EDN1

Summary

EDN1 (endothelin 1, HGNC:3176) is a protein-coding gene on chromosome 6p24.1, encoding Endothelin-1 (P05305). Endothelins are endothelium-derived vasoconstrictor peptides.

This gene encodes a preproprotein that is proteolytically processed to generate a secreted peptide that belongs to the endothelin/sarafotoxin family. This peptide is a potent vasoconstrictor and its cognate receptors are therapeutic targets in the treatment of pulmonary arterial hypertension. Aberrant expression of this gene may promote tumorigenesis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1906 — RefSeq curated summary.

At a glance

• Gene–disease (curated): auriculocondylar syndrome 3 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 71 total — 4 pathogenic
• Phenotypes (HPO): 42
• MANE Select transcript: NM_001955

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3176
Approved symbol	EDN1
Name	endothelin 1
Location	6p24.1
Locus type	gene with protein product
Status	Approved
Aliases	ET1
Ensembl gene	ENSG00000078401
Ensembl biotype	protein_coding
OMIM	131240
Entrez	1906

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000379375, ENST00000877364, ENST00000877365, ENST00000877366, ENST00000877367, ENST00000877368, ENST00000877369, ENST00000877370, ENST00000877371, ENST00000877372, ENST00000877373, ENST00000916855, ENST00000971811, ENST00000971812, ENST00000971813, ENST00000971814

RefSeq mRNA: 5 — MANE Select: NM_001955 NM_001168319, NM_001416563, NM_001416564, NM_001416565, NM_001955

CCDS: CCDS4522

Canonical transcript exons

ENST00000379375 — 5 exons

Exon	Start	End
ENSE00000615812	12292341	12292509
ENSE00000685322	12293941	12294096
ENSE00000685325	12294261	12294404
ENSE00001480726	12290361	12290693
ENSE00001563781	12295962	12297194

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 90.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.7447 / max 863.8771, expressed in 1201 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65864	34.7447	1201

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower lobe of lung	UBERON:0008949	90.82	gold quality
buccal mucosa cell	CL:0002336	89.62	gold quality
right lung	UBERON:0002167	89.31	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.30	gold quality
upper lobe of left lung	UBERON:0008952	88.99	gold quality
lung	UBERON:0002048	88.96	gold quality
upper lobe of lung	UBERON:0008948	88.58	gold quality
skin of hip	UBERON:0001554	86.94	gold quality
penis	UBERON:0000989	86.01	gold quality
islet of Langerhans	UBERON:0000006	85.49	gold quality
tibial nerve	UBERON:0001323	84.98	gold quality
rectum	UBERON:0001052	84.83	gold quality
colonic mucosa	UBERON:0000317	84.77	gold quality
calcaneal tendon	UBERON:0003701	84.33	gold quality
gall bladder	UBERON:0002110	84.26	gold quality
adult organism	UBERON:0007023	83.78	gold quality
mammalian vulva	UBERON:0000997	83.62	gold quality
upper leg skin	UBERON:0004262	83.55	gold quality
mucosa of sigmoid colon	UBERON:0004993	83.44	gold quality
jejunal mucosa	UBERON:0000399	82.95	gold quality
omental fat pad	UBERON:0010414	82.43	gold quality
peritoneum	UBERON:0002358	82.39	gold quality
right coronary artery	UBERON:0001625	82.34	gold quality
left uterine tube	UBERON:0001303	82.27	gold quality
inferior olivary complex	UBERON:0002127	82.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.95	gold quality
adipose tissue	UBERON:0001013	81.90	gold quality
visceral pleura	UBERON:0002401	81.85	gold quality
adipose tissue of abdominal region	UBERON:0007808	81.64	gold quality
minor salivary gland	UBERON:0001830	81.58	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	4839.23
E-GEOD-135922	yes	863.36
E-MTAB-8205	yes	600.64
E-GEOD-83139	yes	271.89
E-MTAB-10287	yes	31.43
E-GEOD-125970	yes	12.97
E-ANND-3	yes	8.01
E-MTAB-10137	no	1517.24
E-MTAB-6678	no	2.42

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
MC1R	Activation
MYH7	Activation
NPPA	Activation
NPPB	Activation
PPARG	Repression

Upstream regulators (CollecTRI, top): AP1, ATF4, CEBPA, CEBPG, CREB1, CTNNB1, ESR1, FOS, FOXO1, GATA1, GATA2, GATA3, GATA4, GLI2, HIF1A, HIF3A, IRF6, JUN, KLF2, KLF4, NFATC1, NFATC3, NFKB1, NFKB, NR1H3, NR1H4, NR1I3, NR3C1, NR3C2, PPARA, RARA, RELA, SMAD3, SRF, STAT1, TBPL1, TCF7L2, TP53, VEZF1

miRNA regulators (miRDB)

