CCN3

Summary

CCN3 (cellular communication network factor 3, HGNC:7885) is a protein-coding gene on chromosome 8q24.12, encoding CCN family member 3 (P48745). Immediate-early protein playing a role in various cellular processes including proliferation, adhesion, migration, differentiation and survival.

The protein encoded by this gene is a small secreted cysteine-rich protein and a member of the CCN family of regulatory proteins. CNN family proteins associate with the extracellular matrix and play an important role in cardiovascular and skeletal development, fibrosis and cancer development.

Source: NCBI Gene 4856 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 61 total — 4 pathogenic
• MANE Select transcript: NM_002514

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7885
Approved symbol	CCN3
Name	cellular communication network factor 3
Location	8q24.12
Locus type	gene with protein product
Status	Approved
Aliases	IGFBP9
Ensembl gene	ENSG00000136999
Ensembl biotype	protein_coding
OMIM	164958
Entrez	4856

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000259526, ENST00000520082, ENST00000864983, ENST00000960553

RefSeq mRNA: 1 — MANE Select: NM_002514 NM_002514

CCDS: CCDS6328

Canonical transcript exons

ENST00000259526 — 5 exons

Exon	Start	End
ENSE00000702270	119416744	119416969
ENSE00000702271	119418058	119418309
ENSE00000702273	119419131	119419345
ENSE00001176168	119422836	119424434
ENSE00001176176	119416446	119416616

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 99.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.0500 / max 525.6365, expressed in 942 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
90393	3.9255	748
90391	1.5824	585
90392	0.4328	229
90394	0.1092	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	99.48	gold quality
blood vessel layer	UBERON:0004797	99.46	gold quality
adrenal cortex	UBERON:0001235	99.33	gold quality
left adrenal gland cortex	UBERON:0035825	99.32	gold quality
right adrenal gland	UBERON:0001233	99.31	gold quality
right adrenal gland cortex	UBERON:0035827	99.29	gold quality
ascending aorta	UBERON:0001496	99.25	gold quality
thoracic aorta	UBERON:0001515	99.24	gold quality
aorta	UBERON:0000947	99.03	gold quality
left adrenal gland	UBERON:0001234	98.97	gold quality
popliteal artery	UBERON:0002250	98.94	gold quality
tibial artery	UBERON:0007610	98.94	gold quality
descending thoracic aorta	UBERON:0002345	98.90	gold quality
artery	UBERON:0001637	98.72	gold quality
adrenal gland	UBERON:0002369	98.47	gold quality
saphenous vein	UBERON:0007318	97.88	gold quality
coronary artery	UBERON:0001621	97.79	gold quality
left coronary artery	UBERON:0001626	97.71	gold quality
adrenal tissue	UBERON:0018303	96.63	gold quality
skin of hip	UBERON:0001554	92.21	gold quality
endothelial cell	CL:0000115	91.83	silver quality
calcaneal tendon	UBERON:0003701	91.00	gold quality
vena cava	UBERON:0004087	90.24	gold quality
upper leg skin	UBERON:0004262	89.24	gold quality
CA1 field of hippocampus	UBERON:0003881	87.76	silver quality
synovial joint	UBERON:0002217	87.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.38	gold quality
left lobe of thyroid gland	UBERON:0001120	87.13	gold quality
tendon	UBERON:0000043	87.04	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.00	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-36	yes	1833.17
E-GEOD-81383	yes	1486.78
E-MTAB-10042	yes	7.82
E-CURD-112	yes	6.19
E-ANND-3	yes	3.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ERG, FOXO1, JUN, KLF2, MZF1, NFKB, NR5A1, PAWR, PAX3, TP53, WT1

miRNA regulators (miRDB)

