ELN

Summary

ELN (elastin, HGNC:3327) is a protein-coding gene on chromosome 7q11.23, encoding Elastin (P15502). Major structural protein of tissues such as aorta and nuchal ligament, which must expand rapidly and recover completely. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein that is one of the two components of elastic fibers. Elastic fibers comprise part of the extracellular matrix and confer elasticity to organs and tissues including the heart, skin, lungs, ligaments, and blood vessels. The encoded protein is rich in hydrophobic amino acids such as glycine and proline, which form mobile hydrophobic regions bounded by crosslinks between lysine residues. Degradation products of the encoded protein, known as elastin-derived peptides or elastokines, bind the elastin receptor complex and other receptors and stimulate migration and proliferation of monocytes and skin fibroblasts. Elastokines can also contribute to cancer progression. Deletions and mutations in this gene are associated with supravalvular aortic stenosis (SVAS) and autosomal dominant cutis laxa.

Source: NCBI Gene 2006 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cutis laxa, autosomal dominant 1 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,269 total — 137 pathogenic, 56 likely-pathogenic
• Phenotypes (HPO): 317
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 2 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000501

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3327
Approved symbol	ELN
Name	elastin
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Aliases	WBS, WS, SVAS
Ensembl gene	ENSG00000049540
Ensembl biotype	protein_coding
OMIM	130160
Entrez	2006

Gene structure

Transcript identifiers

Ensembl transcripts: 179 — 166 protein_coding, 10 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000252034, ENST00000320399, ENST00000320492, ENST00000357036, ENST00000380553, ENST00000380562, ENST00000380575, ENST00000380576, ENST00000380584, ENST00000414324, ENST00000416107, ENST00000417091, ENST00000419398, ENST00000428787, ENST00000429192, ENST00000431562, ENST00000438880, ENST00000438906, ENST00000442310, ENST00000445912, ENST00000458204, ENST00000462506, ENST00000466878, ENST00000468517, ENST00000473323, ENST00000477397, ENST00000479432, ENST00000480728, ENST00000492003, ENST00000492210, ENST00000493839, ENST00000494160, ENST00000621115, ENST00000685240, ENST00000692049, ENST00000869803, ENST00000869804, ENST00000869805, ENST00000869806, ENST00000869807, ENST00000869808, ENST00000869809, ENST00000869810, ENST00000869811, ENST00000869812, ENST00000869813, ENST00000869814, ENST00000869815, ENST00000869816, ENST00000869817, ENST00000869818, ENST00000869819, ENST00000869820, ENST00000869821, ENST00000869822, ENST00000869823, ENST00000869824, ENST00000869825, ENST00000869826, ENST00000869827, ENST00000869828, ENST00000869829, ENST00000869830, ENST00000869831, ENST00000869832, ENST00000869833, ENST00000869834, ENST00000869835, ENST00000869836, ENST00000869837, ENST00000869838, ENST00000869839, ENST00000869840, ENST00000869841, ENST00000869842, ENST00000869843, ENST00000869844, ENST00000869845, ENST00000869846, ENST00000869847, ENST00000869848, ENST00000869849, ENST00000869850, ENST00000869851, ENST00000869852, ENST00000869853, ENST00000869854, ENST00000869855, ENST00000869856, ENST00000929651, ENST00000929652, ENST00000929653, ENST00000929654, ENST00000929655, ENST00000953816, ENST00000953817, ENST00000953818, ENST00000953819, ENST00000953820, ENST00000953821, ENST00000953822, ENST00000953823, ENST00000953824, ENST00000953825, ENST00000953826, ENST00000953827, ENST00000953828, ENST00000953829, ENST00000953830, ENST00000953831, ENST00000953832, ENST00000953833, ENST00000953834, ENST00000953835, ENST00000953836, ENST00000953837, ENST00000953838, ENST00000953839, ENST00000953840, ENST00000953841, ENST00000953842, ENST00000953843, ENST00000953844, ENST00000953845, ENST00000953846, ENST00000953847, ENST00000953848, ENST00000953849, ENST00000953850, ENST00000953851, ENST00000953852, ENST00000953853, ENST00000953854, ENST00000953855, ENST00000953856, ENST00000953857, ENST00000953858, ENST00000953859, ENST00000953860, ENST00000953861, ENST00000953862, ENST00000953863, ENST00000953864, ENST00000953865, ENST00000953866, ENST00000953867, ENST00000953868, ENST00000953869, ENST00000953870, ENST00000953871, ENST00000953872, ENST00000953873, ENST00000953874, ENST00000953875, ENST00000953876, ENST00000953877, ENST00000953878, ENST00000953879, ENST00000953880, ENST00000953881, ENST00000953882, ENST00000953883, ENST00000953884, ENST00000953885, ENST00000953886, ENST00000953887, ENST00000953888, ENST00000953889, ENST00000953890, ENST00000953891, ENST00000953892, ENST00000953893, ENST00000953894, ENST00000953895, ENST00000953896, ENST00000953897, ENST00000953898, ENST00000953899, ENST00000953900