76 targeting EDN1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-345-3P	99.89	70.23	1421

Literature-anchored findings (GeneRIF, showing 40)

• Activated human neutrophils express prepro-ET-1 mRNA and secrete appreciable levels of mature peptide into the culture medium in the presence of various neutrophil stimulants. (PMID:11448123)
• 21 amino acid peptide exerts a wide range of biological activities including vasoconstriction, mitogenesis and inotropic effects on the heart (PMID:11693192)
• Results suggest endothelin-1 is produced by colorectal cancers and may play a role in the growth of colorectal cancer acting through ET(A) receptors. ET(A) antagonists are indicated as potential anti-cancer agents. (PMID:11742499)
• Endothelin receptor remodeling induces the portal venous hyper-response to endothelin-1 following endotoxin pretreatment. (PMID:11795667)
• Endothelin-1 enhances TF expression & activity in monocytes from health individuals. No additional stimulation was seen in monocytes from heart failure subjects, who nonetheless have 2.5 times as much TF as controls. (PMID:11858185)
• Shear-induced changes in endothelin-1 secretion of microvascular endothelial cells (PMID:11866544)
• Study of structure-activity relationships of ET1 using truncated analogs and molecular modelling and nmr studies to elucidate secondary protein structure. (PMID:11932487)
• leptin upregulates ET-1 production in HUVECs via a mechanism potentially involving jun binding members of the bZIP family (PMID:11934840)
• ET-1 may be implicated in the pathogenesis of bronchoconstriction. (PMID:11991554)
• Distinct signaling pathways mediate cardiomyocyte phospholipase D stimulation by endothelin-1 and thrombin (PMID:11991733)
• plasma levels in cyclosporine-treated stable renal transplant patients (PMID:12009599)
• ET1 polymorphism is a risk factor for ventricular arrhythmia (PMID:12011762)
• The expression of endothelin-1 gene in blood vessels and in the heart of hypertensive rats may occur in the absence of exposure to DOCA and salt. Endothelin-1 gene overexpression in hypertension occurs early in non-renin-dependent, volume-expanded models. (PMID:12013496)
• Sickle erythrocytes increased the endothelial cell production of prostacyclin and endothelin-1 under venous wall shear stress conditions of 1dyncm2 (PMID:12068797)
• Elevated levels of ET-1 in hypertensive patients on hemodialysis contribute to systemic vasoconstriction and may be a marker for vascular dysfunction in this patient population. (PMID:12087564)
• Ocular hyperperfusion following onset of Intensified insulin therapy is inversely correlated with plasma levels in type I diabetes. (PMID:12107733)
• The biosynthetic pathway of ET-1 is activated to a higher degree in the peripheral vasculature of African American hypertensive patients than in white hypertensives. (PMID:12117726)
• Follicular fluid adrenomedullin concentrations in spontaneous and stimulated cycles are relationed to ovarian function and endothelin-1 and nitric oxide. (PMID:12137974)
• Our results showed that circulating ET-1 values were increased in microalbuminuric, normotensive, type 2 diabetic patients and correlated with albumin excretion rate, confirm that endothelial dysfunction, as expressed by ET-1 levels, occurs early (PMID:12144123)
• An in vitro model of the blood-brain barrier increased its expression of ET-1 mRNA and secretion of ET-1 peptide when infected with HIV-1. (PMID:12151765)
• UV-induction of keratinocyte endothelin-1 downregulates E-cadherin in melanocytes and melanoma cells (PMID:12189238)
• Endothelin-1 decreases basic apoptotic rates in human melanoma cell lines. (PMID:12230494)
• Data suggest that endothelin-1 promotes collagen matrix reorganization through the enhancement of mesangial cell alpha1beta1 integrin-dependent migration and MMP-2 activity. (PMID:12459174)
• The expression of ET-1 was significantly correleted with the tumor grading. (PMID:12508654)
• Association of endothelin-1 polymorphism with hypertension. (PMID:12511547)
• ET-1 could be implicated in the pathogenesis of appendicitis by inducing appendiceal ischemia through vasoconstriction (PMID:12529269)
• endothelin-1 (ET-1), interleukin-2 (IL-2) and amino-terminal propeptide type III procollagen (PIII NP) can be used as markers for diagnosis of human cases infected with chronic and acute filariasis (PMID:12557940)
• Data show that double heterozygote variants of two endothelin-1 gene polymorphisms were associated with significantly less risk for chronic heart failure with higher levels of big endothelin. (PMID:12565798)
• Acts as a morphogen; different levels pattern specific positions, shapes and sizes of bones along the dorso-ventral axis. (PMID:12588850)
• a severely hyperinsulinemic state may regulate VSMC and EC proliferation via activation of vasoactive substances such as ET-1 and nitric oxide induced by insulin. (PMID:12620701)
• Immunoreactive ET1 has been detected in cyst epithelia, mesangial cells and vascular smooth muscle cells, suggesting continuing ET1 synthesis in autosomal-dominant polycystic kidney disease. (PMID:12629276)
• endothelin-1 is a mediator of pancreatic and intestinal ischemia in acute pancreatitis. (PMID:12657945)
• ROS were involved in ET-1-induced fibroblast proliferation and mediated ET-1-induced activation of ERK pathways, which culminated in ET-1 gene expression. (PMID:12695528)
• differences in cellular response to gastric inhibitory polypeptide(GIP) mediated by endothelin-1 may be related to differences in activation of GIP receptor splice variants (PMID:12721154)
• Data do not support a role for ET-1 as a valid quantitative indicator for stage or progression in endemic goiter, Graves’ disease or Hashimoto’s thyroiditis (PMID:12746758)
• GATA-2-dependent transcriptional activity of the endothelin 1 promotor is suppressed by the SUMO E3 ligase PIASy. (PMID:12750312)
• Emerging pathophysiological role for endothelin in myocardial infarction, stroke and hepato-renal syndrome. (Review) (PMID:12855940)
• data suggest that amniotic fluid concentrations of human brain natriuretic peptide and endothelin-1 were highest in the twins with polyhydramnios and lowest in oligohydramnios, suggesting their importance in the regulation of amniotic fluid vo (PMID:12861161)
• Endothelin-1 decreases gap junctional intercellular communication by inducing phosphorylation of connexin 43 in ovarian tumor cells (PMID:12907686)
• role in pathogenesis of osteoblastic bone metastases (PMID:12941866)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	edn1	ENSDARG00000036912
mus_musculus	Edn1	ENSMUSG00000021367
rattus_norvegicus	Edn1	ENSRNOG00000014361