96 targeting CCN3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• expression of this protein appears to be associated with a higher risk of developing metastases in Ewing’s sarcoma (PMID:11891184)
• association with Notch1 extracellular domain and inhibition of myoblast differentiation via Notch signaling pathway (PMID:12050162)
• NOVH concentration was significantly modified in malignant but not benign adrenocortical tumors; the concentration of NOVH was significantly decreased in patients suffering from astrocytomas or multiple sclerosis (PMID:12519873)
• in endothelial cells, CCN3 supports cell adhesion, induces directed cell migration (chemotaxis), and promotes cell survival (PMID:12695522)
• NOVH increases cell adhesion and migration of glioblastoma cells via matrix metalloprotease 3 expression and a PDGFR-alpha dependent mechanism. (PMID:14519668)
• evidence that adenylate cyclase as well as one or several protein kinases might be involved in the mechanoregulation of Cyr61, CTGF and Nov genes (PMID:15053922)
• Cx43 is able to regulate cell growth via an up-regulation of NOV transcription (PMID:15181016)
• CCN3 has a role in cutaneous wound healing in skin fibroblasts (PMID:15611078)
• expression of CCN3 in Ewing’s sarcoma primary tumors may be associated with a higher risk of developing lung and/or bone metastases (PMID:15824736)
• Data indicates that NOV is associated with carcinogenesis and the progression of renal cell carcinoma, and the NOV expression level is different in papillary-type and clear cell-type RCC. (PMID:16145471)
• Results suggest that NOV (nephroblastoma overexpressed) is a specific cell fate regulator in the myogenic lineage, acting negatively on key myogenic genes thus controlling the transition from progenitor cells to myoblasts. (PMID:16600215)
• Transfecting CCN3 into BCR-ABL+ cells inhibited proliferation and decreased clonogenic potential in acute myeloid leukemia. (PMID:16670264)
• In early-onset pre-eclamptic placentae, NOV was expressed at a significantly lower level compared with normal matched controls, indicating a potential role of this molecule in the pathogenesis of early-onset pre-eclampsia. (PMID:16675545)
• DDR1 knockdown decreased melanocyte adhesion to collagen IV and shifted melanocyte localization in a manner similar to CCN3 knockdown. (PMID:17101694)
• CCN protein also interact with several other receptors and ligands that play critical roles in the regulation of cell signaling and communication (PMID:17163153)
• Data suggest that the production of CCN3 varies throughout the cell cycle, and that CCN3-induced inhibition of cell growth can be partially reversed by specific antibodies raised against a C-terminal peptide of CCN3. (PMID:17340618)
• Nov is identified as being essential for the functional integrity of hematopoietic stem and progenitor cells (PMID:17463287)
• reduced expression of NOV in childhood adrenocortical tumors may play an important role in the process of childhood childhood adrenocortical tumors tumorigenesis (PMID:17566092)
• results suggest that the lack of CCN3 in advanced melanoma cells contributes to their invasive phenotype (PMID:17968313)
• the lack of CCN3 in advanced melanoma cells contributes to their invasive phenotype. (PMID:17968313)
• Our data suggest expression of a truncated nuclear CCN3 variant lacking the thrombospondin type-1-like domain and cytoplasmic full-length CCN3 protein in Wilms’ tumor cells. (PMID:18066593)
• Reduction of CCN1/CCN3 in preeclampsia could be responsible for the failure of uterine vascular remodeling. (PMID:18089610)
• CCN3 may play a role in the progression and metastatic potential of melanomas (PMID:18245471)
• CCN3, but not CCN1 or CCN2, may be a prognosis factor for human osteosarcomas (PMID:18245529)
• Thus, elevated levels of CCN3 protein regulated by p53 might influence cell adhesion (PMID:18418052)
• TACC1 and a three-gene expression signature (TACC1, NOV, and PTTG1) were identified as independent prognostic markers. (PMID:18984771)
• These findings identify a new paracrine role of NOV in the development of cerebellar granule neurons. (PMID:19286457)
• expression of the full-length CCN3 in Ewing sarcoma is associated with a worse prognosis (PMID:19695675)
• CCN3 increases the activity of the small GTPase Rac1, thereby revealing a pathway that links Cx43 directly to actin reorganization. (PMID:19706598)
• The angiogenic gene CCN3/nov was specifically downregulated in the plexiform neurofibromas and malignant peripheral nerve sheath tumor. (PMID:20010302)
• CCN3 suppresses neointimal thickening through the inhibition of vascular smooth cell migration and proliferation. (PMID:20139355)
• CCN3 counter-regulates positive signals from TGF-beta and Wnt for fibrillin fibrillogenesis and profibrotic gene expression. (PMID:20182440)
• CYR61 and NOV are regulated by HIF-1alpha and TGF-beta3 in the trophoblast cell line JEG3, and their enhanced secretion could be implicated in appropriate placental invasion. (PMID:20237132)
• Only defined binding properties between Cx43 and CCN3 leading to an upregulation of CCN3 are needed for signaling. (PMID:20336664)
• NOV acts through alphavbeta5 integrin to activate ILK and Akt, which in turn activates c-Jun and AP-1, resulting in the activations of COX-2 and contributing the migration of human osteosarcoma cells. (PMID:21145881)
• Recombinant expression, purification, and functional characterisation of connective tissue growth factor and nephroblastoma-overexpressed protein (PMID:21209863)
• CCN3 enhances the migration of chondrosarcoma cells by increasing MMP-13 expression through the alphavbeta3/alphavbeta5 integrin receptor, FAK, PI3K, Akt, p65, and NF-kappaB signal transduction pathway. (PMID:21344378)
• Data show reduced CCN3 levels in aRMS cells following small interfering RNA knockdown of PAX3-FKHR. (PMID:21423212)
• CCN3 regulates the differentiation of bone resident cells to create a resorptive environment that promotes the formation of osteolytic breast cancer metastases (PMID:21514448)
• CCN3 protein regulates the decrease in Jeg3 cell numbers independent of its glycosylation status (PMID:21784733)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ccn3	ENSMUSG00000037362
rattus_norvegicus	Ccn3	ENSRNOG00000085949