RefSeq mRNA: 13 — MANE Select: NM_000501 NM_000501, NM_001081752, NM_001081753, NM_001081754, NM_001081755, NM_001278912, NM_001278913, NM_001278914, NM_001278915, NM_001278916, NM_001278917, NM_001278918, NM_001278939

CCDS: CCDS43598, CCDS43599, CCDS47611, CCDS47612, CCDS5562, CCDS64673, CCDS64674, CCDS64675, CCDS64676, CCDS64677, CCDS64678, CCDS75616, CCDS75617

Canonical transcript exons

ENST00000252034 — 33 exons

Exon	Start	End
ENSE00000693530	74057640	74057696
ENSE00000843176	74046188	74046217
ENSE00000843187	74051750	74051839
ENSE00000843194	74056271	74056435
ENSE00000843206	74061101	74061139
ENSE00001148831	74066732	74066776
ENSE00001148838	74065944	74065997
ENSE00001148848	74065694	74065732
ENSE00001148857	74063621	74063695
ENSE00001148865	74063310	74063369
ENSE00001205048	74060376	74060501
ENSE00001221524	74063153	74063224
ENSE00001221659	74045222	74045293
ENSE00001670879	74060140	74060184
ENSE00001753559	74059886	74060047
ENSE00001805023	74056672	74056713
ENSE00001951583	74068657	74069907
ENSE00003465672	74035364	74035414
ENSE00003473499	74042614	74042706
ENSE00003476941	74028173	74028269
ENSE00003480321	74043879	74043920
ENSE00003492869	74041216	74041251
ENSE00003522326	74036555	74036584
ENSE00003589573	74037707	74037739
ENSE00003606417	74048503	74048556
ENSE00003610437	74053163	74053309
ENSE00003622936	74042984	74043034
ENSE00003633608	74047675	74047716
ENSE00003651376	74043118	74043168
ENSE00003673416	74054716	74054769
ENSE00003784418	74051924	74051983
ENSE00003784630	74046696	74046767
ENSE00003787224	74048142	74048201

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 99.81.

FANTOM5 (CAGE): breadth broad, TPM avg 27.2691 / max 4872.3826, expressed in 714 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79037	18.7958	553
79035	3.1920	559
79036	1.7999	398
79054	0.4623	141
79052	0.4554	142
79056	0.3150	110
79033	0.2712	152
79034	0.2623	152
79055	0.2262	95
79058	0.1655	82

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
descending thoracic aorta	UBERON:0002345	99.81	gold quality
ascending aorta	UBERON:0001496	99.78	gold quality
thoracic aorta	UBERON:0001515	99.78	gold quality
right coronary artery	UBERON:0001625	99.64	gold quality
right lung	UBERON:0002167	99.54	gold quality
aorta	UBERON:0000947	99.41	gold quality
popliteal artery	UBERON:0002250	99.21	gold quality
tibial artery	UBERON:0007610	99.21	gold quality
mucosa of stomach	UBERON:0001199	99.19	gold quality
left coronary artery	UBERON:0001626	99.15	gold quality
coronary artery	UBERON:0001621	98.97	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.91	gold quality
lower esophagus	UBERON:0013473	98.88	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.83	gold quality
right atrium auricular region	UBERON:0006631	98.37	gold quality
upper lobe of left lung	UBERON:0008952	97.99	gold quality
gall bladder	UBERON:0002110	97.88	gold quality
endocervix	UBERON:0000458	97.84	gold quality
cardiac atrium	UBERON:0002081	97.78	gold quality
upper lobe of lung	UBERON:0008948	97.68	gold quality
blood vessel layer	UBERON:0004797	97.52	gold quality
left uterine tube	UBERON:0001303	97.40	gold quality
body of pancreas	UBERON:0001150	97.29	gold quality
omental fat pad	UBERON:0010414	96.73	gold quality
peritoneum	UBERON:0002358	96.64	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.58	gold quality
minor salivary gland	UBERON:0001830	96.48	gold quality
body of uterus	UBERON:0009853	96.46	gold quality
apex of heart	UBERON:0002098	96.45	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.34	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	1058.15
E-MTAB-6108	yes	869.62
E-MTAB-7407	yes	844.24
E-HCAD-1	yes	79.73
E-HCAD-10	yes	33.37
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

