TIMP3

Summary

TIMP3 (TIMP metallopeptidase inhibitor 3, HGNC:11822) is a protein-coding gene on chromosome 22q12.3, encoding Metalloproteinase inhibitor 3 (P35625). Mediates a variety of processes including matrix regulation and turnover, inflammation, and angiogenesis, through reversible inhibition of zinc protease superfamily enzymes, primarily matrix metalloproteinases (MMPs).

This gene belongs to the TIMP gene family. The proteins encoded by this gene family are inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix (ECM). Expression of this gene is induced in response to mitogenic stimulation and this netrin domain-containing protein is localized to the ECM. Mutations in this gene have been associated with the autosomal dominant disorder Sorsby’s fundus dystrophy.

Source: NCBI Gene 7078 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Sorsby fundus dystrophy (Definitive, ClinGen)
• GWAS associations: 9
• Clinical variants (ClinVar): 31 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000362

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11822
Approved symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100234
Ensembl biotype	protein_coding
OMIM	188826
Entrez	7078

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000266085, ENST00000908983, ENST00000908984, ENST00000948415

RefSeq mRNA: 1 — MANE Select: NM_000362 NM_000362

CCDS: CCDS13911

Canonical transcript exons

ENST00000266085 — 5 exons

Exon	Start	End
ENSE00000653439	32857249	32857360
ENSE00000653440	32858017	32858138
ENSE00001166470	32849452	32849534
ENSE00001166483	32801705	32802122
ENSE00001947194	32859180	32863041

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 201.7905 / max 10852.8646, expressed in 1516 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191883	197.5497	1514
191905	2.5958	679
191932	0.5374	228
191902	0.2982	149
191903	0.2174	104
191907	0.1803	75
191904	0.1616	56
191906	0.1494	69
191929	0.1008	34

Top tissues by expression

309 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
synovial joint	UBERON:0002217	99.90	gold quality
decidua	UBERON:0002450	99.88	gold quality
pigmented layer of retina	UBERON:0001782	99.87	gold quality
retina	UBERON:0000966	99.85	gold quality
urethra	UBERON:0000057	99.83	gold quality
right lung	UBERON:0002167	99.79	gold quality
lower lobe of lung	UBERON:0008949	99.77	gold quality
vena cava	UBERON:0004087	99.56	gold quality
adult organism	UBERON:0007023	99.56	gold quality
placenta	UBERON:0001987	99.54	gold quality
saphenous vein	UBERON:0007318	99.54	gold quality
upper lobe of lung	UBERON:0008948	99.54	gold quality
upper lobe of left lung	UBERON:0008952	99.53	gold quality
left uterine tube	UBERON:0001303	99.48	gold quality
adipose tissue	UBERON:0001013	99.47	gold quality
mucosa of stomach	UBERON:0001199	99.47	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.45	gold quality
calcaneal tendon	UBERON:0003701	99.45	gold quality
parietal pleura	UBERON:0002400	99.44	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.44	gold quality
omental fat pad	UBERON:0010414	99.44	gold quality
seminal vesicle	UBERON:0000998	99.43	gold quality
peritoneum	UBERON:0002358	99.43	gold quality
myometrium	UBERON:0001296	99.42	gold quality
metanephros cortex	UBERON:0010533	99.42	gold quality
olfactory bulb	UBERON:0002264	99.38	gold quality
right atrium auricular region	UBERON:0006631	99.38	gold quality
endocervix	UBERON:0000458	99.37	gold quality
trigeminal ganglion	UBERON:0001675	99.37	gold quality
cardiac atrium	UBERON:0002081	99.37	gold quality

Single-cell (SCXA)

Detected in 49 experiment(s), a significant marker in 47.

Experiment	Marker?	Max mean expression
E-GEOD-81383	yes	28011.75
E-MTAB-6678	yes	20369.46
E-HCAD-23	yes	18720.10
E-MTAB-6701	yes	13563.88
E-HCAD-24	yes	9630.92
E-ANND-2	yes	5745.90
E-GEOD-83139	yes	5356.09
E-MTAB-8322	yes	3789.11
E-GEOD-134144	yes	3670.06
E-HCAD-15	yes	3219.16
E-MTAB-10287	yes	3013.80
E-MTAB-11121	yes	2937.94
E-GEOD-98556	yes	2801.21
E-MTAB-9841	yes	2582.52
E-CURD-88	yes	2511.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF3, BARX2, DNMT1, EGR1, ELF3, FOXN1, FOXO1, GLI2, JUN, NFKB, PGR, PPARG, SMAD2, SMAD3, SMAD4, SMO, SP1, SRF, STAT1, STAT3, TCF3, TP53, TP73, TXK

miRNA regulators (miRDB)