Paralogs (5): CCN5 (ENSG00000064205), CCN4 (ENSG00000104415), CCN6 (ENSG00000112761), CCN2 (ENSG00000118523), CCN1 (ENSG00000142871)

Protein

Protein identifiers

CCN family member 3 — P48745 (reviewed: P48745)

Alternative names: Cellular communication network factor 3, Insulin-like growth factor-binding protein 9, Nephro blastoma-overexpressed gene protein homolog, Protein NOV homolog

All UniProt accessions (1): P48745

UniProt curated annotations — full annotation on UniProt →

Function. Immediate-early protein playing a role in various cellular processes including proliferation, adhesion, migration, differentiation and survival. Acts by binding to integrins or membrane receptors such as NOTCH1. Essential regulator of hematopoietic stem and progenitor cell function. Inhibits myogenic differentiation through the activation of Notch-signaling pathway. Inhibits vascular smooth muscle cells proliferation by increasing expression of cell-cycle regulators such as CDKN2B or CDKN1A independently of TGFB1 signaling. Ligand of integrins ITGAV:ITGB3 and ITGA5:ITGB1, acts directly upon endothelial cells to stimulate pro-angiogenic activities and induces angiogenesis. In endothelial cells, supports cell adhesion, induces directed cell migration (chemotaxis) and promotes cell survival. Also plays a role in cutaneous wound healing acting as integrin receptor ligand. Supports skin fibroblast adhesion through ITGA5:ITGB1 and ITGA6:ITGB1 and induces fibroblast chemotaxis through ITGAV:ITGB5. Seems to enhance bFGF-induced DNA synthesis in fibroblasts. Involved in bone regeneration as a negative regulator. Enhances the articular chondrocytic phenotype, whereas it repressed the one representing endochondral ossification. Impairs pancreatic beta-cell function, inhibits beta-cell proliferation and insulin secretion. Plays a role as negative regulator of endothelial pro-inflammatory activation reducing monocyte adhesion, its anti-inflammatory effects occur secondary to the inhibition of NF-kappaB signaling pathway. Contributes to the control and coordination of inflammatory processes in atherosclerosis. Attenuates inflammatory pain through regulation of IL1B- and TNF-induced MMP9, MMP2 and CCL2 expression. Inhibits MMP9 expression through ITGB1 engagement. Brain osteoanabolic hormone. Drives osteogenesis in osteochondral skeletal stem cells. During lactation, maintains the maternal skeleton and viability of offspring.

