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10 sources retrieved · Most recent: April 2026 · Index updated 14 days ago
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TIMP4
TIMP metallopeptidase inhibitor 4
Chromosome 3 · 3p25.2
NCBI Gene: 7079Ensembl: ENSG00000157150.6HGNC: HGNC:11823UniProt: Q99727
74PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
metalloendopeptidase inhibitor activityresponse to hormoneresponse to cytokinenegative regulation of membrane protein ectodomain proteolysisneurodegenerative diseasetype 2 diabetes mellitushypothyroidismacne
✦AI Summary

TIMP4 (TIMP metallopeptidase inhibitor 4) is an extracellular matrix regulator that complexes with metalloproteinases and irreversibly inactivates them by binding to their catalytic zinc cofactor, targeting MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. The gene spans approximately 6-7 kb with five exons and is located on chromosome 3 in humans and chromosome 3 in mice, positioned within intron 5 of the synapsin 2 gene 12. TIMP4 exhibits tissue-specific expression patterns, with highest levels in heart, ovary, and brain, suggesting specialized roles in maintaining extracellular matrix homeostasis in these tissues 2. In cancer contexts, TIMP4 appears to have dual roles - it can be regulated by the LOX/SNAI2 axis and promotes cancer progression through secretion mechanisms 3, while paradoxically showing decreased expression in oral squamous cell carcinoma associated with poor prognosis 4. TIMP4 deficiency has significant clinical implications, with loss-of-function variants associated with early-onset high myopia through disruption of scleral collagen homeostasis and ocular development 5. The protein also shows associations with cardiovascular diseases, fragility fractures, and various psychiatric disorders, highlighting its broad physiological importance 67.

Sources cited
1
TIMP4 gene structure with five exons spanning 6 kb and chromosomal localization to 3p25 in humans
PMID: 9693046
2
Murine Timp4 gene characterization, tissue distribution, and location within synapsin 2 gene intron
PMID: 12151094
3
LOX/SNAI2 axis regulation of TIMP4 secretion in cancer progression
PMID: 27029493
4
Decreased TIMP4 expression in oral squamous cell carcinoma associated with poor prognosis
PMID: 39984587
5
TIMP4 loss-of-function variants associated with early-onset high myopia and ocular development defects
PMID: 38069250
6
TIMP4 associations with cardiovascular diseases and fragility fractures
PMID: 39919333
7
TIMP4 identified as comorbidity locus for depression and schizophrenia
PMID: 38637810
Disease Associationsⓘ20
neurodegenerative diseaseOpen Targets
0.44Moderate
type 2 diabetes mellitusOpen Targets
0.38Weak
hypothyroidismOpen Targets
0.36Weak
acneOpen Targets
0.35Weak
myxedemaOpen Targets
0.32Weak
myeloid leukemiaOpen Targets
0.31Weak
Abnormality of skin pigmentationOpen Targets
0.26Weak
atrial fibrillationOpen Targets
0.26Weak
ACPA-positive rheumatoid arthritisOpen Targets
0.21Weak
Abnormality of the skeletal systemOpen Targets
0.20Weak
HypercholesterolemiaOpen Targets
0.17Weak
hemorrhagic diseaseOpen Targets
0.16Weak
metabolic diseaseOpen Targets
0.16Weak
hyperlipidemiaOpen Targets
0.16Weak
anorexia nervosaOpen Targets
0.15Weak
thrombocytopenia 4Open Targets
0.15Weak
diabetes mellitusOpen Targets
0.13Weak
adolescent idiopathic scoliosisOpen Targets
0.11Weak
alcohol drinkingOpen Targets
0.10Weak
TinnitusOpen Targets
0.10Weak
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
TIMP2Protein interaction98%HPXProtein interaction96%MMP1Protein interaction96%MMP2Protein interaction96%MMP7Protein interaction96%MMP9Protein interaction96%
Tissue Expression6 tissues
Heart
100%
Brain
31%
Lung
27%
Ovary
13%
Liver
3%
Bone Marrow
3%
Gene Interaction Network
Click a node to explore
TIMP4TIMP2HPXMMP1MMP2MMP7MMP9
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted · UniProt Q99727
View on AlphaFold ↗
Constraintⓘ
LOEUFⓘ
1.40LoF Tolerant
pLIⓘ
0.00Tolerant
Observed/Expected LoF1.01 [0.75–1.40]
RankingsWhere TIMP4 stands among ~20K protein-coding genes
  • #6,434of 20,598
    Most Researched74
  • #14,473of 17,882
    Most Constrained (LOEUF)1.40
Genes detectedTIMP4
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
Dissecting the shared genetic landscape of anxiety, depression, and schizophrenia.
PMID: 38637810
J Transl Med · 2024
1.00
2
Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers.
PMID: 27029493
Clin Cancer Res · 2016
0.90
3
Cloning of the human tissue inhibitor of metalloproteinase-4 gene (TIMP4) and localization of the TIMP4 and Timp4 genes to human chromosome 3p25 and mouse chromosome 6, respectively.
PMID: 9693046
Genomics · 1998
0.80
4
TIMP4 serves as a novel potential prognostic biomarker for oral squamous cell carcinoma.
PMID: 39984587
Sci Rep · 2025
0.70
5
Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigation.
PMID: 39919333
EBioMedicine · 2025
0.60