194 targeting TIMP3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1468-3P	99.96	72.74	3797

Literature-anchored findings (GeneRIF, showing 40)

• Expression of Sorsby’s fundus dystrophy mutations in human retinal pigment epithelial cells reduces matrix metalloproteinase inhibition and may promote angiogenesis (PMID:11821400)
• Tissue inhibitor of metalloproteinase-3 induces a Fas-associated death domain-dependent type II apoptotic pathway (PMID:11827969)
• Novel mutation in TIMP3 gene causes Sorsby Fundus Dystrophy. (PMID:11879143)
• Engineering N-terminal domain of tissue inhibitor of metalloproteinase (TIMP)-3 to be a better inhibitor against tumour necrosis factor-alpha-converting enzyme (PMID:11988096)
• role in inducing apoptosis in retinal pigment epithelium and other cells (PMID:12372614)
• TIMP-3 may contribute to the regulation of myocardial remodeling and its reduction may promote a transition from compensated to end-stage congestive heart failure. (PMID:12388270)
• we demonstrate the ability of TIMP3 to inhibit vascular endothelial factor (VEGF)-mediated angiogenesis (PMID:12652295)
• This protein is downregulated in lymphangioleiomyomatosis as a consequence of abnormal serum response factor expression. (PMID:12654640)
• TIMP-3 promotes apoptosis in melanoma cells through stabilization of three distinct death receptors and activation of their apoptotic signaling cascade through caspase-8. (PMID:12687014)
• Down-regulation of TIMP3 expression by methylation is associated with uveal melanoma development (PMID:12845640)
• Peaks during the early to mid-luteal phase. Seems to play role in hormonal regulation and endometrial tissue remodeling. (PMID:12969699)
• ADAM-17/TACE and TIMP-3 might play an important role in the pathogenesis of prostate cancer (PMID:14532978)
• Our analysis of the entire coding region of TIMP-1, -2, and -3, which are the main inhibitors of metalloproteinase activity in the extracellular matrix, failed to show an association between genetic polymorphisms and an intracranial aneurysm (PMID:14605322)
• TIMP-3 is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) (PMID:15123717)
• Reactive oxygen species mediate TGF-beta1-induced TIMP-3 gene expression (PMID:15203191)
• Dermal wound healing in red Duroc pigs show unique mRNA expression of HSP47,BMP-1,TIMP1-3 and hypercontracted,hyperpigmented scars. (PMID:15225209)
• Promoter methylation of the TIMP3 is involved in suppression of TIMP3 expression in choriocarcinoma. (PMID:15297175)
• HBV affects the malignance of hepatocellular cancer by suppressing TIMP-3. (PMID:15313474)
• role in down regulation of proMMP-2 activation in scirrhous gastric carcinoma (PMID:15387372)
• Decreased expression of TIMP-3 protein correlates with invasive activity and metastasis in esophageal squamous cell carcinoma (PMID:15467768)
• Activation of ERK-MAPK pathway and Sp1 transcription factor play a pivotal role in the induction of TIMP-3 by TGF-beta in chondrocytes. (PMID:15468069)
• The TIMP3 modulate extracellular matrix remodeling during embryonic development and disease. (PMID:15538971)
• TIMP3 inactivation occurs in the progression to secondary gliomas. (PMID:15592495)
• negative effect of TGFbeta1 on ADAMTS-1, -5, -9, and -15 coupled with increases in their inhibitor, TIMP-3 may aid the accumulation of versican in the stromal compartment of the prostate in BPH and prostate cancer (PMID:15599946)
• Reduced expression of TIMP-3 protein in esophageal adenocarcinoma is associated with increased tumour invasiveness (PMID:15688381)
• TIMP3 seems to play an important role in the tumorigenesis of primary pancreatic adenocarcinomas (PMID:15714128)
• Sequence analysis showed a single base pair change resulting in a Ser170Cys mutation in exon 5 of TIMP3 (PMID:15824229)
• Intracellularly produced TIMP-3 not only induces apoptosis, but also modulates the apoptosis-inhibiting effects of TNF-alpha in human rheumatoid arthritis synovial fibroblast-like cells. (PMID:15879156)
• genetic variation in TIMP3 may contribute to the pathogenesis of abdominal aortic aneurysm (PMID:15944607)
• TIMP-3 reactive site mutations disrupt inhibition of matrix metalloproteinases but not TACE (PMID:16079149)
• Increased deposition of active TIMP-3, rather than dysregulation of metalloproteinase inhibition, is likely to be the primary, initiating event in Sorsby’s fundus dystrophy . (PMID:16223891)
• role in reduction of metastasis in breast cancer cell line (PMID:16225775)
• Review discusses how, despite the lack of inherited mutations in the structural gene, the TIMP3 protein might play a role in the onset and progression of age-related macular degeneration. (PMID:16259644)
• The inhibition of ADAMTS-2 by TIMP-3 alone out of 4 TIMP proteins is reported. (PMID:16771712)
• Aberrant methylation and hence silencing of TIMP3, SLC5A8, DAPK and RARbeta2, in association with BRAF mutation, may be an important step in PTC tumorigenesis and progression. (PMID:16858683)
• In idiopathic pulmonary fibrosis tissues TIMP3 gene expression was increased and the protein was localized to fibroblastic foci and extracellular matrix. Our findings suggest that TGF-beta1-induced TIMP3 may be an important mediator in lung fibrogenesis. (PMID:16908447)
• A novel mutation in TIMP3 causes a late-onset form of SFD (Sorsby fundus dystrophy) in this family. (PMID:16989765)
• TIMP-3 has a role in the pericyte-induced stabilization of newly formed vascular networks that are predisposed to undergo regression and reveal specific molecular targets of the inhibitors regulating these events. (PMID:17030988)
• We observed a moderately increased risk for breast cancer in the C allele carriers of the TIMP3-1296 T/C SNP (OR 1.25, 95% CI 1.05-1.50) (PMID:17033924)
• APMCF1 participates at least partially in cell cycle regulation through regulating genes such as p21 and TIMP3. (PMID:17080297)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Timp3	ENSMUSG00000020044
rattus_norvegicus	Timp3	ENSRNOG00000004303
drosophila_melanogaster	Timp	FBGN0025879
caenorhabditis_elegans		WBGENE00019478

