Reviewed March 2007
What is the official name of the PCSK9 gene?
The official name of this gene is “proprotein convertase subtilisin/kexin type 9.”
PCSK9 is the gene's official symbol. The PCSK9 gene is also known by other names, listed below.
What is the normal function of the PCSK9 gene?
The PCSK9 gene provides instructions for making a protein that helps regulate the amount of cholesterol in the bloodstream. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals.
The PCSK9 protein appears to control the number of low-density lipoprotein receptors, which are proteins on the surface of cells. These receptors play a critical role in regulating blood cholesterol levels. The receptors bind to particles called low-density lipoproteins (LDLs), which are the primary carriers of cholesterol in the blood. Low-density lipoprotein receptors are particularly abundant in the liver, the organ responsible for removing most excess cholesterol from the body.
The number of low-density lipoprotein receptors on the surface of liver cells determines how quickly cholesterol (in the form of low-density lipoproteins) is removed from the bloodstream. Studies suggest that the PCSK9 protein helps control blood cholesterol levels by breaking down low-density lipoprotein receptors before they reach the cell surface.
How are changes in the PCSK9 gene related to health conditions?
- hypercholesterolemia - caused by mutations in the PCSK9 gene
Researchers have identified several PCSK9 mutations that cause an inherited form of high cholesterol (hypercholesterolemia). These mutations change a single protein building block (amino acid) in the PCSK9 protein. Researchers describe the mutations responsible for hypercholesterolemia as "gain-of-function" because they appear to enhance the activity of the PCSK9 protein or give the protein a new, atypical function.
The overactive PCSK9 protein significantly reduces the number of low-density lipoprotein receptors on the surface of liver cells. Researchers speculate that the altered protein may cause these receptors to be broken down more quickly than usual. With fewer receptors to remove low-density lipoproteins from the blood, people with gain-of-function mutations in the PCSK9 gene have very high blood cholesterol levels. As the excess cholesterol circulates through the bloodstream, it is deposited abnormally in tissues such as the skin, tendons, and arteries that supply blood to the heart (coronary arteries). A buildup of cholesterol in the walls of coronary arteries greatly increases a person's risk of having a heart attack.
- other disorders - associated with the PCSK9 gene
Other mutations in the PCSK9 gene result in reduced blood cholesterol levels (hypocholesterolemia). These genetic changes reduce the activity of the PCSK9 protein or decrease the amount of this protein that is produced in cells. Researchers describe this type of mutation as "loss-of-function." Loss-of-function mutations in the PCSK9 gene appear to be more common than gain-of-function mutations, which are responsible for hypercholesterolemia.
Loss-of-function mutations in the PCSK9 gene lead to an increase in the number of low-density lipoprotein receptors on the surface of liver cells. The extra receptors can remove low-density lipoproteins from the blood more quickly than usual, which decreases the amount of cholesterol circulating in the bloodstream. Studies suggest that people with reduced cholesterol levels caused by PCSK9 mutations have a significantly lower-than-average risk of developing heart disease.
Researchers suspect that normal changes (polymorphisms) in the PCSK9 gene are responsible for some of the variation in blood cholesterol levels among people without inherited cholesterol disorders. In particular, scientists are working to determine which polymorphisms are associated with relatively low levels of cholesterol in the blood and a reduced risk of heart disease.
Where is the PCSK9 gene located?
Cytogenetic Location: 1p32.3
Molecular Location on chromosome 1: base pairs 55,039,476 to 55,064,853
The PCSK9 gene is located on the short (p) arm of chromosome 1 at position 32.3.
More precisely, the PCSK9 gene is located from base pair 55,039,476 to base pair 55,064,853 on chromosome 1.
See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.
Where can I find additional information about PCSK9?
You and your healthcare professional may find the following resources about PCSK9 helpful.
Educational resources - Information pages
- Indiana University School of Medicine: LDL Receptors (http://themedicalbiochemistrypage.org/lipoproteins.html)
- Molecular Biology of the Cell (fourth Edition, 2002): The receptor-mediated endocytosis of LDL (http://www.ncbi.nlm.nih.gov/books/NBK26870/?rendertype=figure&id=A2398)
- Molecular Cell Biology (fourth edition, 2000): The LDL Receptor Binds and Internalizes Cholesterol-Containing Particles (http://www.ncbi.nlm.nih.gov/books/NBK21639/)
- News Release: Study reveals potential new target for cholesterol-lowering drugs (UT Southwestern Medical Center, March 29, 2005) (http://www.utsouthwestern.edu/newsroom/news-releases/year-2005/study-reveals-potential-new-target-for-cholesterol-lowering-drugs.html)
- Gene Reviews - Clinical summary (http://www.ncbi.nlm.nih.gov/books/NBK174884)
Genetic Testing Registry - Repository of genetic test information
- GTR: Genetic tests for PCSK9 (http://www.ncbi.nlm.nih.gov/gtr/tests/?term=255738%5Bgeneid%5D)
You may also be interested in these resources, which are designed for genetics professionals and researchers.
- PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/pubmed?term=%28%28PCSK9%5BTIAB%5D%29%20OR%20%28proprotein%20convertase%20subtilisin/kexin%20type%209%5BTIAB%5D%29%29%20AND%20%28%28Genes%5BMH%5D%29%20OR%20%28Genetic%20Phenomena%5BMH%5D%29%29%20AND%20english%5Bla%5D%20AND%20human%5Bmh%5D%20AND%20%22last%201800%20days%22%5Bdp%5D)
- OMIM - Genetic disorder catalog (http://omim.org/entry/607786)
Research Resources - Tools for researchers
- Atlas of Genetics and Cytogenetics in Oncology and Haematology (http://atlasgeneticsoncology.org/Genes/GC_PCSK9.html)
- HGNC Gene Family: Proprotein convertase subtilisin/kexin (http://www.genenames.org/cgi-bin/genefamilies/set/973)
- HGNC Gene Symbol Report (http://www.genenames.org/cgi-bin/gene_symbol_report?q=data/hgnc_data.php&hgnc_id=20001)
- NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/255738)
What other names do people use for the PCSK9 gene or gene products?
- hypercholesterolemia, autosomal dominant 3
- neural apoptosis regulated convertase 1
- Proprotein convertase PC9
- Subtilisin/kexin-like protease PC9
See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.
What glossary definitions help with understanding PCSK9?
amino acid ;
autosomal dominant ;
heart attack ;
low-density lipoproteins ;
You may find definitions for these and many other terms in the Genetics Home Reference
- Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003 Jun;34(2):154-6. (http://www.ncbi.nlm.nih.gov/pubmed/12730697?dopt=Abstract)
- Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabès JP. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat. 2005 Nov;26(5):497. Erratum in: Hum Mutat. 2005 Dec;26(6):592. (http://www.ncbi.nlm.nih.gov/pubmed/16211558?dopt=Abstract)
- Berge KE, Ose L, Leren TP. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol. 2006 May;26(5):1094-100. Epub 2006 Jan 19. (http://www.ncbi.nlm.nih.gov/pubmed/16424354?dopt=Abstract)
- Cameron J, Holla ØL, Ranheim T, Kulseth MA, Berge KE, Leren TP. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum Mol Genet. 2006 May 1;15(9):1551-8. Epub 2006 Mar 28. (http://www.ncbi.nlm.nih.gov/pubmed/16571601?dopt=Abstract)
- Chen SN, Ballantyne CM, Gotto AM Jr, Tan Y, Willerson JT, Marian AJ. 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. J Am Coll Cardiol. 2005 May 17;45(10):1611-9. Epub 2005 Apr 21. (http://www.ncbi.nlm.nih.gov/pubmed/15893176?dopt=Abstract)
- Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006 Mar 23;354(12):1264-72. (http://www.ncbi.nlm.nih.gov/pubmed/16554528?dopt=Abstract)
- Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci. 2007 Feb;32(2):71-7. Epub 2007 Jan 9. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17215125?dopt=Abstract)
- Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, Hobbs HH. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet. 2006 Mar;78(3):410-22. Epub 2006 Jan 20. (http://www.ncbi.nlm.nih.gov/pubmed/16465619?dopt=Abstract)
- Maxwell KN, Breslow JL. Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia. Curr Opin Lipidol. 2005 Apr;16(2):167-72. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15767856?dopt=Abstract)
- Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2069-74. Epub 2005 Jan 27. (http://www.ncbi.nlm.nih.gov/pubmed/15677715?dopt=Abstract)
- NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/255738)
- Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 2006 Sep;79(3):514-23. Epub 2006 Jul 18. (http://www.ncbi.nlm.nih.gov/pubmed/16909389?dopt=Abstract)
The resources on this site should not be used as a substitute for
professional medical care or advice. Users seeking information about
a personal genetic disease, syndrome, or condition should consult with a qualified
See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.