EFEMP2

Summary

EFEMP2 (EGF-like fibulin extracellular matrix protein 2, HGNC:3219) is a protein-coding gene on chromosome 11q13.1, encoding EGF-containing fibulin-like extracellular matrix protein 2 (O95967). Plays a crucial role in elastic fiber formation in tissue, and in the formation of ultrastructural connections between elastic laminae and smooth muscle cells in the aorta, therefore participates in terminal differentiation and maturation of smooth muscle cell (SMC) and in the m….

A large number of extracellular matrix proteins have been found to contain variations of the epidermal growth factor (EGF) domain and have been implicated in functions as diverse as blood coagulation, activation of complement and determination of cell fate during development. The protein encoded by this gene contains four EGF2 domains and six calcium-binding EGF2 domains. This gene is necessary for elastic fiber formation and connective tissue development. Defects in this gene are cause of an autosomal recessive cutis laxa syndrome. Alternatively spliced transcript variants have been identified for this gene.

Source: NCBI Gene 30008 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cutis laxa, autosomal recessive, type 1B (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 618 total — 26 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 119
• MANE Select transcript: NM_016938

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3219
Approved symbol	EFEMP2
Name	EGF-like fibulin extracellular matrix protein 2
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	FBLN4, UPH1
Ensembl gene	ENSG00000172638
Ensembl biotype	protein_coding
OMIM	604633
Entrez	30008

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 26 protein_coding, 7 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000307998, ENST00000524408, ENST00000525392, ENST00000526624, ENST00000526628, ENST00000526911, ENST00000527277, ENST00000527378, ENST00000527969, ENST00000528176, ENST00000528409, ENST00000529870, ENST00000530806, ENST00000530850, ENST00000531005, ENST00000531645, ENST00000531972, ENST00000532084, ENST00000532648, ENST00000533347, ENST00000907916, ENST00000907917, ENST00000907918, ENST00000907919, ENST00000907920, ENST00000907921, ENST00000907922, ENST00000907923, ENST00000907924, ENST00000907925, ENST00000907926, ENST00000907927, ENST00000947415, ENST00000947416, ENST00000947417, ENST00000947418, ENST00000947419, ENST00000947420, ENST00000947421

RefSeq mRNA: 1 — MANE Select: NM_016938 NM_016938

CCDS: CCDS8116

Canonical transcript exons

ENST00000307998 — 11 exons

Exon	Start	End
ENSE00001190629	65871970	65872018
ENSE00001331322	65866441	65867079
ENSE00001378145	65872683	65872800
ENSE00003476291	65870536	65870658
ENSE00003480071	65867861	65868056
ENSE00003486957	65872244	65872361
ENSE00003518953	65871157	65871363
ENSE00003545056	65869857	65869976
ENSE00003560891	65868295	65868421
ENSE00003678237	65868510	65868629
ENSE00003786685	65870121	65870237

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 58.7588 / max 675.0234, expressed in 1396 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120718	48.1714	1240
120720	4.0843	1095
120714	1.6626	636
120719	1.2987	695
120715	1.2301	612
120721	0.8317	510
120717	0.5937	393
120716	0.3561	235
120713	0.2264	105
120712	0.1324	65

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.25	gold quality
tendon of biceps brachii	UBERON:0008188	98.77	gold quality
ascending aorta	UBERON:0001496	98.24	gold quality
thoracic aorta	UBERON:0001515	98.23	gold quality
descending thoracic aorta	UBERON:0002345	98.20	gold quality
right coronary artery	UBERON:0001625	98.19	gold quality
body of uterus	UBERON:0009853	98.08	gold quality
apex of heart	UBERON:0002098	97.87	gold quality
right ovary	UBERON:0002118	97.81	gold quality
left ovary	UBERON:0002119	97.81	gold quality
right atrium auricular region	UBERON:0006631	97.81	gold quality
aorta	UBERON:0000947	97.67	gold quality
coronary artery	UBERON:0001621	97.66	gold quality
left coronary artery	UBERON:0001626	97.65	gold quality
endocervix	UBERON:0000458	97.60	gold quality
left uterine tube	UBERON:0001303	97.56	gold quality
cardiac atrium	UBERON:0002081	97.37	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.30	gold quality
popliteal artery	UBERON:0002250	97.29	gold quality
tibial artery	UBERON:0007610	97.29	gold quality
artery	UBERON:0001637	97.27	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.25	gold quality
lower esophagus	UBERON:0013473	97.21	gold quality
myometrium	UBERON:0001296	97.08	gold quality
left lobe of thyroid gland	UBERON:0001120	97.04	gold quality
mucosa of stomach	UBERON:0001199	97.02	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.91	gold quality
thyroid gland	UBERON:0002046	96.82	gold quality
right lobe of thyroid gland	UBERON:0001119	96.76	gold quality
gall bladder	UBERON:0002110	96.75	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	117.08
E-MTAB-10287	yes	112.55
E-HCAD-1	yes	74.57
E-MTAB-8410	yes	59.90
E-HCAD-10	yes	52.34
E-HCAD-11	yes	46.43
E-MTAB-6678	yes	26.93
E-ANND-3	yes	18.07
E-CURD-112	yes	16.03
E-HCAD-13	yes	13.00
E-MTAB-10553	yes	5.42
E-HCAD-9	yes	5.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

