TIMP3 (Tissue Inhibitor of Metalloproteinases 3)
Key regulator of extracellular matrix remodeling and inhibitor of angiogenesis; mutations cause Sorsby fundus dystrophy.
Gene Information Card
| Symbol | TIMP3 |
|---|---|
| Full Name | TIMP metallopeptidase inhibitor 3 |
| Gene Type | protein-coding |
| Chromosomal Location | 22q12.3 |
| NCBI Gene ID | 7078 ncbi.nlm.nih.gov/gene/7078 |
| Ensembl ID | ENSG00000100234 |
| UniProt ID | P35625 |
| OMIM ID | 188826 |
| HGNC ID | 11822 |
| Aliases | SFD, HSMRK222, TIMP-3 |
Description
TIMP3 encodes a member of the tissue inhibitor of metalloproteinases (TIMP) family. The protein inhibits matrix metalloproteinases (MMPs) and ADAM metalloproteinases, regulating extracellular matrix (ECM) turnover, cell migration, and angiogenesis. TIMP3 is unique among TIMPs due to its tight binding to the ECM. Loss-of-function mutations in TIMP3 cause Sorsby fundus dystrophy, an autosomal dominant macular degeneration. The gene is also implicated in cancer, cardiovascular disease, and arthritis.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Sorsby fundus dystrophy (SFD) | Missense mutations (e.g., Ser181Cys) disrupt disulfide bonding, impairing MMP inhibition and leading to ECM accumulation in Bruch's membrane. | OMIM #136900; ClinVar pathogenic variants. |
| Age-related macular degeneration (AMD) | Polymorphisms in TIMP3 may alter ECM homeostasis, contributing to drusen formation. | GWAS studies; NCBI PubMed. |
| Cancer (various) | TIMP3 promoter hypermethylation silences expression, reducing MMP inhibition and promoting tumor invasion. | COSMIC; NCBI PubMed. |
| Cardiovascular disease | TIMP3 deficiency increases MMP activity, leading to ECM degradation and plaque instability. | NCBI PubMed. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Adipose tissue | 5.2 | Low |
| Brain | 3.1 | Low |
| Heart | 12.8 | Medium |
| Kidney | 8.5 | Medium |
| Liver | 4.0 | Low |
| Lung | 15.3 | Medium |
| Placenta | 20.1 | High |
| Skeletal muscle | 6.7 | Medium |
| Skin | 18.4 | High |
| Vascular endothelium | 22.5 | High |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HUVEC (endothelial) | 25.3 | High expression |
| HeLa (cervical) | 8.1 | Medium |
| A549 (lung) | 12.4 | Medium |
| MCF7 (breast) | 6.0 | Low |
| HEK293 (embryonic kidney) | 9.7 | Medium |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.542C>G (p.Ser181Cys) | Missense | Pathogenic in SFD | Disrupts disulfide bond, reduces MMP inhibition. |
| c.611G>A (p.Gly204Asp) | Missense | Pathogenic in SFD | Alters ECM binding. |
| c.563A>G (p.Tyr188Cys) | Missense | Pathogenic in SFD | Causes protein misfolding. |
| Promoter hypermethylation | Epigenetic | Frequent in cancers | Silences TIMP3 expression. |
Mutation functional classification
Loss of Function (LOF)
Promoter hypermethylation or nonsense mutations reduce TIMP3 protein levels, increasing MMP activity and ECM degradation.
Gain of Function (GOF)
Not reported for TIMP3.
Dominant Negative (DN)
Missense mutations (e.g., Ser181Cys) produce a defective protein that interferes with wild-type TIMP3 function, leading to Sorsby fundus dystrophy.
View complete mutation data：
Gene Ontology (GO)
| • metalloendopeptidase inhibitor activity (GO:0008191) | • extracellular matrix (GO:0005578) |
| • extracellular space (GO:0005615) | • cell adhesion (GO:0007155) |
| • angiogenesis (GO:0001525) | • extracellular structure organization (GO:0043062) |
Pathways
• Matrix Metalloproteinase (MMP) Inhibition Pathway
• Extracellular Matrix Remodeling
• Angiogenesis (negative regulation)
Protein Summary
TIMP3 is a 211-amino-acid secreted protein (24.5 kDa) that binds to the ECM via its N-terminal domain. It inhibits MMP-1, -2, -3, -7, -9, -13, and ADAM-17. The protein contains 12 cysteine residues forming six disulfide bonds, critical for stability. Mutations in these cysteines cause Sorsby fundus dystrophy. TIMP3 also has anti-angiogenic properties independent of MMP inhibition.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TIMP3 Knockout HEK293 Cell Line | EDJ-KQ5933 | Human | 7078 | Details Get a Quote |
| TIMP3 Knockout A-549 Cell Line | EDJ-KQ28198 | Human | 7078 | Details Get a Quote |
| TIMP3 Knockout HCT 116 Cell Line | EDJ-KQ29478 | Human | 7078 | Details Get a Quote |
| TIMP3 Knockout HeLa Cell Line | EDJ-KQ29479 | Human | 7078 | Details Get a Quote |
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