93 targeting ELN, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Synthetic peptides derived from exon 26A of human elastin cause dose-dependent relaxation in rat thoracic aortic rings. (PMID:11809415)
• Elastin as a self-organizing biomaterial: use of recombinantly expressed human elastin polypeptides as a model for investigations of structure and self-assembly of elastin. (PMID:11911775)
• Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome. (PMID:12016585)
• Data suggest that the external region of the myometrium is more elastic than the inner region and that elastin is found throughout the arteriolar tree of the human uterus. (PMID:12029074)
• Microdeletion of chromosome 7q in patients with Williams syndrome have loss of medial elastin that affects the discharge of baroreceptors and consequently the baroreflex sensitivity (PMID:12102453)
• In pedigrees studied, exonic polymorphisms in ELN do not play a major role in the genetic vulnerability to panic disorder. (PMID:12555228)
• the level at which elastin expression is upregulated after elastase exposure (PMID:12679320)
• In a Central European sample, we found no allelic association between the elastin polymorphism haplotype found in Japan & intracranial aneurysm, probably reflecting increased genetic heterogeneity of intracranial aneurysm in Europe compared with Japan. (PMID:12690215)
• examination of mechanism of assembly of tropoelastin monomer into elastin polymer (PMID:14500713)
• elastin derived peptides following interactions with S-Gal elastin receptor can favor melanoma cells invasion through a three-dimensional type I collagen matrix by upregulating MMP-2 activation. (PMID:15009703)
• Review. Structural and functional changes in elastin result in the loss of skin elasticity in skin aging. (PMID:15036271)
• Association with integrin alpha(v)beta(3) was localized to the C-terminal 16 residues of tropoelastin, encompassing the region encoded by exon 36 (PMID:15134831)
• strong evidence for racial/ethnic differences in the association of SNP and specific haplotypes of the elastin gene with the intracranial aneurysm phenotype. (PMID:15218274)
• These results demonstrate that microfibril-associated glycoprotein-1 is capable of cumulative binding to distinct regions on tropoelastin, with different apparent dissociation constants and different amounts of bound protein. (PMID:15233806)
• variants and haplotypes within the elastin gene are associated with the risk of sporadic subarachnoid hemorrhage in Dutch patients (PMID:15297630)
• Elastin gene mutation results in an autosomal dominant form of cutis laxa. (PMID:15381555)
• demonstrates the existence of two opposite iron-dependent mechanisms that may affect the steady state of elastin message (PMID:15537639)
• analysis of tropoelastin exon 30 amyloid-like assembly (PMID:15550396)
• abnormal production of tropoelastin and fibrillin by heat in human skin and that their degradation by various MMP, such as MMP-12, may contribute to the accumulation of elastotic material in photoaged skin. (PMID:15654955)
• Changing the extracellular matrix composition of a myocardial infarct by increasing elastin fragment content attenuated scar expansion, ventricular dilation, and onset of heart dysfunction. (PMID:15681698)
• Results provide evidence for specific protein domain contact points between tropoelastin monomers during association by coacervation. (PMID:15721581)
• Heparan sulphate-tropoelastin interactions may play a role in tissue elastin fibrogenesis as well as modulating elastin stability with time and in diseases (PMID:15748998)
• importance of elastin derived peptides as stimuli for Th-1 differentiation, whether T cells are in an inactivated state or already orientated toward a Th-1 (IL-12) or Th-2 (IL-4) response (PMID:15860743)
• a conserved hydrophobic region in tropoelastin, domain 26 (D26)is essentially unstructured in solution and does not interact with intact tropoelastin; no significant structural changes occur for this domain over the temperature range 278-308K (PMID:15866738)
• analysis of supramolecular organization of polypeptide sequences coded by particular exons in human tropoelastin (PMID:15890261)
• ELN does not appear to be the gene responsible for familial intracranial aneurysm (IA) in the linked Utah IA pedigrees (PMID:15890991)
• Human derman fibroblasts pretreated with a digest of bovine ligamentum nuchae produced abundant elastin after their injection into the skin of athymic nude mice. (PMID:15925490)
• genetic variations in ELN gene may contribute to pathogenesis of aortic abdominal aneurysm (PMID:15944607)
• detailed structures adopted by the oxidized (native) and reduced forms of the free synthetic peptide with sequence encoded by exon 36 of human tropoelastin (PMID:15961300)
• During the coacervation stage of elastin assembly, domains 2-18 of the N-terminal region of tropoelastin interact with the PF2 segment of fibrillin-1 (PMID:16042404)
• Results suggest that the G773D variant of elastin confers structural and functional consequences relevant to the pathogenesis of chronic obstructive pulmonary disease. (PMID:16081882)
• Mutations may cause severe aortic disease in patients with cutis laxa. (PMID:16085695)
• The interaction of elastin and fibulin-5 alleles results in elastic fibers susceptible to inflammatory destruction. (PMID:16374472)
• Elastin and LIMK1 SNPs effect in the at-risk haplotype possibly by weakening the vascular wall and promoting the development of IA (PMID:16611674)
• Elastin fragments induce NF-kappaB activation, leading to IL-1beta upregulation in invasive melanoma cells (PMID:16675961)
• ELN is deleted in the Williams syndrome. (PMID:16691586)
• 2 novel mutations of ELN in 2 unrelated Korean patients with isolated supravalvular aortic stenosis; findings confirm functional haploinsufficiency of elastin is responsible for pathogenesis associated with isolated SVAS from different ethnic backgrounds (PMID:16820942)
• The results of this study suggest that the defect of human tropoelastin (hTE) gene expression should induce the impaired elastogenesis and enhanced proliferation of Costello fibroblasts. (PMID:16829682)
• These studies are used to propose a coherent recomposition of the elastin pieces (domains) in order to give an acceptable solution to the elastin structure-function problem. (PMID:16878986)
• These studies indicate a role for the 5’ end of the first exon of the elastin gene in regulating strong transcriptional activity in elastogenic cells. (PMID:16899711)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Eln	ENSMUSG00000029675
rattus_norvegicus	Eln	ENSRNOG00000001469