Subunit / interactions. Interacts with FBLN1. Interacts (via CTCK domain) with NOTCH1 (via the EGF-like repeat region). Interacts with GJA1/CX43. Interacts with ITGA5:ITGB1, ITGAV:ITGB3 and ITGAV:ITGB5. Interacts with ZDHHC22; the interaction may lead to CCN3 palmitoylation.

Subcellular location. Secreted. Cytoplasm. Cell junction. Gap junction.

Tissue specificity. Expressed in endothelial cells (at protein level). Expressed in bone marrow and thymic cells.

Post-translational modifications. May be palmitoylated on Cys-244, which is important for extracellular secretion.

Induction. Expression is down-regulated by WT1. Expression is down-regulated by pro-inflammatory stimuli such as TNF or IL1B. Expression is induced by laminar shear stress and statins.

Similarity. Belongs to the CCN family.

RefSeq proteins (1): NP_002505* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000867	IGFBP-like	Domain
IPR000884	TSP1_rpt	Repeat
IPR001007	VWF_dom	Domain
IPR006207	Cys_knot_C	Domain
IPR006208	Glyco_hormone_CN	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR012395	IGFBP_CNN	Family
IPR017891	Insulin_GF-bd_Cys-rich_CS	Conserved_site
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR043973	TSP1_CCN	Domain
IPR050941	CCN	Family

Pfam: PF00007, PF00093, PF00219, PF19035

UniProt features (26 total): disulfide bond 11, domain 4, sequence conflict 4, sequence variant 2, glycosylation site 2, signal peptide 1, chain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48745-F1	77.88	0.36

Functional residue map

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

Post-translational modifications (1): 244

Disulfide bonds (11): 39–63, 43–64, 50–67, 75–89, 81–102, 264–301, 281–315, 292–331, 295–333, 300–337, 35–61

Glycosylation sites (2): 97, 280

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 336 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_CELL_CHEMOTAXIS, KANG_FLUOROURACIL_RESISTANCE_UP, GOBP_NEGATIVE_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN

GO Biological Process (27): angiogenesis (GO:0001525), chondrocyte differentiation (GO:0002062), cell adhesion (GO:0007155), signal transduction (GO:0007165), fibroblast migration (GO:0010761), negative regulation of myotube differentiation (GO:0010832), smooth muscle cell migration (GO:0014909), negative regulation of cell growth (GO:0030308), cell adhesion mediated by integrin (GO:0033627), endothelial cell chemotaxis (GO:0035767), type B pancreatic cell proliferation (GO:0044342), positive regulation of cell differentiation (GO:0045597), positive regulation of Notch signaling pathway (GO:0045747), positive regulation of ossification (GO:0045778), negative regulation of insulin secretion (GO:0046676), smooth muscle cell proliferation (GO:0048659), negative regulation of inflammatory response (GO:0050728), cell chemotaxis (GO:0060326), negative regulation of SMAD protein signal transduction (GO:0060392), hematopoietic stem cell homeostasis (GO:0061484), endothelial cell-cell adhesion (GO:0071603), negative regulation of monocyte chemotaxis (GO:0090027), negative regulation of non-canonical NF-kappaB signal transduction (GO:1901223), negative regulation of chondrocyte proliferation (GO:1902731), negative regulation of sensory perception of pain (GO:1904057), bone regeneration (GO:1990523), regulation of developmental process (GO:0050793)