Paralogs (2): EDN3 (ENSG00000124205), EDN2 (ENSG00000127129)

Protein

Protein identifiers

Endothelin-1 — P05305 (reviewed: P05305)

Alternative names: Preproendothelin-1

All UniProt accessions (2): P05305, Q6FH53

UniProt curated annotations — full annotation on UniProt →

Function. Endothelins are endothelium-derived vasoconstrictor peptides. Probable ligand for G-protein coupled receptors EDNRA and EDNRB which activates PTK2B, BCAR1, BCAR3 and, GTPases RAP1 and RHOA cascade in glomerular mesangial cells. Also binds the DEAR/FBXW7-AS1 receptor. Promotes mesenteric arterial wall remodeling via activation of ROCK signaling and subsequent colocalization of NFATC3 with F-actin filaments. NFATC3 then translocates to the nucleus where it subsequently promotes the transcription of the smooth muscle hypertrophy and differentiation marker ACTA2.

Subcellular location. Secreted.

Tissue specificity. Expressed in lung, placental stem villi vessels and in cultured placental vascular smooth muscle cells.

Disease relevance. Question mark ears, isolated (QME) [MIM:612798] An auricular abnormality characterized by a cleft between the lobule and the lower part of the helix, sometimes accompanied by a prominent or deficient upper part of the helix, shallow skin dimple on the posterior surface of the ear, or transposition of the ear lobe/antitragus. The disease is caused by variants affecting the gene represented in this entry. Auriculocondylar syndrome 3 (ARCND3) [MIM:615706] An autosomal recessive form of auriculocondylar syndrome, a craniofacial malformation syndrome characterized by variable mandibular anomalies, including mild to severe micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark (question-mark ear). Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia. Glossoptosis, masticatory abnormalities, orthodontic problems, and malocclusion occur in a majority of affected subjects. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the endothelin/sarafotoxin family.