Paralogs (3): TIMP2 (ENSG00000035862), TIMP1 (ENSG00000102265), TIMP4 (ENSG00000157150)

Protein

Protein identifiers

Metalloproteinase inhibitor 3 — P35625 (reviewed: P35625)

Alternative names: Protein MIG-5, Tissue inhibitor of metalloproteinases 3

All UniProt accessions (1): P35625

UniProt curated annotations — full annotation on UniProt →

Function. Mediates a variety of processes including matrix regulation and turnover, inflammation, and angiogenesis, through reversible inhibition of zinc protease superfamily enzymes, primarily matrix metalloproteinases (MMPs). Regulates extracellular matrix (ECM) remodeling through inhibition of matrix metalloproteinases (MMP) including MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, MMP-14 and MMP-15. Additionally, modulates the processing of amyloid precursor protein (APP) and apolipoprotein E receptor ApoER2 by inhibiting two alpha-secretases ADAM10 and ADAM17. Functions as a tumor suppressor and a potent inhibitor of angiogenesis. Exerts its anti-angiogenic effect by directly interacting with vascular endothelial growth factor (VEGF) receptor-2/KDR, preventing its binding to the VEGFA ligand. Selectively induces apoptosis in angiogenic endothelial cells through a caspase-independent cell death pathway. Mechanistically, inhibits matrix-induced focal adhesion kinase PTK2 tyrosine phosphorylation and association with paxillin/PXN and disrupts the incorporation of ITGB3, PTK2 and PXN into focal adhesion contacts on the matrix.

Subunit / interactions. Interacts with EFEMP1. Interacts with KDR.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Disease relevance. Sorsby fundus dystrophy (SFD) [MIM:136900] Rare autosomal dominant macular disorder with an age of onset in the fourth decade. It is characterized by loss of central vision from subretinal neovascularization and atrophy of the ocular tissues. Generally, macular disciform degeneration develops in the patients eye within 6 months to 6 years. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the protease inhibitor I35 (TIMP) family.