GO Molecular Function (7): Notch binding (GO:0005112), integrin binding (GO:0005178), hormone activity (GO:0005179), growth factor activity (GO:0008083), heparin binding (GO:0008201), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), cytosol (GO:0005829), gap junction (GO:0005921), extracellular matrix (GO:0031012), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell differentiation	2
cellular process	2
signaling receptor binding	2
receptor ligand activity	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cartilage development	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ameboidal-type cell migration	1
regulation of myotube differentiation	1
myotube differentiation	1
negative regulation of striated muscle cell differentiation	1
muscle cell migration	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
cell adhesion	1
endothelial cell migration	1
cell chemotaxis	1
epithelial cell proliferation	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
positive regulation of signal transduction	1
ossification	1
regulation of ossification	1
positive regulation of multicellular organismal process	1
insulin secretion	1
negative regulation of protein secretion	1
regulation of insulin secretion	1
negative regulation of peptide hormone secretion	1
muscle cell proliferation	1
inflammatory response	1

Protein interactions and networks

STRING

668 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCN3	NOTCH1	P46531	766
CCN3	SPARC	P09486	758
CCN3	IGFBP7	Q16270	702
CCN3	VWF	P04275	694
CCN3	WNT1	P04628	665
CCN3	POLR2G	P52433	639
CCN3	POSTN	Q15063	617
CCN3	GJA1	P17302	586
CCN3	SRC	P12931	558
CCN3	PLXNA1	Q9UIW2	549
CCN3	S100A4	P26447	526
CCN3	FBLN1	P23142	512
CCN3	PGAP2	Q9UHJ9	506
CCN3	TJP1	Q07157	484
CCN3	IGF2	P01344	464

IntAct

55 interactions, top by confidence:

A	B	Type	Score
CCN3	HOXA1	psi-mi:“MI:0915”(physical association)	0.670
MACO1	CCN3	psi-mi:“MI:0915”(physical association)	0.560
CCN3	MACO1	psi-mi:“MI:0915”(physical association)	0.560
FRS3	CCN3	psi-mi:“MI:0915”(physical association)	0.560
CCN3	LCE3D	psi-mi:“MI:0915”(physical association)	0.560
CCN3	POU4F2	psi-mi:“MI:0915”(physical association)	0.560
CCN3	ZNF330	psi-mi:“MI:0915”(physical association)	0.560
CCN3	TNIP3	psi-mi:“MI:0915”(physical association)	0.560
COL8A1	CCN3	psi-mi:“MI:0915”(physical association)	0.560
CCN3	ANKRD11	psi-mi:“MI:0915”(physical association)	0.560
CCN3	NID2	psi-mi:“MI:0915”(physical association)	0.560
CCN3	LCE1A	psi-mi:“MI:0915”(physical association)	0.560
CCN3	FAM90A1	psi-mi:“MI:0915”(physical association)	0.560
CCN3	APOL6	psi-mi:“MI:0915”(physical association)	0.560
CCN3	RECK	psi-mi:“MI:0915”(physical association)	0.560
CCN3	KRTAP5-6	psi-mi:“MI:0915”(physical association)	0.560
CCN3	C11orf87	psi-mi:“MI:0915”(physical association)	0.560
CCN3	FXR1	psi-mi:“MI:0915”(physical association)	0.370
CCN3	FXR2	psi-mi:“MI:0915”(physical association)	0.370
CCN3	ADSL	psi-mi:“MI:0915”(physical association)	0.370
CCN3	NFKB1	psi-mi:“MI:0914”(association)	0.350
FRS3	CCN3	psi-mi:“MI:0915”(physical association)	0.000
LCE3D	CCN3	psi-mi:“MI:0915”(physical association)	0.000
RECK	CCN3	psi-mi:“MI:0915”(physical association)	0.000
KRTAP5-6	CCN3	psi-mi:“MI:0915”(physical association)	0.000
CCN3	HOXA1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (45): NFKB1 (Affinity Capture-MS), RELA (Affinity Capture-MS), FBXO21 (Affinity Capture-MS), S100A4 (Two-hybrid), S100A4 (Reconstituted Complex), NFKB1 (Affinity Capture-MS), RELA (Affinity Capture-MS), ITGAV (Reconstituted Complex), FN1 (Reconstituted Complex), NOV (Two-hybrid), NOV (Two-hybrid), NOV (Two-hybrid), NOV (Two-hybrid), NOV (Two-hybrid), FRS3 (Two-hybrid)