Protein

Protein identifiers

Elastin — P15502 (reviewed: P15502)

Alternative names: Tropoelastin

All UniProt accessions (16): A0A8I5QKI6, A7L3I8, B3KRT8, P15502, E7EN51, E7EN65, E7ENM0, E7ENW7, E7EP82, E7EQH8, E7ETP7, E7EWS8, E9PGX4, G3V0G6, G5E950, H7C3K0

UniProt curated annotations — full annotation on UniProt →

Function. Major structural protein of tissues such as aorta and nuchal ligament, which must expand rapidly and recover completely. Molecular determinant of the late arterial morphogenesis, stabilizing arterial structure by regulating proliferation and organization of vascular smooth muscle.

Subunit / interactions. The polymeric elastin chains are cross-linked together into an extensible 3D network. Forms a ternary complex with BGN and MFAP2. Interacts with MFAP2 via divalent cations (calcium > magnesium > manganese) in a dose-dependent and saturating manner. Interacts with FBLN5. Interacts with FBN1. Forms a ternary complex with FBN1 and FBLN2 or FBLN5. Interacts with MFAP4 in a Ca (2+)-dependent manner; this interaction promotes ELN self-assembly. Interacts with EFEMP2 with moderate affinity.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed within the outer myometrial smooth muscle and throughout the arteriolar tree of uterus (at protein level). Also expressed in the large arteries, lung and skin.

Post-translational modifications. Elastin is formed through the cross-linking of its soluble precursor tropoelastin. Cross-linking is initiated through the action of lysyl oxidase on exposed lysines to form allysine. Subsequent spontaneous condensation reactions with other allysine or unmodified lysine residues result in various bi-, tri-, and tetrafunctional cross-links. The most abundant cross-links in mature elastin fibers are lysinonorleucine, allysine aldol, desmosine, and isodesmosine. Hydroxylation on proline residues within the sequence motif, GXPG, is most likely 4-hydroxy as this fits the requirement for 4-hydroxylation in vertebrates.