RefSeq proteins (1): NP_000353* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001134	Netrin_domain	Domain
IPR001820	TIMP	Family
IPR008993	TIMP-like_OB-fold	Homologous_superfamily
IPR027465	TIMP_C	Homologous_superfamily
IPR030490	TIMP_CS	Conserved_site

Pfam: PF00965

UniProt features (35 total): strand 8, disulfide bond 6, sequence variant 5, helix 3, turn 3, region of interest 3, sequence conflict 2, signal peptide 1, chain 1, domain 1, binding site 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3CKI	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35625-F1	87.49	0.76

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 85 (involved in metalloproteinase-binding)

Ligand- & substrate-binding residues (1): 24

Disulfide bonds (6): 36–143, 145–192, 150–155, 163–184, 24–91, 26–118

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation

MSigDB gene sets: 473 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, MODULE_52, WANG_CLIM2_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, CHIBA_RESPONSE_TO_TSA_UP, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, MODULE_255, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, DITTMER_PTHLH_TARGETS_UP

GO Biological Process (6): visual perception (GO:0007601), response to hormone (GO:0009725), negative regulation of extracellular matrix disassembly (GO:0010716), response to cytokine (GO:0034097), negative regulation of membrane protein ectodomain proteolysis (GO:0051045), negative regulation of proteolysis (GO:0045861)

GO Molecular Function (5): metalloendopeptidase inhibitor activity (GO:0008191), metal ion binding (GO:0046872), enzyme inhibitor activity (GO:0004857), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (7): extracellular region (GO:0005576), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), extracellular matrix (GO:0031012), platelet dense granule lumen (GO:0031089), secretory granule lumen (GO:0034774)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory perception of light stimulus	1
response to endogenous stimulus	1
response to chemical	1
regulation of extracellular matrix disassembly	1
extracellular matrix disassembly	1
negative regulation of extracellular matrix organization	1
response to peptide	1
membrane protein ectodomain proteolysis	1
negative regulation of protein catabolic process	1
negative regulation of proteolysis	1
regulation of membrane protein ectodomain proteolysis	1
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
metalloendopeptidase activity	1
endopeptidase inhibitor activity	1
cation binding	1
catalytic activity	1
enzyme regulator activity	1
molecular function inhibitor activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular anatomical structure	1
extracellular matrix	1
intracellular membrane-bounded organelle	1
external encapsulating structure	1
secretory granule lumen	1
platelet dense granule	1
secretory granule	1
cytoplasmic vesicle lumen	1

Protein interactions and networks

STRING

2714 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIMP3	KDR	P35968	965
TIMP3	EFEMP1	Q12805	953
TIMP3	ADAM17	P78536	947
TIMP3	MMP9	P14780	942
TIMP3	MMP2	P08253	909
TIMP3	MMP7	P09237	890
TIMP3	MMP14	P50281	872
TIMP3	MMP3	P08254	851
TIMP3	ADAMTS5	Q9UNA0	837
TIMP3	AGTR2	P50052	801
TIMP3	ADAMTS4	O75173	781
TIMP3	TIMP2	P16035	770
TIMP3	TGFB1	P01137	736
TIMP3	RECK	O95980	732
TIMP3	PRPH2	P23942	730

IntAct

93 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
FAM136A	RBFOX3	psi-mi:“MI:0914”(association)	0.640
VWCE	HSPA5	psi-mi:“MI:0914”(association)	0.640
TIMP3	AGTR2	psi-mi:“MI:0915”(physical association)	0.580
AGTR2	TIMP3	psi-mi:“MI:0915”(physical association)	0.580
KLRG2	GXYLT2	psi-mi:“MI:0914”(association)	0.530
VWCE	ZNF316	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
DKK3	NME4	psi-mi:“MI:0914”(association)	0.530
IFI30	PRC1	psi-mi:“MI:0914”(association)	0.530
IGFBP1	SUSD5	psi-mi:“MI:0914”(association)	0.530
TIMP2	ZMYM6	psi-mi:“MI:0914”(association)	0.530
ASGR2	MT-CO1	psi-mi:“MI:0914”(association)	0.530
MMP3	APOE	psi-mi:“MI:0914”(association)	0.530
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.530
TIMP3	ZZEF1	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
ADAMTS5	ACAN	psi-mi:“MI:0570”(protein cleavage)	0.440

