PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9): Genetics, Function, and Clinical Significance
A comprehensive biomedical overview of PCSK9, its role in cholesterol metabolism, associated diseases, expression patterns, and mutation landscape.
Gene Information Card
| Symbol | PCSK9 |
|---|---|
| Full Name | Proprotein Convertase Subtilisin/Kexin Type 9 |
| Gene Type | Protein coding |
| Chromosomal Location | 1p32.3 |
| NCBI Gene ID | 255738 ncbi.nlm.nih.gov/gene/255738 |
| Ensembl ID | ENSG00000169174 |
| UniProt ID | Q8NBP7 |
| OMIM ID | 607786 |
| HGNC ID | 20001 |
| Aliases | FH3, HCHOLA3, NARC-1, PC9 |
Description
PCSK9 encodes a proprotein convertase that regulates cholesterol homeostasis by promoting the degradation of the low-density lipoprotein receptor (LDLR). It is primarily expressed in the liver, intestine, and kidney. Gain-of-function mutations cause autosomal dominant hypercholesterolemia, while loss-of-function mutations are associated with hypocholesterolemia and reduced cardiovascular risk. PCSK9 is a major therapeutic target for lipid-lowering therapy.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Familial hypercholesterolemia 3 (FH3) | Gain-of-function mutations increase LDLR degradation, reducing hepatic LDL clearance and elevating plasma LDL cholesterol. | OMIM #603776; ClinVar pathogenic variants |
| Hypocholesterolemia (protective) | Loss-of-function mutations reduce LDLR degradation, leading to lower LDL cholesterol levels and reduced cardiovascular risk. | ClinVar; population studies (e.g., Cohen et al., 2006) |
| Atherosclerosis / Cardiovascular disease | Elevated PCSK9 activity contributes to hypercholesterolemia and atherosclerosis; inhibition reduces cardiovascular events. | Clinical trials (FOURIER, ODYSSEY) |
| Hepatocellular carcinoma (potential) | PCSK9 overexpression may promote tumor growth via lipid metabolism modulation; evidence is preliminary. | COSMIC; experimental studies |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | High (nTPM ~ 100) | Highest expression; primary site of LDLR regulation |
| Intestine | Moderate (nTPM ~ 20) | Expression in enterocytes; role in lipid absorption |
| Kidney | Low (nTPM ~ 5) | Expression in renal tubules; function less defined |
| Brain | Low (nTPM ~ 2) | Expression in neurons; potential role in neurodevelopment |
| Pancreas | Low (nTPM ~ 1) | Expression in islet cells; possible role in glucose metabolism |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 | High | Liver cancer cell line; used for LDLR studies |
| Caco-2 | Moderate | Intestinal epithelial cells; lipid transport studies |
| HEK293 | Low | Embryonic kidney cells; often used for recombinant expression |
| SH-SY5Y | Low | Neuroblastoma; neuronal PCSK9 expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| D374Y | Gain-of-function | Rare (0.1% in some populations) | Severe hypercholesterolemia; increased LDLR degradation |
| R496W | Gain-of-function | Rare | Familial hypercholesterolemia; reduced LDLR activity |
| R46L | Loss-of-function | ~2% in European populations | Lower LDL cholesterol; reduced cardiovascular risk |
| C679X | Loss-of-function | Rare | Nonsense mutation; hypocholesterolemia |
| A53V | Loss-of-function | Rare | Reduced PCSK9 secretion; lower LDL |
Mutation functional classification
Loss of Function (LOF)
Mutations that impair PCSK9 synthesis, processing, or secretion, or reduce its ability to bind LDLR, leading to increased LDLR levels and lower plasma LDL cholesterol. Examples: R46L, C679X.
Gain of Function (GOF)
Mutations that enhance PCSK9 activity or stability, increasing LDLR degradation and causing hypercholesterolemia. Examples: D374Y, R496W.
Dominant Negative (DN)
No well-characterized dominant-negative mutations have been reported for PCSK9; most mutations act via haploinsufficiency or gain-of-function.
View complete mutation data：
Gene Ontology (GO)
| • GO:0008233 - peptidase activity | • GO:0004252 - serine-type endopeptidase activity |
| • GO:0005576 - extracellular region | • GO:0005615 - extracellular space |
| • GO:0005886 - plasma membrane | • GO:0008201 - heparin binding |
| • GO:0016020 - membrane | • GO:0030168 - platelet activation |
| • GO:0043231 - intracellular membrane-bounded organelle | • GO:0055085 - transmembrane transport |
Pathways
• LDL receptor recycling and degradation (PCSK9-mediated)
• Cholesterol metabolism (HMG-CoA reductase pathway)
• Lipoprotein metabolism (LDL clearance)
• Regulation of lipid homeostasis (SREBP signaling)
Protein Summary
PCSK9 is a 692-amino acid glycoprotein synthesized as a zymogen that undergoes autocatalytic cleavage in the endoplasmic reticulum. The mature protease is secreted and binds to the epidermal growth factor-like repeat A (EGF-A) domain of LDLR, targeting it for lysosomal degradation. This reduces hepatic LDL uptake, raising plasma LDL cholesterol. PCSK9 also has roles in neuronal development, inflammation, and viral entry (e.g., hepatitis C). Therapeutic monoclonal antibodies (evolocumab, alirocumab) and siRNA (inclisiran) target PCSK9 to lower LDL cholesterol.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| PCSK9 Knockout HEK293 Cell Line | EDJ-KQ3896 | Human | 255738 | Details Get a Quote |
| PCSK9 Knockout A-549 Cell Line | EDJ-KQ26111 | Human | 255738 | Details Get a Quote |
| PCSK9 Knockout HCT 116 Cell Line | EDJ-KQ26112 | Human | 255738 | Details Get a Quote |
| PCSK9 Knockout HeLa Cell Line | EDJ-KQ26113 | Human | 255738 | Details Get a Quote |
| PCSK9 Knockout Hep-G2 Cell Line | EDJ-KQ78068 | Human | 255738 | Details Get a Quote |
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