Disease relevance. Cutis laxa, autosomal dominant, 1 (ADCL1) [MIM:123700] A connective tissue disorder characterized by loose, hyperextensible skin with decreased resilience and elasticity leading to a premature aged appearance. Face, hands, feet, joints, and torso may be differentially affected. Additional variable clinical features are gastrointestinal diverticula, hernia, and genital prolapse. Rare manifestations are pulmonary artery stenosis, aortic aneurysm, bronchiectasis, and emphysema. The disease is caused by variants affecting the gene represented in this entry. Supravalvular aortic stenosis (SVAS) [MIM:185500] Congenital narrowing of the ascending aorta which can occur sporadically, as an autosomal dominant condition, or as one component of Williams-Beuren syndrome. The disease is caused by variants affecting the gene represented in this entry. ELN is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of ELN may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.

Similarity. Belongs to the elastin family.

Isoforms (13)

UniProt ID	Names	Canonical?
P15502-3	3	yes
P15502-1	1
P15502-2	2
P15502-4	4
P15502-5	5
P15502-6	6
P15502-7	7
P15502-8	8
P15502-9	9
P15502-10	10
P15502-11	11
P15502-12	12
P15502-13	13

RefSeq proteins (13): NP_000492, NP_001075221, NP_001075222, NP_001075223, NP_001075224, NP_001265841, NP_001265842, NP_001265843, NP_001265844, NP_001265845, NP_001265846, NP_001265847, NP_001265868 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003979	Tropoelastin	Family

UniProt features (79 total): modified residue 57, splice variant 10, sequence conflict 4, sequence variant 3, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15502-F1	36.20	0.00

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 (57): 116, 156, 167, 170, 177, 190, 241, 261, 265, 283, 286, 290, 312, 315, 327, 342, 347, 352, 355, 360 …

Disulfide bonds (1): 776–781

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1566948	Elastic fibre formation
R-HSA-2129379	Molecules associated with elastic fibres

MSigDB gene sets: 796 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_CIRCULATORY_SYSTEM_PROCESS, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, MODULE_45, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_EXTRACELLULAR_MATRIX_ASSEMBLY, GOBP_MUSCLE_CELL_PROLIFERATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GGGTGGRR_PAX4_03

GO Biological Process (11): outflow tract morphogenesis (GO:0003151), aortic valve morphogenesis (GO:0003180), skeletal muscle tissue development (GO:0007519), respiratory gaseous exchange by respiratory system (GO:0007585), blood circulation (GO:0008015), animal organ morphogenesis (GO:0009887), regulation of actin filament polymerization (GO:0030833), stress fiber assembly (GO:0043149), regulation of smooth muscle cell proliferation (GO:0048660), extracellular matrix assembly (GO:0085029), extracellular matrix organization (GO:0030198)

GO Molecular Function (4): extracellular matrix structural constituent (GO:0005201), extracellular matrix constituent conferring elasticity (GO:0030023), extracellular matrix binding (GO:0050840), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), extracellular matrix (GO:0031012), elastic fiber (GO:0071953), obsolete collagen-containing extracellular matrix (GO:0062023)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Extracellular matrix organization	2
Elastic fibre formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure morphogenesis	2
binding	2
heart morphogenesis	1
aortic valve development	1
heart valve morphogenesis	1
striated muscle tissue development	1
skeletal muscle organ development	1
multicellular organismal process	1
circulatory system process	1
animal organ development	1
regulation of actin polymerization or depolymerization	1
actin filament polymerization	1
regulation of protein polymerization	1
contractile actin filament bundle assembly	1
actomyosin structure organization	1
regulation of cell population proliferation	1
smooth muscle cell proliferation	1
cellular component assembly	1
extracellular matrix organization	1
extracellular structure organization	1
external encapsulating structure organization	1
structural molecule activity	1
extracellular matrix	1
extracellular matrix structural constituent	1
structural molecule activity conferring elasticity	1
cellular anatomical structure	1
external encapsulating structure	1
supramolecular fiber	1
non-collagenous component of interstitial matrix	1

Protein interactions and networks

STRING

2652 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ELN	FBN1	P35555	999
ELN	FN1	P02751	998
ELN	FBLN5	Q9UBX5	997
ELN	VTN	P01141	992
ELN	MFAP2	P55001	991
ELN	DCN	P07585	990
ELN	GLB1	P16278	987
ELN	MFAP4	P55083	987
ELN	BGN	P13247	984
ELN	LGALS3	P17931	979
ELN	EFEMP2	O95967	976
ELN	MMP9	P14780	972
ELN	FBLN2	P98095	960
ELN	LOX	P28300	952
ELN	FBN2	P35556	950