19 targeting EFEMP2, 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-629-3P	99.85	67.99	1875
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-198	98.70	67.32	920
HSA-MIR-3158-3P	98.45	64.25	560
HSA-MIR-6867-3P	98.12	66.07	1305
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-4287	97.55	67.24	1247
HSA-MIR-4685-3P	97.55	67.35	1255
HSA-MIR-6859-3P	97.26	64.69	428
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-3194-5P	96.80	64.90	1027
HSA-MIR-1258	96.08	67.74	700
HSA-MIR-2861	95.24	65.47	1056

Literature-anchored findings (GeneRIF, showing 31)

• Fibulin-4, expressed in chondrocytes and recognized as an autoantigen mainly in osteoarthritis (OA) rather than in rheumatoid arthritis, may play pathogenic roles in OA. (PMID:16493080)
• ternary complex formation between fibrillin-1, fibulins, and tropoelastin demonstrated that fibulin-2 and -5 but much less fibulin-4, are able to act as molecular adaptors between fibrillin-1 and tropoelastin (PMID:17255108)
• fibulin-5 controlled elastin deposition on microfibrils, although fibulin-4 can also bind fibrillin-1. (PMID:19570982)
• Fibulin-4, considered as a structural protein, may also participate in regulating elastic-fibre formation in human cells through the regulation of tropoelastin expression. (PMID:19627254)
• patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms, arterial tortuosity and stenosis; evidence for the involvement of altered TGFbeta signaling in the pathogenesis of FBLN4 mutations (PMID:20389311)
• FBLN4 has 10 coding exons (PMID:22070778)
• In this largest cohort of reported patients with a mutated EFEMP2 gene, we illustrate the phenotypic spectrum of inherited AA due to a novel EFEMP2 mutation. (PMID:22440127)
• The expression level of EFEMP2 is dramatically increased in colorectal cancer patients, even at the early stage, compared with healthy controls. (PMID:22506683)
• Data indicate mutations of FBLN4, FBLN5, and LTBP4 in 12 probands presenting with type 1 recessive cutis laxa. (PMID:22829427)
• EFEMP2 is a novel PITX2-interacting protein that may bear importance for the development of anterior segment dysgenesis (ASD) and glaucoma. (PMID:22919265)
• A lethal, genetic disorder characterized by severe deformation of elastic arteries, was linked to novel mutations in the FBLN4 gene. (PMID:22943132)
• Low EFEMP2 expression is associated with malignant pleural mesothelioma. (PMID:23313295)
• Studied Fibulin-4 expression in aortic wall to find out its role in aortic dissection development. Used samples of aortic wall from 10 patients operated for acute ascending aortic dissection and five patients for chronic ascending aortic dissection. (PMID:23518852)
• Solid phase binding assays detected strong calcium-dependent binding of the short fibulins to immobilized heparin, suggesting that these fibulins may bind cell surface-located heparan sulfate (PMID:23782690)
• This study demonstrated that fibulin-4 may serve as a new prognostic factor and as a potential therapeutic target for patients with cervical carcinoma. (PMID:24737201)
• Homozygous mutations in exon 7 of the FBLN4 gene can produce lethal vasculopathy. (PMID:24838734)
• pulmonary emphysema in aneurysmal Fibulin-4 deficient (Fibulin-4(R)) mice (PMID:25255451)
• Data indicates that Fibulin-4 is a novel gene that is found overexpressed in ovarian cancer and associated with poor prognostic clinicopathologic features. (PMID:25885889)
• Findings suggested that fibulin-4 is important for the proteolytic activation of lysyl oxidase which has a pivotal role in cross-linking of collagen and elastin. (PMID:26690653)
• different mutations in the fibulin-4 gene result in different molecular defects affecting secretion rates, protein stability, LOX-induced cross-linking, or binding to other ECM components and molecules of the TGF-beta pathway. (PMID:27339457)
• link between Fibulin-4 and the canonical Wnt/beta-catenin pathway that may contribute to our understanding of the molecular mechanisms of OA (PMID:28238906)
• The results revealed that fibulin-4 expression was upregulated in osteosarcoma, and was positively correlated with low differentiation, lymph node metastasis, and poor prognosis. Fibulin-4 was also found to be over-expressed in highly invasive cell lines and in the highly invasive subclones (PMID:28339091)
• These results are consistent with a role of FBLN2 in mammary epithelial basement membrane stability, and that its down-regulation in breast cancer is associated with loss of the basement membrane and early invasion. (PMID:30237579)
• These results may explain the changes in protease cleavage sites, reduced secretion and impaired extracellular assembly of the E126K and D203A fibulin-4 mutants and provide further insight into understanding the molecular basis of the associated clinical phenotypes. (PMID:31125616)
• EFEMP2 indicates assembly of M0 macrophage and more malignant phenotypes of glioma. (PMID:32396873)
• Downregulation of fibulin-4 inhibits autophagy and promotes the sensitivity of esophageal squamous cell carcinoma cells to apatinib by activating the Akt-mTOR signaling pathway. (PMID:35950373)
• EFEMP2 increases the invasion ability of cervical cancer cells by promoting EMT via the Raf/MEK/ERK signaling pathway. (PMID:36004647)
• STEAP2 promotes osteosarcoma progression by inducing epithelial-mesenchymal transition via the PI3K/AKT/mTOR signaling pathway and is regulated by EFEMP2. (PMID:36316642)
• Protective Role of Endothelial Fibulin-4 in Valvulo-Arterial Integrity. (PMID:36565192)
• EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells. (PMID:37420173)
• Whole-exome sequencing uncovers a novel EFEMP2 gene variant (c.C247T) associated with dominant nonsyndromic thoracic aortic aneurysm. (PMID:38113391)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	efemp2b	ENSDARG00000020811
danio_rerio	efemp2a	ENSDARG00000094324
mus_musculus	Efemp2	ENSMUSG00000024909
rattus_norvegicus	Efemp2	ENSRNOG00000020587