ESM2 similar proteins: A4IIA2, A5A6L1, D3Z5L9, O00622, O43184, O54775, O95388, O95389, P08833, P15473, P17936, P18406, P19336, P21743, P21744, P24591, P24593, P24594, P47876, P47878, P47879, P48745, P51609, P59384, P59511, P97857, Q05717, Q07079, Q28985, Q501P1, Q5XHC5, Q61824, Q64299, Q68SA9, Q6Q484, Q76HP2, Q76HP3, Q8BNJ2, Q8TE58, Q90WV8

Diamond homologs: A5A6L1, D3Z5L9, D3ZKF5, O00622, O18739, O19113, O54775, O76076, O95388, O95389, P18406, P19336, P28686, P29268, P29279, P42642, P48745, P51609, Q64299, Q99PP0, Q9ES72, Q9JHC6, Q9QZQ5, Q9R1E9, Q9Z0G4, E1BJW1, Q98UI9, Q9NQ30, A2RT60, A4IIA2, A9JRB3, P12843, P47877, Q5XHC5, Q9JLL0, Q9NZV1, Q80T14, P97682, Q9QYY7, Q7T3Q2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MZF1	“up-regulates quantity by expression”	CCN3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	46
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1807843	GRCh37/hg19 8q24.11-24.12(chr8:118645068-121684174)x1	Pathogenic
2580301	GRCh37/hg19 8q24.11-24.13(chr8:118185471-126635744)x1	Pathogenic
3245402	NC_000008.10:g.(?118649470)(122282519_?)del	Pathogenic
60406	GRCh38/hg38 8q24.11-24.13(chr8:118059192-121574437)x1	Pathogenic

SpliceAI

412 predictions. Top by Δscore:

Variant	Effect	Δscore
8:119416612:GACAG:G	donor_gain	1.0000
8:119416614:CAGG:C	donor_loss	1.0000
8:119416615:AGGT:A	donor_loss	1.0000
8:119416616:GGTA:G	donor_loss	1.0000
8:119416617:G:GG	donor_gain	1.0000
8:119418035:A:AG	acceptor_gain	1.0000
8:119418035:ACTTT:A	acceptor_gain	1.0000
8:119418048:A:AG	acceptor_gain	1.0000
8:119419129:A:AG	acceptor_gain	1.0000
8:119419130:G:GG	acceptor_gain	1.0000
8:119419342:TAAGG:T	donor_loss	1.0000
8:119419344:AG:A	donor_loss	1.0000
8:119419345:GG:G	donor_loss	1.0000
8:119419347:T:G	donor_loss	1.0000
8:119422832:TTA:T	acceptor_loss	1.0000
8:119422833:TAG:T	acceptor_loss	1.0000
8:119422834:A:AG	acceptor_gain	1.0000
8:119422835:G:GG	acceptor_gain	1.0000
8:119422835:G:GT	acceptor_loss	1.0000
8:119422835:GA:G	acceptor_gain	1.0000
8:119422835:GAAA:G	acceptor_gain	1.0000
8:119416613:ACAG:A	donor_gain	0.9900
8:119416614:CAG:C	donor_gain	0.9900
8:119417007:GCAGC:G	donor_gain	0.9900
8:119417011:C:CG	donor_gain	0.9900
8:119417011:C:G	donor_gain	0.9900
8:119418036:C:G	acceptor_gain	0.9900
8:119418049:A:G	acceptor_gain	0.9900
8:119418050:T:G	acceptor_gain	0.9900
8:119418054:CTAGC:C	acceptor_loss	0.9900

