterol levels in the bloodstream, primarily by controlling the number of low-density lipoprotein receptors. The PCSK9 gene encodes a protein involved in the metabolism of cholesterol.
PCSK9 is located on the short (p) arm of chromosome 1, at band 1p32.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 1 in the library →Overview
The PCSK9 gene, also known as proprotein convertase subtilisin/kexin type 9, is integral to the body's cholesterol management system. It produces a protein that modulates the number of low-density lipoprotein (LDL) receptors on cell surfaces. These receptors are vital for clearing LDL cholesterol, often referred to as 'bad' cholesterol, from the bloodstream.
Dysregulation of PCSK9 activity, either through increased or decreased function, can significantly impact an individual's cholesterol levels. This gene is classified under the ACMG Secondary Findings v3.2 framework as Tier 1, indicating its established clinical actionability for certain conditions.
What the gene does
The PCSK9 protein helps regulate the amount of cholesterol in the bloodstream by influencing the availability of low-density lipoprotein (LDL) receptors on cell surfaces. These receptors are particularly abundant in the liver and are responsible for binding to and internalising LDL particles, thereby removing cholesterol from circulation.
The PCSK9 protein functions by breaking down these LDL receptors before they can reach the cell surface. This action reduces the number of functional receptors available to clear LDL cholesterol, leading to higher levels of cholesterol remaining in the bloodstream. Conversely, reduced PCSK9 activity can increase the number of LDL receptors, resulting in lower blood cholesterol levels. This intricate balance is crucial for maintaining healthy lipid profiles within the body.
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Chromosome location
The PCSK9 gene is located on the short arm of chromosome 1, specifically at position 1p32.3. This region of the human genome contains instructions for the production of the PCSK9 protein. The gene spans a defined segment of DNA, dictating the sequence for the protein comprising 692 amino acids.
Protein structure
The PCSK9 protein is composed of several functional regions. It features an Inhibitor I9 domain, located between amino acids 77 and 149, which is crucial for its regulatory activity. Adjacent to this is the Peptidase S8 domain, spanning amino acids 155 to 461, indicating its role in proteolytic processes. The protein also contains a C-terminal domain, located from amino acids 450 to 692, which contributes to its overall structure and function.
Key variants
Variants within the PCSK9 gene can influence its activity and, consequently, an individual's cholesterol levels. Some variants may lead to an increased function of the PCSK9 protein, enhancing its ability to break down LDL receptors. These 'gain-of-function' variants are often associated with elevated cholesterol levels. Conversely, 'loss-of-function' variants can reduce PCSK9 activity, resulting in more LDL receptors and lower circulating cholesterol. The spectrum of PCSK9 variants highlights its significant role in lipoprotein 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.1120G>C | p.Asp374His | Pathogenic/Likely pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1120G>T | p.Asp374Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | Homozygous familial hypercholesterolemia |
c.381T>A | p.Ser127Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hypercholesterolemia |
c.644G>A | p.Arg215His | Pathogenic/Likely pathogenic | ★★☆☆ | PCSK9-related disorder |
c.94G>A | p.Glu32Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Homozygous familial hypercholesterolemia |
c.381T>G | p.Ser127Arg | Pathogenic | ★☆☆☆ | Hypercholesterolemia, autosomal dominant, 3 |
c.42_43insTG | p.Leu15fs | Pathogenic | ★☆☆☆ | Hypercholesterolemia, familial, 1 |
c.1402A>G | p.Thr468Ala | Pathogenic | - | Hypercholesterolemia, familial, 1 |
c.1411G>T | p.Ala471Ser | Pathogenic | - | Hypercholesterolemia, familial, 1 |
c.2005G>C | p.Glu669Gln | Pathogenic | - | Hypercholesterolemia, familial, 1 |
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 PCSK9 gene are primarily associated with inherited disorders of cholesterol metabolism, such as Familial hypercholesterolaemia. This condition is characterised by significantly elevated levels of low-density lipoprotein (LDL) cholesterol, which can increase the risk of premature cardiovascular disease. The specific impact of a PCSK9 variant depends on whether it leads to an increase or decrease in the protein's function.