Paralogs (6): FBLN1 (ENSG00000077942), EFEMP1 (ENSG00000115380), FBLN5 (ENSG00000140092), VWDE (ENSG00000146530), FBLN2 (ENSG00000163520), EYS (ENSG00000188107)

Protein

Protein identifiers

EGF-containing fibulin-like extracellular matrix protein 2 — O95967 (reviewed: O95967)

Alternative names: Fibulin-4, Protein UPH1

All UniProt accessions (11): O95967, E9PI47, E9PKA3, E9PNB8, E9PRQ8, E9PRU1, E9PSC1, H0YCB5, H0YCR9, H0YET5, H0YEU0

UniProt curated annotations — full annotation on UniProt →

Function. Plays a crucial role in elastic fiber formation in tissue, and in the formation of ultrastructural connections between elastic laminae and smooth muscle cells in the aorta, therefore participates in terminal differentiation and maturation of smooth muscle cell (SMC) and in the mechanical properties and wall integrity maintenance of the aorta. In addition, is involved in the control of collagen fibril assembly in tissue throught proteolytic activation of LOX leading to cross- linking of collagen and elastin. Also promotes ELN coacervation and participates in the deposition of ELN coacervates on to microfibrils but also regulates ELN cross- linking through LOX interaction. Moreover adheres to the cells through heparin binding in a calcium-dependent manner and regulates vascularlar smooth muscle cells proliferation through angiotensin signaling.