RefSeq proteins (5): NP_001161791, NP_001403492, NP_001403493, NP_001403494, NP_001946* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001928	Endothln-like_toxin	Domain
IPR019764	Endothelin_toxin_CS	Conserved_site
IPR020475	Endothelin	Family

Pfam: PF00322

UniProt features (21 total): sequence variant 5, propeptide 2, disulfide bond 2, strand 2, peptide 2, region of interest 2, compositionally biased region 2, signal peptide 1, helix 1, turn 1, site 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
1T7H	X-RAY DIFFRACTION	1.13
6DK5	X-RAY DIFFRACTION	1.85
1EDN	X-RAY DIFFRACTION	2.18
5GLH	X-RAY DIFFRACTION	2.8
8IY5	ELECTRON MICROSCOPY	2.8
8XVE	ELECTRON MICROSCOPY	3
8HCQ	ELECTRON MICROSCOPY	3.01
8IY6	ELECTRON MICROSCOPY	3.13
8XGR	ELECTRON MICROSCOPY	3.2
8XWP	ELECTRON MICROSCOPY	3.21
8XVH	ELECTRON MICROSCOPY	3.26
8XVI	ELECTRON MICROSCOPY	3.32
8HCX	ELECTRON MICROSCOPY	3.5
8ZRT	ELECTRON MICROSCOPY	3.62
8XWQ	ELECTRON MICROSCOPY	4.6
1EDP	SOLUTION NMR
1V6R	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05305-F1	65.62	0.01

Antibody-complex structures (SAbDab): 9 — 8HCQ, 8HCX, 8IY5, 8XGR, 8XVE, 8XVH, 8XVI, 8XWP, 8XWQ

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): 73–74 (cleavage; by kel)

Disulfide bonds (2): 53–67, 55–63

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity

MSigDB gene sets: 962 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EXCRETION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, MODULE_92, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CELL_MIGRATION_INVOLVED_IN_HEART_DEVELOPMENT, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_ICOSANOID_SECRETION

GO Biological Process (143): negative regulation of transcription by RNA polymerase II (GO:0000122), branching involved in blood vessel morphogenesis (GO:0001569), in utero embryonic development (GO:0001701), histamine secretion (GO:0001821), response to amphetamine (GO:0001975), glomerular filtration (GO:0003094), regulation of systemic arterial blood pressure by endothelin (GO:0003100), cardiac neural crest cell migration involved in outflow tract morphogenesis (GO:0003253), noradrenergic neuron differentiation (GO:0003357), transcription by RNA polymerase II (GO:0006366), intracellular calcium ion homeostasis (GO:0006874), regulation of pH (GO:0006885), mitochondrion organization (GO:0007005), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), positive regulation of cytosolic calcium ion concentration (GO:0007204), cell-cell signaling (GO:0007267), respiratory gaseous exchange by respiratory system (GO:0007585), body fluid secretion (GO:0007589), positive regulation of cell population proliferation (GO:0008284), dorsal/ventral pattern formation (GO:0009953), response to ozone (GO:0010193), positive regulation of heart rate (GO:0010460), positive regulation of endothelial cell migration (GO:0010595), positive regulation of cardiac muscle hypertrophy (GO:0010613), negative regulation of gene expression (GO:0010629), regulation of D-glucose transmembrane transport (GO:0010827), neural crest cell fate commitment (GO:0014034), response to activity (GO:0014823), artery smooth muscle contraction (GO:0014824), vein smooth muscle contraction (GO:0014826), regulation of vasoconstriction (GO:0019229), calcium-mediated signaling (GO:0019722), signal transduction involved in regulation of gene expression (GO:0023019), peptide hormone secretion (GO:0030072), nitric oxide transport (GO:0030185), negative regulation of blood coagulation (GO:0030195), heparin proteoglycan metabolic process (GO:0030202)

GO Molecular Function (7): cytokine activity (GO:0005125), hormone activity (GO:0005179), endothelin A receptor binding (GO:0031707), endothelin B receptor binding (GO:0031708), signaling receptor binding (GO:0005102), protein binding (GO:0005515), receptor ligand activity (GO:0048018)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), transport vesicle (GO:0030133), Weibel-Palade body (GO:0033093), basal part of cell (GO:0045178), rough endoplasmic reticulum lumen (GO:0048237)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
MITF-M-regulated melanocyte development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	3
cellular anatomical structure	3
receptor ligand activity	2
bombesin receptor binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
angiogenesis	1
blood vessel morphogenesis	1
branching morphogenesis of an epithelial tube	1
chordate embryonic development	1
secretion	1
histamine transport	1
response to amine	1
renal filtration	1
regulation of systemic arterial blood pressure by hormone	1
neural crest cell migration	1
outflow tract morphogenesis	1
cell migration involved in heart development	1
cardiac neural crest cell development involved in outflow tract morphogenesis	1
neuron differentiation	1
DNA-templated transcription	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
monoatomic cation homeostasis	1
biological regulation	1
organelle organization	1
G protein-coupled receptor activity	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
G protein-coupled receptor signaling pathway	1
phospholipase C activator activity	1
regulation of biological quality	1
cell communication	1
signaling	1
multicellular organismal process	1
protein binding	1
binding	1
signaling receptor binding	1
signaling receptor activator activity	1