Inheritance pattern
Conditions caused by pathogenic PCSK9 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the PCSK9 gene is a key focus within the NHS Genomic Medicine Service (GMS) pathways due to its clinical significance. It is included on several NHS England National Genomic Test Directory panels, specifically for conditions such as Familial hypercholesterolaemia, including the green-rated 'Familial hypercholesterolaemia (GMS)' panel (R134). Additionally, it is part of panels related to 'Additional findings health related', 'Likely inborn error of metabolism' (R98), and 'Undiagnosed metabolic disorders', indicating its broad relevance in genetic diagnostics.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle is generally recommended for supporting cardiovascular health, especially for individuals with cholesterol concerns. A balanced diet rich in fruits, vegetables, and whole grains, along with regular physical activity, can contribute to overall well-being. Limiting saturated and trans fats, as well as dietary cholesterol, is often suggested to help manage lipid levels in the general population. These lifestyle measures are supportive and should be considered part of a broader health management plan.
Supplement considerations
While some dietary supplements are marketed for cholesterol management, there is no conclusive evidence that specific supplements can prevent or treat conditions associated with PCSK9 gene variants. Individuals considering supplements for cholesterol concerns should discuss this with a healthcare provider. supplements should not replace prescribed medications or established medical advice for managing high cholesterol.
Frequently asked questions
What does the PCSK9 gene do?
The PCSK9 gene provides instructions for making a protein that helps control the amount of LDL (low-density lipoprotein) cholesterol in the bloodstream by regulating the number of LDL receptors on cell surfaces.
How does PCSK9 affect cholesterol levels?
The PCSK9 protein works by reducing the number of LDL receptors, which are responsible for clearing cholesterol from the blood. Fewer receptors mean more cholesterol remains in circulation, potentially leading to higher levels.
What is Familial hypercholesterolaemia?
Familial hypercholesterolaemia is an inherited condition characterised by very high levels of LDL cholesterol, which significantly increases the risk of early heart disease. It can be caused by certain variants in the PCSK9 gene.
Are there different types of PCSK9 variants?
Yes, there are 'gain-of-function' variants that increase PCSK9 activity, leading to higher cholesterol, and 'loss-of-function' variants that decrease PCSK9 activity, often resulting in lower cholesterol levels.
Is the PCSK9 gene relevant to UK genomic testing?
Yes, the PCSK9 gene is included in several NHS England National Genomic Test Directory panels, particularly for Familial hypercholesterolaemia and other related metabolic disorders.
References
- Hopkins PN, Defesche J, Fouchier SW. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. Circulation. Cardiovascular genetics. 2015. PMID: 26374825
- Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends in biochemical sciences. 2007. PMID: 17215125
- Berge KE, Ose L, Leren TP. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arteriosclerosis, thrombosis, and vascular biology. 2006. PMID: 16424354
- Kotowski IK, Pertsemlidis A, Luke A. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. American journal of human genetics. 2006. PMID: 16465619
- Cohen JC, Boerwinkle E, Mosley TH Jr. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. The New England journal of medicine. 2006. PMID: 16554528
- Cameron J, Holla ØL, Ranheim T. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Human molecular genetics. 2006. PMID: 16571601
- Zhao Z, Tuakli-Wosornu Y, Lagace TA. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. American journal of human genetics. 2006. PMID: 16909389
- Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proceedings of the National Academy of Sciences of the United States of America. 2005. PMID: 15677715
- Maxwell KN, Breslow JL. Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia. Current opinion in lipidology. 2005. PMID: 15767856
- Chen SN, Ballantyne CM, Gotto AM Jr. A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. Journal of the American College of Cardiology. 2005. PMID: 15893176
- Allard D, Amsellem S, Abifadel M. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Human mutation. 2005. PMID: 16211558
- Abifadel M, Varret M, Rabès JP. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature genetics. 2003. PMID: 12730697