Subunit / interactions. Homodimer; disulfide-linked. Multimer; allows heparin binding. Monomer. Interacts with FBN1 (via N-terminal domain); this interaction inhibits EFEMP2 binding to LOX and ELN. Interacts with LOX (via propeptide); this interaction is strong and facilitates formation of ternary complexes with ELN during elastic fiber assembly; this interaction limits interaction of EFEMP2 with FBLN5. Interacts with PITX2. Interacts with ELN with moderate affinity; this interaction regulates ELN self-assembly maturation stage. Interacts with FBLN5 with moderate affinity. Interacts with LOXL1 (via propeptide), LTBP1 and TGFB1 stronger than with LOXL2 and LTBP3. Interacts with PCOLCE. Interacts with collagen type IV trimer (COL4A1-COL4A1-COL4A2), NID2 and moderately with COL15A1-derived endostatin. Interacts with EMILIN1; this interaction promotes the incorporation of EFEMP2 into the extracellular matrix. Interacts with LTBP4; the LTBP4 long form (LTBP4L) has a stronger binding affinity than the LTBP4 short form and the LTBP4 long form promotes fibrillar deposition of EFEMP2.

Subcellular location. Secreted. Extracellular space. Extracellular matrix. Basement membrane.

Post-translational modifications. N-glycosylated; contains mostly complex-type glycans. Not O-glycosylated. Cleaved by ELANE; produces a 50-55 kDa fragment. Cleaved by MMP2 and MMP9; produces several fragments.

Disease relevance. Cutis laxa, autosomal recessive, 1B (ARCL1B) [MIM:614437] 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. The clinical spectrum of autosomal recessive cutis laxa is highly heterogeneous with respect to organ involvement and severity. ARCL1B features include emphysema, lethal pulmonary artery occlusion, aortic aneurysm, cardiopulmonary insufficiency, birth fractures, arachnodactyly, and fragility of blood vessels. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the fibulin family.

RefSeq proteins (1): NP_058634* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR013032	EGF-like_CS	Conserved_site
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR026823	cEGF	Domain
IPR049883	NOTCH1_EGF-like	Domain
IPR052235	Nephronectin_domain	Family
IPR055088	Fibulin_C	Domain

Pfam: PF07645, PF12661, PF12662, PF22914

UniProt features (52 total): disulfide bond 18, sequence variant 9, sequence conflict 9, domain 6, site 3, strand 3, glycosylation site 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2KL7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95967-F1	82.95	0.55

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 (3): 92–93 (cleavage); 87–88 (cleavage; by elane); 90–91 (cleavage; by mmp2, mmp3, mmp7, mmp9, mmp12)

Disulfide bonds (18): 58–121, 65–80, 71–109, 127–140, 134–149, 151–162, 168–177, 173–186, 188–201, 207–217, 213–226, 228–241, 247–258, 254–267, 269–281, 287–300, 294–309, 315–327

Glycosylation sites (2): 198, 394

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2129379	Molecules associated with elastic fibres

MSigDB gene sets: 455 (showing top): RNGTGGGC_UNKNOWN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_ARTERY_DEVELOPMENT, GOBP_EXTRACELLULAR_MATRIX_ASSEMBLY, GOBP_VASCULAR_ASSOCIATED_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_MUSCLE_CELL_PROLIFERATION, CHANDRAN_METASTASIS_DN, chr11q13, GOBP_REGULATION_OF_EXTRACELLULAR_MATRIX_ORGANIZATION

GO Biological Process (10): aorta development (GO:0035904), elastic fiber assembly (GO:0048251), aorta smooth muscle tissue morphogenesis (GO:0060414), vascular associated smooth muscle cell development (GO:0097084), regulation of collagen fibril organization (GO:1904026), positive regulation of collagen fibril organization (GO:1904028), negative regulation of vascular associated smooth muscle cell proliferation (GO:1904706), positive regulation of aortic smooth muscle cell differentiation (GO:1904831), positive regulation of smooth muscle cell-matrix adhesion (GO:1905609), artery development (GO:0060840)