Protein interactions and networks

STRING

3738 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EDN1	EDNRA	P25101	999
EDN1	EDNRB	P24530	999
EDN1	ECE1	P42892	939
EDN1	AGT	P01019	926
EDN1	REN	P00797	914
EDN1	ECE2	P0DPD6	913
EDN1	VWF	P04275	895
EDN1	ANGPT2	O15123	891
EDN1	NOS3	P29474	884
EDN1	ADM	P35318	830
EDN1	NPPA	P01160	797
EDN1	INS	P01308	797
EDN1	EGF	P01133	796
EDN1	CXCL8	P10145	795
EDN1	AGTR1	P30556	785

IntAct

10 interactions, top by confidence:

A	B	Type	Score
H2BC21	EDN1	psi-mi:“MI:0915”(physical association)	0.400
H2BC9	EDN1	psi-mi:“MI:0915”(physical association)	0.400
EDNRA	EDN1	psi-mi:“MI:0915”(physical association)	0.400
EDN1	EDNRA	psi-mi:“MI:0915”(physical association)	0.400
EDNRB	EDN1	psi-mi:“MI:0915”(physical association)	0.400
EDN1	EDNRB	psi-mi:“MI:0915”(physical association)	0.400
EDN1	COPS6	psi-mi:“MI:0915”(physical association)	0.000
EDN1	BAG6	psi-mi:“MI:0915”(physical association)	0.000
EDN1	UBQLN4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): BAG6 (Two-hybrid), COPS6 (Two-hybrid), EDN1 (Positive Genetic), EDN1 (Co-localization), EDN1 (Two-hybrid), EDN1 (Reconstituted Complex), EDN1 (Co-crystal Structure), EDN1 (Reconstituted Complex)

ESM2 similar proteins: A0A023VZR2, A0A023W0B6, A0A023W0C3, A0A023W0V9, A0A023W0W9, A0A023W157, A0A023W163, A0A023W168, A0A3G1VU73, A0A3G1VU77, A0A3G1VU78, A0A3G1VU81, A0A3G1VU84, B9TQX1, B9TQX3, B9WZ56, E2AIS8, G7NYP9, O02036, O42143, O42144, P01362, P05305, P06308, P0CJ15, P0CJ16, P0CV00, P0DPY2, P0DQF5, P0DQG1, P10552, P17685, P17686, P21259, P41870, P41876, P49794, P61364, P61365, P61366

Diamond homologs: A5A752, P05305, P09558, P12064, P13206, P13207, P13211, P14138, P17322, P19998, P20800, P22387, P22388, P22389, P23943, P29560, P48299, P80163, P97740, Q5NRP8, Q5NRP9, Q5NRQ0, Q5NRQ1, Q765Z4, Q765Z5, Q867A9, Q867D0, Q8MJW9, Q9BG76, P0DJK0, Q28469, P0DJK1, P13208, Q28470, Q09GK2, Q6RY98

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
EDN1	up-regulates	EDNRA	binding
EDN1	up-regulates	EDNRB	binding
HBB	“down-regulates activity”	EDN1
HBA1	“down-regulates activity”	EDN1
EDN1	“up-regulates quantity by expression”	MYH7	“transcriptional regulation”
“UVB radiation”	up-regulates	EDN1
EDN1	“up-regulates quantity by expression”	MC1R	“transcriptional regulation”
CMA1	“up-regulates activity”	EDN1	cleavage
VEZF1	“up-regulates quantity by expression”	EDN1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	38
Likely benign	11
Benign	14

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
120212	NM_001955.5(EDN1):c.271A>G (p.Lys91Glu)	Pathogenic
120213	NM_001955.5(EDN1):c.230C>A (p.Pro77His)	Pathogenic
120214	NM_001955.5(EDN1):c.191T>A (p.Val64Asp)	Pathogenic
120215	NM_001955.5(EDN1):c.249T>G (p.Tyr83Ter)	Pathogenic

SpliceAI

415 predictions. Top by Δscore:

Variant	Effect	Δscore
6:12292335:CCCCA:C	acceptor_loss	1.0000
6:12292338:CA:C	acceptor_loss	1.0000
6:12292338:CAGCA:C	acceptor_gain	1.0000
6:12292339:A:AG	acceptor_gain	1.0000
6:12292339:AGCAG:A	acceptor_gain	1.0000
6:12292340:G:A	acceptor_loss	1.0000
6:12292340:G:GT	acceptor_gain	1.0000
6:12292340:GC:G	acceptor_gain	1.0000
6:12292340:GCA:G	acceptor_gain	1.0000
6:12292340:GCAGT:G	acceptor_gain	1.0000
6:12292505:CCCGA:C	donor_gain	1.0000
6:12292507:CGAGT:C	donor_loss	1.0000
6:12292508:GA:G	donor_gain	1.0000
6:12292509:AG:A	donor_loss	1.0000
6:12292510:G:GG	donor_gain	1.0000
6:12292510:G:T	donor_loss	1.0000
6:12292511:T:G	donor_loss	1.0000
6:12293931:T:TA	acceptor_gain	1.0000
6:12293932:G:A	acceptor_gain	1.0000
6:12293936:A:AG	acceptor_gain	1.0000
6:12293936:AATAG:A	acceptor_gain	1.0000
6:12293937:A:G	acceptor_gain	1.0000
6:12293938:TA:T	acceptor_loss	1.0000
6:12293939:A:AG	acceptor_gain	1.0000
6:12293939:AG:A	acceptor_gain	1.0000
6:12293940:G:GG	acceptor_gain	1.0000
6:12293940:GG:G	acceptor_gain	1.0000
6:12293940:GGC:G	acceptor_gain	1.0000
6:12293940:GGCA:G	acceptor_gain	1.0000
6:12293940:GGCAC:G	acceptor_gain	1.0000

AlphaMissense

1393 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:12292495:G:C	W73C	0.999
6:12292495:G:T	W73C	0.999
6:12292475:T:A	C67S	0.998
6:12292476:G:C	C67S	0.998
6:12292463:T:A	C63S	0.997
6:12292464:G:C	C63S	0.997
6:12292472:T:C	F66L	0.997
6:12292474:C:A	F66L	0.997
6:12292474:C:G	F66L	0.997
6:12292476:G:A	C67Y	0.997
6:12292477:C:G	C67W	0.996
6:12292433:T:A	C53S	0.995
6:12292434:G:C	C53S	0.995
6:12292473:T:G	F66C	0.995
6:12292475:T:C	C67R	0.995
6:12292476:G:T	C67F	0.995
6:12292493:T:A	W73R	0.995
6:12292493:T:C	W73R	0.995
6:12292439:T:A	C55S	0.994
6:12292440:G:C	C55S	0.994
6:12292463:T:C	C63R	0.994
6:12292465:T:G	C63W	0.993
6:12292478:C:G	H68D	0.993
6:12292440:G:A	C55Y	0.992
6:12292455:A:T	D60V	0.992
6:12292480:C:A	H68Q	0.992
6:12292480:C:G	H68Q	0.992
6:12292485:A:T	D70V	0.992
6:12292441:C:G	C55W	0.991
6:12292454:G:C	D60H	0.991

dbSNP variants (sampled 300 via entrez): RS1000150231 (6:12274901 A>G), RS1000159551 (6:12265943 C>G), RS1000167224 (6:12269638 G>C), RS1000277328 (6:12262624 C>A,G), RS1000343100 (6:12275307 C>G,T), RS1000347776 (6:12275690 G>C), RS1000403973 (6:12265433 C>T), RS1000420017 (6:12287448 C>T), RS1000598094 (6:12270694 A>G), RS1000701242 (6:12255588 T>A,C), RS1000773285 (6:12255885 A>C), RS1000791190 (6:12279516 G>C), RS1000802245 (6:12275901 G>A), RS1000843423 (6:12279884 T>C), RS1000954854 (6:12276733 A>G)

Disease associations

OMIM: gene MIM:131240 | disease phenotypes: MIM:615706, MIM:612798

GenCC curated gene-disease

Disease	Classification	Inheritance
question mark ears, isolated	Strong	Autosomal dominant
auriculocondylar syndrome 3	Strong	Autosomal recessive
auriculocondylar syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
auriculocondylar syndrome	Limited	AR

Mondo (3): auriculocondylar syndrome 3 (MONDO:0014312), question mark ears, isolated (MONDO:0013013), auriculocondylar syndrome (MONDO:0000107)

Orphanet (1): Auriculocondylar syndrome (Orphanet:137888)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000162	Glossoptosis
HP:0000171	Microglossia
HP:0000175	Cleft palate
HP:0000183	Tongue muscle weakness
HP:0000193	Bifid uvula
HP:0000256	Macrocephaly
HP:0000278	Retrognathia
HP:0000293	Full cheeks
HP:0000324	Facial asymmetry
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000364	Hearing abnormality
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag
HP:0000402	Stenosis of the external auditory canal
HP:0000508	Ptosis
HP:0000656	Ectropion
HP:0000678	Dental crowding
HP:0000689	Dental malocclusion
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0002098	Respiratory distress
HP:0002870	Obstructive sleep apnea
HP:0003577	Congenital onset
HP:0007627	Mandibular condyle aplasia
HP:0007628	Mandibular condyle hypoplasia

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001853_6	Circulating vasoactive peptide levels	1.000000e-27
GCST003472_20	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	7.000000e-06
GCST003784_9	Multiple system atrophy	4.000000e-07
GCST005194_34	Coronary artery disease	2.000000e-07
GCST005951_152	Body mass index	2.000000e-09
GCST006629_53	Pulse pressure	7.000000e-14
GCST007269_263	Pulse pressure	4.000000e-10
GCST010396_51	Gut microbiota (bacterial taxa, hurdle binary method)	7.000000e-06
GCST010397_116	Gut microbiota (bacterial taxa, rank normal transformation method)	4.000000e-07
GCST90002383_224	Hematocrit	3.000000e-16
GCST90002384_125	Hemoglobin	1.000000e-14
GCST90002403_374	Red blood cell count	7.000000e-15

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0005196	vasoactive peptide measurement
EFO:0007679	oppositional defiant disorder measurement
EFO:0004340	body mass index
EFO:0005763	pulse pressure measurement
EFO:0007874	gut microbiome measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538270	Auriculo-condylar syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs5370	Toxicity	3	muraglitazar	Diabetes Mellitus;Edema;Hyperlipidemias
rs5370	Efficacy	3	atenolol;irbesartan	Essential hypertension
rs5370	Efficacy	3	bevacizumab	Breast Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs5370	EDN1	3	3.00	3	muraglitazar;atenolol;irbesartan;bevacizumab

Binding affinities (BindingDB)

125 measured of 518 human assays (518 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-acetyl-1-(2-chlorophenyl)pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(4-fluorophenyl)-1-[4-(2-methoxyethoxy)phenyl]-4-methylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-[4-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-methyl-2-phenyl-5,6,7,8-tetrahydroisoquinolin-1-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-(1H-pyrazol-4-yl)-2-[4-(trifluoromethoxy)phenyl]-5,6,7,8-tetrahydroisoquinolin-1-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-cyclopentyl-1-phenylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-cyclohexyl-1-phenylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
butyl 4-(6-oxo-1-phenyl-3-pyridinyl)pyrazole-1-carboxylate	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-(6-oxo-1-phenyl-3-pyridinyl)-N-propan-2-ylpyrazole-1-carboxamide	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(4-fluorophenyl)-1-(2-phenylethyl)pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-methyl-1-(2-phenylethyl)pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-[4-(trifluoromethoxy)phenyl]-3H-indol-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(4-fluorophenyl)-4-hydroxy-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-amino-5-(4-fluorophenyl)-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(4-fluorophenyl)-4-(2-morpholin-4-ylethoxy)-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-[2-[[5-(4-fluorophenyl)-2-oxo-1-[4-(trifluoromethoxy)phenyl]-4-pyridinyl]oxy]ethyl]morpholin-3-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-(3,4-dihydro-1H-isoquinolin-2-yl)-5-(1-methylpyrazol-4-yl)-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-[(2,6-difluorophenyl)methylamino]-5-(1-methylpyrazol-4-yl)-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-[(4-methoxyphenyl)methyl-methylamino]-5-(1-methylpyrazol-4-yl)-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
butyl N-[5-(1-methylpyrazol-4-yl)-2-oxo-1-[4-(trifluoromethoxy)phenyl]-4-pyridinyl]carbamate	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
benzyl N-[5-(1-methylpyrazol-4-yl)-2-oxo-1-[4-(trifluoromethoxy)phenyl]-4-pyridinyl]carbamate	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(1-methylpyrazol-4-yl)-4-(2-pyrrolidin-1-ylethoxy)-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-(1,1-dioxothian-4-yl)oxy-5-(1-methylpyrazol-4-yl)-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-[2-[[5-(1-methylpyrazol-4-yl)-2-oxo-1-[4-(trifluoromethoxy)phenyl]-4-pyridinyl]oxy]ethyl]morpholin-3-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(1-methylpyrazol-4-yl)-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(1-methylpyrazol-4-yl)-4-(pyridin-3-ylmethylamino)-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-methyl-1,5-diphenylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-(4-ethoxy-2-methylphenyl)-4-methyl-5-phenylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-(4-chloro-2-methylphenyl)-4-methyl-5-phenylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-(2-fluorophenyl)-4-methyl-5-phenylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-(4-ethoxy-2-methylphenyl)-5-(4-fluorophenyl)-4-methylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(4-fluorophenyl)-4-methyl-1-phenylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(4-fluorophenyl)-4-methyl-1-[3-(trifluoromethyl)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-(2-fluorophenyl)-5-(4-fluorophenyl)-4-methylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(4-fluorophenyl)-4-methyl-1-(3,4,5-trimethoxyphenyl)pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-(1,3-benzodioxol-4-yl)-5-(4-fluorophenyl)-4-methylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-(2,3-dihydro-1,4-benzodioxin-5-yl)-5-(4-fluorophenyl)-4-methylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-(3-aminophenyl)-5-(4-fluorophenyl)-4-methylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
3-[5-(4-fluorophenyl)-4-methyl-2-oxo-1-pyridinyl]-N-methylbenzamide	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(3-chlorophenyl)-4-methyl-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
1-(4-ethoxy-2-methylphenyl)-5-(3-fluorophenyl)-4-methylpyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(3,4-difluorophenyl)-4-methyl-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(3,4-dichlorophenyl)-4-methyl-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(4-chloro-3-fluorophenyl)-4-methyl-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-ethyl-5-(4-fluorophenyl)-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(4-fluorophenyl)-4-propan-2-yl-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-methyl-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(1,3-benzodioxol-5-yl)-4-methyl-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
5-(4-fluorophenyl)-1-[4-(trifluoromethoxy)phenyl]-4-(trifluoromethyl)pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones
4-methyl-5-[4-(1,3-thiazol-5-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]pyridin-2-one	EC50	125000 nM	US-9675593: Anti-fibrotic pyridinones

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, affects cotreatment, increases expression, increases reaction, increases secretion (+2 more)	10
Oxygen	increases expression, increases reaction, increases secretion, affects binding, affects reaction (+1 more)	9
Resveratrol	decreases reaction, increases expression, increases secretion, decreases secretion, affects cotreatment (+1 more)	8
Benzo(a)pyrene	decreases expression, increases expression, affects expression	7
Hydrogen Peroxide	decreases reaction, increases expression, increases secretion, affects expression	7
Valproic Acid	affects expression, increases expression	6
bisphenol A	affects expression, increases expression, decreases expression, decreases secretion	5
cobaltous chloride	affects reaction, decreases reaction, increases expression, increases secretion, affects binding (+2 more)	5
cyclo(Trp-Asp-Pro-Val-Leu)	affects cotreatment, decreases reaction, increases phosphorylation, increases expression, increases localization (+5 more)	5
Glucose	decreases reaction, increases expression, increases secretion, decreases expression, increases chemical synthesis (+3 more)	5
trichostatin A	increases expression, decreases expression, affects cotreatment	4
sodium arsenite	increases expression, decreases reaction, decreases expression, increases abundance, affects reaction	4
Quercetin	decreases reaction, increases expression, increases secretion, decreases expression, decreases secretion	4
Tobacco Smoke Pollution	decreases expression, increases expression	4
Aflatoxin B1	decreases methylation, increases expression, affects expression	4
andrographolide	decreases reaction, increases expression	3
BQ 788	decreases reaction, increases phosphorylation, increases activity, increases secretion, decreases activity (+3 more)	3
SB 203580	increases secretion, increases expression, decreases reaction	3
Carvedilol	decreases reaction, increases expression, decreases expression, decreases secretion	3
Bosentan	decreases activity, decreases expression, decreases reaction, increases expression, increases activity	3
Cocaine	increases expression	3
Doxorubicin	decreases reaction, increases expression, increases activity	3
Indomethacin	decreases activity, decreases reaction, decreases secretion, increases expression	3
Nitric Oxide	increases chemical synthesis, decreases expression, increases expression	3
Simvastatin	decreases expression, decreases reaction, decreases secretion, increases expression, increases secretion	3
Vitamin K 3	increases expression, affects expression	3
Particulate Matter	increases abundance, decreases methylation, decreases expression	3
methylmercuric chloride	affects reaction, increases expression	2
nylestriol	decreases expression	2
zafirlukast	decreases reaction, increases expression, decreases expression	2

Clinical trials (associated diseases)

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