BioGRID (114): TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), Pcsk5 (Affinity Capture-Western), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), TIMP3 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M9PFP2, A1L2K1, A4IGL3, A4IH88, A8WFR0, B0S5G3, F1LW30, L7VG99, O42146, O73746, O75339, O93449, O97591, P12032, P15203, P16035, P16176, P16368, P20614, P23667, P25785, P26652, P30120, P30121, P30970, P35625, P39876, P48032, P61269, P79121, Q01H84, Q09199, Q28GB8, Q3KTM2, Q5PXZ9, Q60453, Q66K08, Q6DDG2, Q6UXZ4, Q7ZV46

Diamond homologs: O02722, O42146, O73746, O77717, O97563, O97591, P01033, P12032, P16035, P16368, P20414, P20614, P25785, P26652, P30120, P30121, P35624, P35625, P39876, P48032, P49061, P50122, P61269, P79121, P81546, P81556, Q5PXZ9, Q5RC60, Q60453, Q95KL9, Q99727, Q9JHB3, Q9TRZ7, Q9TTY1, Q9TUL9, Q9W6B4, Q9WUC6, O97590, Q21265

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
IL15RA	up-regulates	TIMP3
TIMP3	“down-regulates activity”	Adipogenesis
SMO	“up-regulates quantity by expression”	TIMP3	“transcriptional regulation”
TIMP3	“down-regulates activity”	MMP14	binding
TIMP3	down-regulates	Angiogenesis

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 123 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Collagen degradation	6	13.3×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
extracellular matrix disassembly	5	17.8×	2e-03
extracellular matrix organization	8	9.5×	7e-04
positive regulation of cell migration	11	6.6×	7e-04
proteolysis	13	4.3×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

31 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	18
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
12676	NM_000362.5(TIMP3):c.610A>T (p.Ser204Cys)	Pathogenic
12678	NM_000362.5(TIMP3):c.536C>G (p.Ser179Cys)	Pathogenic
545105	NM_000362.5(TIMP3):c.311T>C (p.Leu104Pro)	Likely pathogenic

SpliceAI

942 predictions. Top by Δscore:

Variant	Effect	Δscore
22:32802123:G:GA	donor_loss	1.0000
22:32802123:G:GG	donor_gain	1.0000
22:32802124:TAAG:T	donor_loss	1.0000
22:32849441:T:A	acceptor_gain	1.0000
22:32849447:T:TA	acceptor_gain	1.0000
22:32849447:TGCA:T	acceptor_loss	1.0000
22:32849449:CAG:C	acceptor_loss	1.0000
22:32849450:A:AG	acceptor_gain	1.0000
22:32849450:A:C	acceptor_loss	1.0000
22:32849450:AGT:A	acceptor_gain	1.0000
22:32849451:G:GG	acceptor_gain	1.0000
22:32849451:GT:G	acceptor_gain	1.0000
22:32849451:GTG:G	acceptor_gain	1.0000
22:32849451:GTGA:G	acceptor_gain	1.0000
22:32849451:GTGAT:G	acceptor_gain	1.0000
22:32849532:AAG:A	donor_loss	1.0000
22:32849534:GGTA:G	donor_loss	1.0000
22:32849535:G:GA	donor_loss	1.0000
22:32849535:G:GG	donor_gain	1.0000
22:32857243:CCACA:C	acceptor_loss	1.0000
22:32857245:ACAG:A	acceptor_loss	1.0000
22:32857246:CAGA:C	acceptor_loss	1.0000
22:32857247:A:AG	acceptor_gain	1.0000
22:32857247:A:G	acceptor_loss	1.0000
22:32857247:AGAT:A	acceptor_gain	1.0000
22:32857248:G:GC	acceptor_gain	1.0000
22:32857248:GA:G	acceptor_gain	1.0000
22:32857248:GAT:G	acceptor_gain	1.0000
22:32857248:GATG:G	acceptor_gain	1.0000
22:32857248:GATGT:G	acceptor_gain	1.0000