IntAct

17 interactions, top by confidence:

A	B	Type	Score
ELN	EFEMP2	psi-mi:“MI:0407”(direct interaction)	0.650
ELN	EFEMP2	psi-mi:“MI:0915”(physical association)	0.650
FBLN5	ELN	psi-mi:“MI:0407”(direct interaction)	0.610
ELN	FBLN5	psi-mi:“MI:0407”(direct interaction)	0.610
LOX	ELN	psi-mi:“MI:0407”(direct interaction)	0.540
ELN	FBN1	psi-mi:“MI:0915”(physical association)	0.520
APP	ELN	psi-mi:“MI:0407”(direct interaction)	0.440
LOX	ELN	psi-mi:“MI:0407”(direct interaction)	0.440
ELN	HSPD1	psi-mi:“MI:0915”(physical association)	0.400
ELN	CKMT2	psi-mi:“MI:0915”(physical association)	0.370
ELN	MAGEH1	psi-mi:“MI:0915”(physical association)	0.370
IGHG1	PDPK1	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): ELN (Protein-RNA), ELN (Proximity Label-MS), BGN (Reconstituted Complex), DCN (Reconstituted Complex), FBN1 (Reconstituted Complex), FBN2 (Reconstituted Complex), FBLN1 (Reconstituted Complex), FBLN2 (Reconstituted Complex), NID2 (Reconstituted Complex), ELN (Biochemical Activity), ELN (Affinity Capture-Western), ELN (Reconstituted Complex), ELN (Reconstituted Complex), ELN (FRET), E (FRET)

ESM2 similar proteins: D5GDH4, H2A0L9, O94426, P02848, P02859, P04704, P04985, P05685, P06674, P06675, P07916, P08416, P08825, P08826, P08827, P08828, P08829, P11547, P13531, P14691, P15502, P21748, P21749, P21750, P24449, P26967, P27781, P33575, P33577, P35085, P43513, P43515, P45586, P45587, P54320, P60607, P80676, P82118, P82165, P82171

Diamond homologs: P04985, P07916, P11547, P15502, P54320, Q99372

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
FBLN5	up-regulates	ELN	binding
EFEMP2	“up-regulates activity”	ELN	binding
FBLN5	“up-regulates activity”	ELN	binding

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 2 cancer types — BRCA, CSCC.

Clinical variants and AI predictions

ClinVar

1269 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	137
Likely pathogenic	56
Uncertain significance	499
Likely benign	368
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068837	NM_000501.4(ELN):c.348del (p.Gly117fs)	Pathogenic
1071054	NM_000501.4(ELN):c.1191_1199del (p.Tyr397_Gly400delinsTer)	Pathogenic
1071495	NM_000501.4(ELN):c.82+1G>C	Pathogenic
1071516	NC_000007.13:g.(?73471702)(73483040_?)del	Pathogenic
1072853	NM_000501.4(ELN):c.8del (p.Gly3fs)	Pathogenic
1076698	NM_000501.4(ELN):c.909_916del (p.Ala304fs)	Pathogenic
1076945	NM_000501.4(ELN):c.948T>A (p.Tyr316Ter)	Pathogenic
1320044	NM_000501.4(ELN):c.582del (p.Phe195fs)	Pathogenic
1359460	NM_000501.4(ELN):c.1393dup (p.Ala465fs)	Pathogenic
1381578	NM_000501.4(ELN):c.96del (p.Ile33fs)	Pathogenic
1382426	NM_000501.4(ELN):c.1351A>T (p.Lys451Ter)	Pathogenic
1445727	NM_000501.4(ELN):c.1168G>T (p.Gly390Ter)	Pathogenic
1454234	NM_000501.4(ELN):c.1075_1082dup (p.Ala362fs)	Pathogenic
1459864	NC_000007.13:g.(?73461985)(73483030_?)del	Pathogenic
163381	NM_000501.4(ELN):c.43dup (p.Leu15fs)	Pathogenic
163382	NM_000501.4(ELN):c.131del (p.Pro44fs)	Pathogenic
163383	NM_000501.4(ELN):c.435del (p.Leu146fs)	Pathogenic
163387	NM_000501.4(ELN):c.800-2A>G	Pathogenic
163388	NM_000501.4(ELN):c.862dup (p.Ala288fs)	Pathogenic
163389	NM_000501.4(ELN):c.1097-1G>A	Pathogenic
163398	NM_000501.4(ELN):c.1918+1G>A	Pathogenic
16719	ELN, 100-KB DEL	Pathogenic
16722	NM_000501.4(ELN):c.1324C>T (p.Gln442Ter)	Pathogenic
16723	NM_000501.4(ELN):c.1621C>T (p.Arg541Ter)	Pathogenic
16726	NM_000501.4(ELN):c.1946del (p.Gly649fs)	Pathogenic
16728	NM_000501.4(ELN):c.1973del (p.Pro658fs)	Pathogenic
16730	NM_000501.4(ELN):c.1040del (p.Pro347fs)	Pathogenic
16731	NM_000501.4(ELN):c.450C>G (p.Tyr150Ter)	Pathogenic
16732	NM_000501.4(ELN):c.526A>T (p.Lys176Ter)	Pathogenic
16734	ELN, EX9-33DUP	Pathogenic

SpliceAI

3672 predictions. Top by Δscore:

Variant	Effect	Δscore
7:74035358:TTTCA:T	acceptor_loss	1.0000
7:74035359:TTCAG:T	acceptor_loss	1.0000
7:74035360:TCA:T	acceptor_loss	1.0000
7:74035361:CAG:C	acceptor_loss	1.0000
7:74035362:A:AG	acceptor_gain	1.0000
7:74035362:AG:A	acceptor_gain	1.0000
7:74035362:AGG:A	acceptor_gain	1.0000
7:74035363:G:GT	acceptor_gain	1.0000
7:74035363:GG:G	acceptor_gain	1.0000
7:74035363:GGG:G	acceptor_gain	1.0000
7:74035363:GGGGT:G	acceptor_gain	1.0000
7:74036553:AG:A	acceptor_gain	1.0000
7:74036554:GG:G	acceptor_gain	1.0000
7:74036727:G:GT	donor_gain	1.0000
7:74037705:A:AG	acceptor_gain	1.0000
7:74037706:G:GG	acceptor_gain	1.0000
7:74042702:GGCTG:G	donor_gain	1.0000
7:74042703:GCTGG:G	donor_gain	1.0000
7:74043159:A:T	donor_gain	1.0000
7:74046691:CACAG:C	acceptor_loss	1.0000
7:74046692:ACAG:A	acceptor_gain	1.0000
7:74046694:A:AG	acceptor_gain	1.0000
7:74046694:A:AT	acceptor_loss	1.0000
7:74046694:AG:A	acceptor_gain	1.0000
7:74046695:G:GT	acceptor_gain	1.0000
7:74046695:GG:G	acceptor_gain	1.0000
7:74046695:GGA:G	acceptor_gain	1.0000
7:74046695:GGAGT:G	acceptor_gain	1.0000
7:74046763:GCCTG:G	donor_gain	1.0000
7:74046768:G:GC	donor_loss	1.0000

AlphaMissense

4335 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:74046751:G:C	K209N	0.996
7:74046751:G:T	K209N	0.996
7:74043168:G:C	G143R	0.995
7:74043899:T:G	Y150D	0.995
7:74046747:T:A	I208N	0.995
7:74043885:G:A	G145E	0.994
7:74046738:G:A	G205E	0.994
7:74046741:A:G	Y206C	0.994
7:74046747:T:C	I208T	0.994
7:74043884:G:T	G145W	0.993
7:74045231:T:G	F160C	0.993
7:74046749:A:G	K209E	0.993
7:74043879:G:A	G143D	0.992
7:74043884:G:A	G145R	0.992
7:74043884:G:C	G145R	0.992
7:74046737:G:A	G205R	0.992
7:74046737:G:C	G205R	0.992
7:74046740:T:C	Y206H	0.992
7:74043893:G:C	G148R	0.991
7:74045249:T:A	L166H	0.991
7:74046747:T:G	I208S	0.991
7:74045230:T:C	F160L	0.990
7:74045232:C:A	F160L	0.990
7:74045232:C:G	F160L	0.990
7:74046756:C:A	P211H	0.990
7:74045242:G:T	G164W	0.989
7:74046760:G:C	K212N	0.989
7:74046760:G:T	K212N	0.989
7:74048201:G:T	G249W	0.989
7:74043168:G:T	G143C	0.988