GO Molecular Function (5): extracellular matrix structural constituent (GO:0005201), calcium ion binding (GO:0005509), heparin binding (GO:0008201), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (7): microfibril (GO:0001527), extracellular region (GO:0005576), basement membrane (GO:0005604), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), elastic fiber (GO:0071953), extracellular vesicle (GO:1903561)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Elastic fibre formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
collagen fibril organization	2
extracellular matrix	2
supramolecular fiber	2
artery development	1
extracellular matrix assembly	1
supramolecular fiber organization	1
aorta morphogenesis	1
smooth muscle tissue development	1
muscle tissue morphogenesis	1
vascular associated smooth muscle cell differentiation	1
muscle cell development	1
regulation of extracellular matrix organization	1
positive regulation of extracellular matrix organization	1
regulation of collagen fibril organization	1
negative regulation of smooth muscle cell proliferation	1
regulation of vascular associated smooth muscle cell proliferation	1
vascular associated smooth muscle cell proliferation	1
aortic smooth muscle cell differentiation	1
regulation of aortic smooth muscle cell differentiation	1
positive regulation of vascular associated smooth muscle cell differentiation	1
positive regulation of cell-matrix adhesion	1
smooth muscle cell-matrix adhesion	1
regulation of smooth muscle cell-matrix adhesion	1
blood vessel development	1
structural molecule activity	1
metal ion binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
elastic fiber	1
cellular anatomical structure	1
external encapsulating structure	1
extracellular vesicle	1
non-collagenous component of interstitial matrix	1
extracellular region	1
vesicle	1
extracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1626 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFEMP2	ELN	P15502	976
EFEMP2	ATP6V0A2	Q9Y487	905
EFEMP2	LOX	P28300	847
EFEMP2	ADAMTS2	O95450	813
EFEMP2	PYCR1	P32322	779
EFEMP2	FBN1	P35555	741
EFEMP2	ADAMTS4	O75173	724
EFEMP2	ALG2	Q9H553	719
EFEMP2	LTBP1	P22064	696
EFEMP2	LTBP4	Q8N2S1	667
EFEMP2	COL3A1	P02461	652
EFEMP2	SLC2A10	O95528	650
EFEMP2	GORAB	Q5T7V8	638
EFEMP2	BGN	P13247	614
EFEMP2	FN1	P02751	609

IntAct

434 interactions, top by confidence:

A	B	Type	Score
SGTB	EFEMP2	psi-mi:“MI:0915”(physical association)	0.830
EFEMP2	SGTB	psi-mi:“MI:0915”(physical association)	0.830
SGTA	EFEMP2	psi-mi:“MI:0915”(physical association)	0.780
EFEMP2	SGTA	psi-mi:“MI:0915”(physical association)	0.780
EFEMP2	LOX	psi-mi:“MI:0915”(physical association)	0.730
EFEMP2	LOX	psi-mi:“MI:0407”(direct interaction)	0.730
EFEMP2	NUFIP2	psi-mi:“MI:0915”(physical association)	0.720
EFEMP2	STK16	psi-mi:“MI:0915”(physical association)	0.720
EFEMP2	CREB5	psi-mi:“MI:0915”(physical association)	0.720
STK16	EFEMP2	psi-mi:“MI:0915”(physical association)	0.720
NUFIP2	EFEMP2	psi-mi:“MI:0915”(physical association)	0.720
PRPF31	EFEMP2	psi-mi:“MI:0915”(physical association)	0.720
MEOX2	EFEMP2	psi-mi:“MI:0915”(physical association)	0.560
EFEMP2		psi-mi:“MI:0915”(physical association)	0.560
RBPMS	EFEMP2	psi-mi:“MI:0915”(physical association)	0.560
HDAC4	EFEMP2	psi-mi:“MI:0915”(physical association)	0.560
EFEMP2	PTGER3	psi-mi:“MI:0915”(physical association)	0.560
EFEMP2	LCE3C	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (159): EFEMP2 (Two-hybrid), EFEMP2 (Two-hybrid), EFEMP2 (Two-hybrid), EFEMP2 (Two-hybrid), EFEMP2 (Two-hybrid), EFEMP2 (Two-hybrid), EFEMP2 (Two-hybrid), EFEMP2 (Two-hybrid), SGTB (Two-hybrid), NUFIP2 (Two-hybrid), CCDC33 (Two-hybrid), C5orf24 (Two-hybrid), LCE2D (Two-hybrid), LCE3C (Two-hybrid), FAM74A4 (Two-hybrid)