AlphaMissense

1382 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:32857315:T:A	C91S	1.000
22:32857316:G:C	C91S	1.000
22:32858072:G:C	W124C	1.000
22:32858072:G:T	W124C	1.000
22:32859228:T:A	C163S	1.000
22:32859229:G:C	C163S	1.000
22:32859293:C:G	C184W	1.000
22:32859323:G:C	W194C	1.000
22:32859323:G:T	W194C	1.000
22:32802107:T:A	C36S	0.999
22:32802108:G:A	C36Y	0.999
22:32802108:G:C	C36S	0.999
22:32849458:G:C	R43P	0.999
22:32849460:G:C	A44P	0.999
22:32849461:C:A	A44D	0.999
22:32849514:T:G	Y62D	0.999
22:32857258:G:C	G72R	0.999
22:32857315:T:C	C91R	0.999
22:32857316:G:A	C91Y	0.999
22:32857316:G:T	C91F	0.999
22:32857317:T:G	C91W	0.999
22:32857352:T:C	L103P	0.999
22:32858017:G:A	G106D	0.999
22:32858052:T:A	C118S	0.999
22:32858052:T:C	C118R	0.999
22:32858053:G:A	C118Y	0.999
22:32858053:G:C	C118S	0.999
22:32858070:T:A	W124R	0.999
22:32858070:T:C	W124R	0.999
22:32858080:T:C	L127P	0.999

dbSNP variants (sampled 300 via entrez): RS1000041933 (22:32837334 C>A,G,T), RS1000042876 (22:32843282 G>A,T), RS1000090574 (22:32802643 C>A,T), RS1000114356 (22:32841931 T>C), RS1000158176 (22:32837106 T>C), RS1000292896 (22:32861143 T>C,G), RS1000300169 (22:32819497 A>G), RS1000314980 (22:32820882 C>T), RS1000352416 (22:32826914 G>C), RS1000428739 (22:32825698 GAT>G), RS1000470231 (22:32827275 C>A,T), RS1000511330 (22:32815623 A>G), RS1000532858 (22:32855679 T>C), RS1000603402 (22:32820535 T>G), RS1000801646 (22:32828894 A>G,T)

Disease associations

OMIM: gene MIM:188826 | disease phenotypes: MIM:136900, MIM:108010

GenCC curated gene-disease

Disease	Classification	Inheritance
Sorsby fundus dystrophy	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Sorsby fundus dystrophy	Definitive	AD

Mondo (4): retinal disorder (MONDO:0005283), Sorsby fundus dystrophy (MONDO:0007640), inherited retinal dystrophy (MONDO:0019118), arteriovenous malformations of the brain (MONDO:0007154)

Orphanet (3): Sorsby fundus dystrophy (Orphanet:59181), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Brain arteriovenous malformation (Orphanet:46724)

HPO phenotypes

21 total (22 of 21 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000501	Glaucoma
HP:0000512	Abnormal electroretinogram
HP:0000533	Chorioretinal atrophy
HP:0000572	Visual loss
HP:0000580	Pigmentary retinopathy
HP:0000610	Abnormal choroid morphology
HP:0000618	Blindness
HP:0000662	Nyctalopia
HP:0001105	Retinal atrophy
HP:0001129	Large central visual field defect
HP:0001141	Severely reduced visual acuity
HP:0007722	Retinal pigment epithelial atrophy
HP:0007754	Macular dystrophy
HP:0011462	Young adult onset
HP:0011506	Choroidal neovascularization
HP:0030491	Choriocapillaris atrophy
HP:0030500	Yellow/white macular lesion
HP:0030602	Abnormal fundus autofluorescence imaging
HP:0030625	Hyporeflective spaces on macular OCT
HP:0031528	Subretinal deposits
HP:0000556	Retinal dystrophy

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000652_1	Age-related macular degeneration	1.000000e-11
GCST000653_5	Age-related macular degeneration	4.000000e-09
GCST001100_5	Age-related macular degeneration	2.000000e-15
GCST001884_15	Age-related macular degeneration	2.000000e-26
GCST002379_7	Pyoderma gangrenosum in inflammatory bowel disease	6.000000e-07
GCST003219_51	Advanced age-related macular degeneration	1.000000e-24
GCST006136_12	Alzheimer’s disease progression score	2.000000e-06
GCST008150_9	Triglyceride levels	2.000000e-07
GCST009391_321	Metabolite levels	4.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006835	pyoderma gangrenosum
EFO:1001492	atrophic macular degeneration
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0004530	triglyceride measurement
EFO:0010431	triacylglycerol 56:4 measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
C564992	Fundus Dystrophy, Pseudoinflammatory, Of Sorsby (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465289 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 36,848 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL265502	SURAMIN	3	36,848