AlphaMissense

2342 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:119419207:G:C	W213C	1.000
8:119419207:G:T	W213C	1.000
8:119418115:T:G	F123C	0.999
8:119418260:G:C	W171C	0.999
8:119418260:G:T	W171C	0.999
8:119419205:T:A	W213R	0.999
8:119419205:T:C	W213R	0.999
8:119422996:T:G	F313C	0.999
8:119419248:G:C	R227P	0.998
8:119419298:T:A	C244S	0.998
8:119419299:G:C	C244S	0.998
8:119419300:C:G	C244W	0.998
8:119419214:T:A	C216S	0.997
8:119419215:G:C	C216S	0.997
8:119419216:C:G	C216W	0.997
8:119419298:T:C	C244R	0.997
8:119419299:G:A	C244Y	0.997
8:119422905:A:C	S283R	0.997
8:119422907:C:A	S283R	0.997
8:119422907:C:G	S283R	0.997
8:119422932:T:A	C292S	0.997
8:119422933:G:A	C292Y	0.997
8:119422933:G:C	C292S	0.997
8:119422996:T:C	F313S	0.997
8:119423050:G:A	C331Y	0.997
8:119423051:C:G	C331W	0.997
8:119418114:T:C	F123L	0.996
8:119418115:T:C	F123S	0.996
8:119418116:T:A	F123L	0.996
8:119418116:T:G	F123L	0.996

dbSNP variants (sampled 300 via entrez): RS1000425252 (8:119417143 G>A,C), RS1000956733 (8:119419439 G>A), RS1002314249 (8:119424441 A>T), RS1002323007 (8:119424343 G>A), RS1002807336 (8:119417140 T>C,G), RS1003098343 (8:119421266 C>A,G,T), RS1003185846 (8:119417485 C>T), RS1003358297 (8:119420030 C>T), RS1003430239 (8:119419830 C>G), RS1004055849 (8:119419820 A>G), RS1004450417 (8:119419583 G>A), RS1004529014 (8:119422750 G>A), RS1005140782 (8:119414900 T>C), RS1005548264 (8:119416418 T>A), RS1005826470 (8:119414645 C>T)

Disease associations

OMIM: gene MIM:164958 | disease phenotypes: MIM:133700

GenCC curated gene-disease

Mondo (3): long QT syndrome (MONDO:0002442), exostoses, multiple, type 1 (MONDO:0007585), hereditary multiple osteochondromas (MONDO:0005508)

Orphanet (1): Multiple osteochondromas (Orphanet:321)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D005097	Exostoses, Multiple Hereditary	C04.557.450.565.575.610.615.325; C04.700.330; C05.116.099.708.670.615.325; C05.116.540.310.500; C16.320.700.330
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression	6
sodium arsenite	decreases expression, increases expression	5
Estradiol	increases expression, affects cotreatment, decreases expression	3
Cadmium Chloride	decreases expression, increases abundance	3
bisphenol A	affects cotreatment, decreases expression, increases expression	2
Fulvestrant	increases expression	2
propionaldehyde	increases expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	increases expression	1
trimellitic anhydride	affects expression	1
afimoxifene	decreases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	increases expression	1
ferrous chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1
ormosil	increases expression, affects binding	1
dorsomorphin	increases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Temozolomide	decreases expression	1
Panobinostat	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Aldehydes	increases expression	1
Arsenic	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea