HMGCR Gene: 3-Hydroxy-3-Methylglutaryl-CoA Reductase
Key enzyme in cholesterol biosynthesis and primary target of statin drugs
Gene Information Card
| Symbol | HMGCR |
|---|---|
| Full Name | 3-hydroxy-3-methylglutaryl-CoA reductase |
| Gene Type | Protein coding |
| Chromosomal Location | 5q13.3 |
| NCBI Gene ID | 3156 ncbi.nlm.nih.gov/gene/3156 |
| Ensembl ID | ENSG00000113161 |
| UniProt ID | P04035 |
| OMIM ID | 142910 |
| HGNC ID | 5006 |
| Aliases | HMG-CoA reductase, LDLCQ3 |
Description
The HMGCR gene encodes 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in the mevalonate pathway that synthesizes cholesterol. This enzyme converts HMG-CoA to mevalonate and is the primary target of statin drugs used to lower cholesterol. HMGCR is regulated by sterol levels through feedback mechanisms and plays a critical role in lipid metabolism and cellular membrane integrity.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hypercholesterolemia, familial, 3 | Variants in HMGCR can affect enzyme activity or regulation, leading to altered cholesterol levels. | OMIM: 142910; ClinVar |
| Mevalonic aciduria (secondary) | Deficiency in HMGCR activity can impair cholesterol synthesis, but primary mevalonic aciduria is due to MVK mutations; HMGCR variants may modify phenotype. | OMIM: 610377 (related) |
| Statin-induced myopathy | Genetic variants in HMGCR influence response to statins, increasing risk of muscle toxicity. | ClinVar; PMID: 28240269 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | High (nTPM ~ 50) | High expression, key site of cholesterol synthesis |
| Adrenal gland | Moderate (nTPM ~ 20) | Steroid hormone production requires cholesterol |
| Small intestine | Moderate (nTPM ~ 15) | Dietary cholesterol absorption and synthesis |
| Brain | Low (nTPM ~ 5) | Low expression, cholesterol is locally synthesized |
| Muscle | Low (nTPM ~ 3) | Low expression, but relevant for statin myopathy |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 | High | Liver cancer cell line, high cholesterol synthesis |
| Caco-2 | Moderate | Intestinal epithelial cells |
| A549 | Low | Lung carcinoma, low expression |
| MCF7 | Low | Breast cancer cell line, low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs3846662 | SNP (intronic) | Allele frequency ~0.4 (global) | Associated with variable statin response and cholesterol levels |
| rs17238540 | SNP (intronic) | Allele frequency ~0.1 (European) | Linked to reduced LDL cholesterol response to statins |
| c.1561C>T (p.Arg521Cys) | Missense | Rare | Reduced enzyme activity, associated with hypocholesterolemia |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in HMGCR reduce enzyme activity, leading to lower cholesterol synthesis. Rare variants may cause hypocholesterolemia but are often compensated by feedback upregulation.
Gain of Function (GOF)
Gain-of-function mutations are rare and may increase enzyme activity, potentially contributing to hypercholesterolemia, but not well documented.
Dominant Negative (DN)
No dominant-negative mutations reported for HMGCR; it functions as a dimer, but such mutations are not characterized.
View complete mutation data：
Gene Ontology (GO)
| • hydroxymethylglutaryl-CoA reductase (NADPH) activity (GO:0004165) | • endoplasmic reticulum membrane (GO:0005783) |
| • cholesterol biosynthetic process (GO:0006695) | • sterol metabolic process (GO:0016125) |
| • cytoplasm (GO:0005737) |
Pathways
• Cholesterol biosynthesis (mevalonate pathway)
• Metabolism of lipids and lipoproteins
• Statin pathway (pharmacodynamic)
Protein Summary
HMGCR is a transmembrane glycoprotein located in the endoplasmic reticulum. It catalyzes the four-electron reduction of HMG-CoA to mevalonate, using NADPH as a cofactor. The enzyme is regulated by sterol-dependent degradation and transcriptional feedback. Its N-terminal domain anchors it to the membrane, while the C-terminal catalytic domain faces the cytosol. HMGCR is the target of statins, which competitively inhibit its active site.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| HMGCR Knockout HAP1 Cell Line | EDJ-KQ78114 | Human | 3156 | Details Get a Quote |
| HMGCR Knockout HEK293T Cell Line | EDJ-KQ78152 | Human | 3156 | Details Get a Quote |
| HMGCR Knockout Hep-G2 Cell Line | EDJ-KQ78153 | Human | 3156 | Details Get a Quote |
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