dbSNP variants (sampled 300 via entrez): RS1000143867 (7:74053047 A>G), RS1000227910 (7:74047931 G>A), RS1000338009 (7:74042108 A>C,T), RS1000565254 (7:74049502 T>C), RS1000828535 (7:74038048 G>A), RS1001009110 (7:74032093 C>T), RS1001079707 (7:74043410 T>C), RS1001179239 (7:74039286 T>C,G), RS1001325742 (7:74027171 G>A), RS1001331083 (7:74033033 A>C,G), RS1001379725 (7:74031677 G>A), RS1001440018 (7:74027405 A>C), RS1001545357 (7:74061378 G>A), RS1001552965 (7:74066172 T>C), RS1001741429 (7:74033319 C>A,T)

Disease associations

OMIM: gene MIM:130160 | disease phenotypes: MIM:185500, MIM:123700, MIM:194050, MIM:606215, MIM:192200

GenCC curated gene-disease

Disease	Classification	Inheritance
cutis laxa, autosomal dominant 1	Definitive	Autosomal dominant
supravalvular aortic stenosis	Definitive	Autosomal dominant
autosomal dominant cutis laxa	Supportive	Autosomal dominant
familial thoracic aortic aneurysm and aortic dissection	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
cutis laxa, autosomal dominant 1	Definitive	AD

Mondo (10): supravalvular aortic stenosis (MONDO:0008504), cutis laxa, autosomal dominant 1 (MONDO:0007411), Williams syndrome (MONDO:0008678), cardiomyopathy (MONDO:0004994), familial atrioventricular septal defect (MONDO:0020290), autosomal dominant cutis laxa (MONDO:0019571), digestive system carcinoma (MONDO:0006181), varicose disease (MONDO:0008638), polyp of large intestine (MONDO:0021392), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625)

Orphanet (5): Supravalvular aortic stenosis (Orphanet:3193), Autosomal dominant cutis laxa (Orphanet:90348), Williams syndrome (Orphanet:904), Rare cardiomyopathy (Orphanet:167848), Atrioventricular septal defect (Orphanet:98722)

HPO phenotypes

317 total (30 of 317 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000014	Abnormality of the bladder
HP:0000015	Bladder diverticulum
HP:0000023	Inguinal hernia
HP:0000025	Functional abnormality of male internal genitalia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000075	Renal duplication
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000093	Proteinuria
HP:0000098	Tall stature
HP:0000121	Nephrocalcinosis
HP:0000122	Unilateral renal agenesis
HP:0000125	Pelvic kidney
HP:0000139	Uterine prolapse
HP:0000147	Polycystic ovaries
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000179	Thick lower lip vermilion
HP:0000194	Open mouth
HP:0000212	Gingival overgrowth
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000270	Delayed cranial suture closure
HP:0000272	Malar flattening
HP:0000275	Narrow face

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006479_132	Diverticular disease	3.000000e-09
GCST008839_198	Height	7.000000e-29

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D014648	Varicose Veins	C14.907.927
D018980	Williams Syndrome	C10.597.606.360.970; C14.280.484.048.750.535.960; C16.131.260.970; C16.320.180.970
C562627	Cutis Laxa, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3713712 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
Doxorubicin	affects expression, decreases expression	2
Lead	affects expression, affects methylation	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
GSK-J4	increases expression	1
bisphenol A	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
monorden	increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
Y 27632	decreases reaction, increases expression	1
CVT 313	decreases expression	1
6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine	decreases expression	1
abrine	decreases expression	1
palbociclib	increases expression	1
seletinoid G	increases expression	1
(+)-JQ1 compound	decreases expression	1
Dasatinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Calcitriol	decreases expression	1
Fluorouracil	affects expression	1
Nickel	decreases expression	1
Penicillamine	affects localization	1
Plant Extracts	increases expression	1
Retinoids	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00768820	PHASE4	RECRUITING	The Psychiatric and Cognitive Phenotypes in Velocardiofacial Syndrome
NCT04807517	PHASE4	COMPLETED	Buspirone Treatment of Anxiety in Williams Syndrome
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT00876200	PHASE2	COMPLETED	Efficacy of Minoxidil in Children With Williams-Beuren Syndrome