ESM2 similar proteins: A2VCU8, A6QR11, O35568, O42182, O55058, O73775, O95967, P07224, P23142, P31515, P35555, P35556, P53813, P60755, P60756, P98118, P98133, Q01974, Q03610, Q08761, Q08879, Q0WYX8, Q12805, Q2VWQ2, Q5EA62, Q5R3Z7, Q5RA73, Q5RC26, Q61220, Q61554, Q61555, Q62918, Q62919, Q7YQD7, Q7Z553, Q7ZXL5, Q8BPB5, Q8MJJ9, Q8UVJ7, Q90827

Diamond homologs: A0A6I8RMG7, B3EWY9, B5DFC9, O35568, O55058, O70244, O73775, O88322, O95967, P10493, P14543, P15306, P23142, P27590, P35444, P35445, P35555, P48960, P49747, Q08879, Q12805, Q14112, Q19267, Q28178, Q2KIT5, Q2Q426, Q2VWQ2, Q4G063, Q4V7F2, Q4V7M2, Q5EA46, Q5EA62, Q5G872, Q5RC26, Q5W7P8, Q60438, Q62919, Q66PY1, Q6NZL8, Q6UXH1

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
FBN1	“down-regulates activity”	EFEMP2	binding
LOX	“up-regulates activity”	EFEMP2	binding
EFEMP2	“up-regulates activity”	ELN	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Keratinization	15	16.7×	7e-13
Formation of the cornified envelope	8	14.1×	6e-06

GO biological processes:

GO term	Partners	Fold	FDR
keratinization	8	24.3×	5e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	15
Uncertain significance	257
Likely benign	253
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070589	NM_016938.5(EFEMP2):c.919_952dup (p.Pro318fs)	Pathogenic
2703407	NM_016938.5(EFEMP2):c.338_339del (p.Gly112_Tyr113insTer)	Pathogenic
2769959	NM_016938.5(EFEMP2):c.917dup (p.Tyr307fs)	Pathogenic
2877716	NM_016938.5(EFEMP2):c.290dup (p.Pro98fs)	Pathogenic
3065562	NM_016938.5(EFEMP2):c.976C>G (p.Arg326Gly)	Pathogenic
3614102	NM_016938.5(EFEMP2):c.229_230dup (p.Tyr78fs)	Pathogenic
3644932	NM_016938.5(EFEMP2):c.1044_1059dup (p.Arg354fs)	Pathogenic
3653395	NM_016938.5(EFEMP2):c.1135del (p.Arg379fs)	Pathogenic
3662053	NM_016938.5(EFEMP2):c.44G>A (p.Trp15Ter)	Pathogenic
39009	NM_016938.5(EFEMP2):c.1189G>A (p.Ala397Thr)	Pathogenic
39012	NM_016938.5(EFEMP2):c.377A>T (p.Glu126Val)	Pathogenic
39013	NM_016938.5(EFEMP2):c.577del (p.Gln193fs)	Pathogenic
39016	NM_016938.5(EFEMP2):c.800G>A (p.Cys267Tyr)	Pathogenic
42041	NM_016938.5(EFEMP2):c.679C>T (p.Arg227Cys)	Pathogenic
4727036	NM_016938.5(EFEMP2):c.695_696del (p.Gly231_Tyr232insTer)	Pathogenic
4730985	NM_016938.5(EFEMP2):c.463del (p.Tyr155fs)	Pathogenic
4764644	NM_016938.5(EFEMP2):c.969dup (p.Glu324Ter)	Pathogenic
4822497	NM_016938.5(EFEMP2):c.111+1G>A	Pathogenic
5423	NM_016938.5(EFEMP2):c.169G>A (p.Glu57Lys)	Pathogenic
5425	NM_016938.5(EFEMP2):c.1070_1073dup (p.Asp359fs)	Pathogenic
650648	NM_016938.5(EFEMP2):c.1174del (p.Ile392fs)	Pathogenic
832127	NC_000011.10:g.(?65871960)(65872944_?)del	Pathogenic
937224	NM_016938.5(EFEMP2):c.861T>A (p.Cys287Ter)	Pathogenic
943459	NM_016938.5(EFEMP2):c.1170+1G>A	Pathogenic
948115	NM_016938.5(EFEMP2):c.499G>T (p.Glu167Ter)	Pathogenic
982404	NM_016938.5(EFEMP2):c.379T>C (p.Cys127Arg)	Pathogenic
1739625	NM_016938.5(EFEMP2):c.1171-2_1195del	Likely pathogenic
2020563	NM_016938.5(EFEMP2):c.848-1_850del	Likely pathogenic
2430490	NM_016938.5(EFEMP2):c.848-1_849del	Likely pathogenic
2501223	NM_016938.5(EFEMP2):c.-7-1_-7delinsAT	Likely pathogenic

SpliceAI

2041 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65866909:T:TA	donor_gain	1.0000
11:65867076:TTTG:T	acceptor_gain	1.0000
11:65867077:TTG:T	acceptor_gain	1.0000
11:65867078:TG:T	acceptor_gain	1.0000
11:65867080:C:CC	acceptor_gain	1.0000
11:65867088:CAG:C	acceptor_gain	1.0000
11:65867089:A:T	acceptor_gain	1.0000
11:65867090:G:C	acceptor_gain	1.0000
11:65867090:G:GC	acceptor_gain	1.0000
11:65867094:G:C	acceptor_gain	1.0000
11:65867094:G:GC	acceptor_gain	1.0000
11:65867855:CCTTA:C	donor_loss	1.0000
11:65867856:CTTAC:C	donor_loss	1.0000
11:65867857:TTAC:T	donor_loss	1.0000
11:65867858:TAC:T	donor_loss	1.0000
11:65867859:A:AC	donor_gain	1.0000
11:65867859:AC:A	donor_gain	1.0000
11:65867860:C:CC	donor_gain	1.0000
11:65867860:C:CT	donor_loss	1.0000
11:65867860:CC:C	donor_gain	1.0000
11:65868054:CGG:C	acceptor_gain	1.0000
11:65868057:C:CC	acceptor_gain	1.0000
11:65868068:G:T	acceptor_gain	1.0000
11:65868292:CA:C	donor_loss	1.0000
11:65868293:A:AC	donor_gain	1.0000
11:65868293:A:C	donor_loss	1.0000
11:65868293:ACTT:A	donor_gain	1.0000
11:65868294:C:CA	donor_gain	1.0000
11:65868294:CT:C	donor_gain	1.0000
11:65868294:CTT:C	donor_gain	1.0000

AlphaMissense

2919 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65867012:A:G	L413P	1.000
11:65867904:A:C	F376C	1.000
11:65867949:A:C	F361C	1.000
11:65868409:C:G	C287S	1.000
11:65868410:A:T	C287S	1.000
11:65868515:C:G	C281S	1.000
11:65868516:A:G	C281R	1.000
11:65868516:A:T	C281S	1.000
11:65868543:C:A	G272C	1.000
11:65868584:C:G	C258S	1.000
11:65868585:A:T	C258S	1.000
11:65868617:C:G	C247S	1.000
11:65868618:A:T	C247S	1.000
11:65869893:C:A	G231C	1.000
11:65869913:A:C	F224C	1.000
11:65869919:C:A	G222V	1.000
11:65869920:C:A	G222W	1.000
11:65869927:G:C	N219K	1.000
11:65869927:G:T	N219K	1.000
11:65869934:C:G	C217S	1.000
11:65869935:A:T	C217S	1.000
11:65869964:C:G	C207S	1.000
11:65869965:A:T	C207S	1.000
11:65870126:C:G	C201S	1.000
11:65870126:C:T	C201Y	1.000
11:65870127:A:G	C201R	1.000
11:65870127:A:T	C201S	1.000
11:65870153:A:C	F192C	1.000
11:65870157:C:A	G191C	1.000
11:65870165:C:G	C188S	1.000

dbSNP variants (sampled 300 via entrez): RS1001125292 (11:65871547 G>T), RS1001580366 (11:65870522 C>T), RS1001714317 (11:65869721 C>T), RS1001945442 (11:65872142 C>T), RS1001955338 (11:65871795 C>G,T), RS1002000200 (11:65866577 A>C), RS1002228928 (11:65869411 C>T), RS1002466766 (11:65865988 A>C,G), RS1003211920 (11:65867537 A>G,T), RS1003628039 (11:65873267 C>A,G,T), RS1003856168 (11:65868297 C>A), RS1005319210 (11:65868943 G>A), RS1005533228 (11:65874005 T>C), RS1005850238 (11:65872808 G>A,C), RS1006202912 (11:65869739 C>A,T)