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

6 potent at pChembl≥5 of 6 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.07	Kd	0.85	nM	CHEMBL5421682
8.81	Kd	1.55	nM	CHEMBL1207514
8.72	Kd	1.9	nM	SURAMIN
8.33	Kd	4.66	nM	CHEMBL1615557
8.16	Kd	6.88	nM	CHEMBL4300424
7.58	Kd	26.5	nM	CHEMBL1206126

PubChem BioAssay actives

6 with measured affinity, of 8 total; 6 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
8-[[4-[[4-[[4-[[4-[(4,6,8-trisulfonaphthalen-1-yl)carbamoyl]phenyl]carbamoyl]phenyl]carbamoylamino]benzoyl]amino]benzoyl]amino]naphthalene-1,3,5-trisulfonic acid	1975750: Binding affinity to FLAG-tagged human TIMP3 expressed in HEK293 cells assessed as dissociation constant	kd	0.0008	uM
8-[[4-fluoro-3-[[3-[[3-[[2-fluoro-5-[(4,6,8-trisulfonaphthalen-1-yl)carbamoyl]phenyl]carbamoyl]phenyl]carbamoylamino]benzoyl]amino]benzoyl]amino]naphthalene-1,3,5-trisulfonic acid	1975750: Binding affinity to FLAG-tagged human TIMP3 expressed in HEK293 cells assessed as dissociation constant	kd	0.0015	uM
8-[4-methyl-3-[(5Z)-5-[(Z)-[5-[[2-methyl-5-[(4,6,8-trisulfo-2H-naphthalen-1-ylidene)carbamoyl]cyclohexa-2,4-dien-1-ylidene]carbamoyl]cyclohexa-2,4-dien-1-ylidene]carbamoyl]iminocyclohexa-1,3-diene-1-carbonyl]iminocyclohexa-1,4-diene-1-carbonyl]imino-7H-naphthalene-1,3,5-trisulfonic acid	1975750: Binding affinity to FLAG-tagged human TIMP3 expressed in HEK293 cells assessed as dissociation constant	kd	0.0019	uM
4-[[3-[[3,5-bis[(2,4-disulfophenyl)carbamoyl]phenyl]carbamoylamino]-5-[(2,4-disulfophenyl)carbamoyl]benzoyl]amino]benzene-1,3-disulfonic acid	1975750: Binding affinity to FLAG-tagged human TIMP3 expressed in HEK293 cells assessed as dissociation constant	kd	0.0047	uM
4-[[3-[[3,5-bis[(4-sulfophenyl)carbamoyl]phenyl]carbamoylamino]-5-[(4-sulfophenyl)carbamoyl]benzoyl]amino]benzenesulfonic acid	1975750: Binding affinity to FLAG-tagged human TIMP3 expressed in HEK293 cells assessed as dissociation constant	kd	0.0069	uM
8-[[3-[[3-[(4,6,8-trisulfonaphthalen-1-yl)carbamoyl]phenyl]carbamoylamino]benzoyl]amino]naphthalene-1,3,5-trisulfonic acid	1975750: Binding affinity to FLAG-tagged human TIMP3 expressed in HEK293 cells assessed as dissociation constant	kd	0.0265	uM

CTD chemical–gene interactions

133 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects binding, increases expression, affects cotreatment, decreases expression	8
bisphenol A	decreases expression, increases methylation, affects cotreatment, increases expression	7
sodium arsenite	affects methylation, decreases expression, increases expression	7
Valproic Acid	decreases methylation, increases expression, affects expression, decreases expression	6
Progesterone	affects cotreatment, decreases expression, increases expression	4
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Decitabine	affects methylation, increases expression	3
Smoke	decreases expression, increases expression	3
Tetrachlorodibenzodioxin	increases expression, affects cotreatment, decreases expression	3
Cyclosporine	decreases expression, increases expression	3
Cadmium Chloride	increases abundance, increases expression, decreases expression	3
nickel sulfate	decreases expression, increases expression	2
Resveratrol	affects cotreatment, decreases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Acrolein	decreases expression, decreases reaction, increases expression	2
Cadmium	decreases expression, increases abundance, increases expression	2
Calcitriol	decreases expression, increases expression	2
Indomethacin	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Selenium	decreases expression, increases expression	2
Triclosan	decreases expression	2
Genistein	decreases expression	2
gamabufotalin	increases expression	1
perfluorotetradecanoic acid	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
deoxynivalenol	decreases expression	1
salinomycin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5328252	Binding	Binding affinity to FLAG-tagged human TIMP3 expressed in HEK293 cells assessed as dissociation constant	Suramin analogues protect cartilage against osteoarthritic breakdown by increasing levels of tissue inhibitor of metalloproteinases 3 (TIMP-3) in the tissue. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 1 embryonic stem cell, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7ZX	Abcam Raji TIMP3 KO	Cancer cell line	Male
CVCL_C0AR	Abcam THP-1 TIMP3 KO	Cancer cell line	Male
CVCL_C1JM	WAe009-A-89	Embryonic stem cell	Female
CVCL_C7CE	Abcam PC-3 TIMP3 KO	Cancer cell line	Male
CVCL_D6NN	SJTUGHi003-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

93 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT01758211	PHASE3	UNKNOWN	Functional Magnetic Resonance Imagine(fMRI)Navigation in Intracranial Arteriovenous Malformation Surgery
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT04297033	PHASE2	UNKNOWN	Lovastatin for Treatment of Brain Arteriovenous Malformations
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT02314377	PHASE1	COMPLETED	Bevacizumab Therapy for Brain Arteriovenous Malformation
NCT04311112	PHASE2/PHASE3	WITHDRAWN	Safety and Efficacy of Zuretinol Acetate in Subjects With Inherited Retinal Disease
NCT04008121	EARLY_PHASE1	RECRUITING	Feasibility and Safety of MB-102 in Ocular Angiography as Compared to Fluorescein Sodium
NCT00259701	Not specified	COMPLETED	Microvascular Reactivity.
NCT00331370	Not specified	UNKNOWN	Hypertension Related Damage to the Microcirculation in South Asian: Emergence, Predictive Power and Reversibility
NCT00618644	Not specified	WITHDRAWN	Ranibizumab for Neovascularization in Sickle Cell Retinopathy
NCT00735657	Not specified	COMPLETED	Anesthesia for Pars Plana Vitrectomy (PPV) With Insulin Needle
NCT00828425	Not specified	COMPLETED	Management of Diabetes Mellitus Patients With Retinopathy
NCT00969956	Not specified	TERMINATED	Time To Complications Occurs in Diabetes
NCT01412905	Not specified	COMPLETED	Telemedicine Retinal Screening Utilizing a Mobile Medical Unit
NCT01546766	Not specified	COMPLETED	Rapid, Non-invasive, Regional Functional Imaging of the Retina. (Diabetic Retinopathy Diagnosis Device)
NCT01552993	Not specified	TERMINATED	Registration and Treatment of Pain During Eye Examination of Prematurity
NCT01815567	Not specified	COMPLETED	DETECT and Retinal Outcomes in Hypertension
NCT02321904	Not specified	COMPLETED	Corneal Confocal Microscopy to Detect Diabetic Neuropathy in Children
NCT02466607	Not specified	COMPLETED	Study of Stimulus Parameters in Flicker Electroretinogram (ERG)
NCT02558478	Not specified	UNKNOWN	Identification of New Genes Implicated in Rare Neurosensory Diseases by Whole Exome Sequencing
NCT02702973	Not specified	UNKNOWN	Characteristic Analysis of Retinopathy Associated With High Doses of Interferon α-2b Therapy
NCT03011541	Not specified	RECRUITING	Stem Cell Ophthalmology Treatment Study II
NCT03542734	Not specified	RECRUITING	Cognitive Impairment, Retinopathy, and Cerebrovascular Lesions in the Elderly
NCT03901898	Not specified	COMPLETED	Feasibility of an Intervention to Increase Diabetic Retinopathy Screening Attendance
NCT04819893	Not specified	RECRUITING	Study of the Involvement of Fatty Acids in Retinopathy of Prematurity: Relationship Between Retinopathy of Prematurity and the Rate of Expression of Transplacental Fatty Acid Receptors.
NCT05921981	Not specified	COMPLETED	Multisensory Stimulation Versus White Noise
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT06355219	Not specified	COMPLETED	Macrovascular and Microvascular Morbidity and Mortality After Metabolic Surgery Versus Medicines
NCT06837181	Not specified	RECRUITING	Studying the Presence of CFRD Complications With Thoughtful Recruitment (SPeCTRuM)
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10