Disease associations

OMIM: gene MIM:604633 | disease phenotypes: MIM:614437, MIM:607086, MIM:219100

GenCC curated gene-disease

Disease	Classification	Inheritance
cutis laxa, autosomal recessive, type 1B	Definitive	Autosomal recessive
lethal arteriopathy syndrome due to fibulin-4 deficiency	Supportive	Autosomal recessive
autosomal recessive cutis laxa type 1	Supportive	Autosomal recessive
thoracic aortic aneurysm	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
cutis laxa, autosomal recessive, type 1B	Definitive	AR

Mondo (7): cutis laxa, autosomal recessive, type 1B (MONDO:0013754), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), cutis laxa (MONDO:0016175), cutis laxa, autosomal recessive, type 1A (MONDO:0009052), thoracic aortic aneurysm (MONDO:0005396), lethal arteriopathy syndrome due to fibulin-4 deficiency (MONDO:0017818), autosomal recessive cutis laxa type 1 (MONDO:0019572)

Orphanet (3): Autosomal recessive cutis laxa type 1 (Orphanet:90349), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Cutis laxa (Orphanet:209)

HPO phenotypes

119 total (30 of 119 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000023	Inguinal hernia
HP:0000076	Vesicoureteral reflux
HP:0000098	Tall stature
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000271	Abnormality of the face
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000414	Bulbous nose
HP:0000444	Convex nasal ridge
HP:0000494	Downslanted palpebral fissures
HP:0000520	Proptosis
HP:0000525	Abnormality iris morphology
HP:0000766	Abnormal sternum morphology
HP:0000767	Pectus excavatum
HP:0000776	Congenital diaphragmatic hernia
HP:0000822	Hypertension
HP:0000929	Abnormal skull morphology
HP:0000965	Cutis marmorata
HP:0000973	Cutis laxa
HP:0000977	Soft skin
HP:0000978	Bruising susceptibility
HP:0001166	Arachnodactyly
HP:0001252	Hypotonia
HP:0001270	Motor delay

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002481_8	Acne (severe)	3.000000e-11
GCST008362_125	Birth weight	2.000000e-08
GCST009959_26	Retinal detachment or retinal break	1.000000e-06
GCST010988_420	Adult body size	3.000000e-19
GCST010989_26	Body size at age 10	3.000000e-18
GCST90002393_432	Monocyte count	7.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0010698	retinal break
EFO:0009819	comparative body size at age 10, self-reported
EFO:0005091	monocyte count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D017545	Aortic Aneurysm, Thoracic	C14.907.055.239.125; C14.907.109.139.125
D003483	Cutis Laxa	C16.320.850.180; C17.300.230; C17.800.827.180
C562628	Cutis Laxa, Autosomal Recessive, Type I (supp.)
C536225	Cutis laxa, recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	6
Tretinoin	decreases expression, increases expression	3
Estradiol	increases expression, decreases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation	1
methylselenic acid	increases expression	1
trichostatin A	decreases expression	1
nickel chloride	increases expression	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
perfluorooctane sulfonic acid	decreases 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, decreases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cadmium	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00339053	PHASE4	UNKNOWN	Immunonutrition and Thoracoabdominal Aorta Aneurysm Repair
NCT02291718	PHASE4	COMPLETED	Thoracoabdominal Arortic CTA Study
NCT01033214	PHASE1	UNKNOWN	ENTRUST - TAArget® Thoracic Stent Graft Clinical Trial
NCT03998631	PHASE1	UNKNOWN	Comparison of Carbon Dioxide and Saline Flush to Saline Flush in TEVAR and TAVI Procedures to Reduce Cerebral Ischemia
NCT00604799	PHASE2/PHASE3	COMPLETED	VALOR: The Talent Thoracic Stent Graft System Clinical Study
NCT07483177	PHASE1/PHASE2	NOT_YET_RECRUITING	HEART: Pilot Randomized Controlled Trial
NCT00111176	Not specified	COMPLETED	STARZ-TX2 Clinical Study: Study of Thoracic Aortic Aneurysm Repair With the Zenith TX2 Endovascular Graft
NCT00413231	Not specified	COMPLETED	Valor II: The Valiant Thoracic Stent Graft System Clinical Study
NCT00435942	Not specified	COMPLETED	Phase II Study of the Safety and Efficacy of the Relay Thoracic Stent-Graft
NCT00549315	Not specified	UNKNOWN	Clinical Study of Thoracic Aortic Aneurysm Exclusion
NCT00583817	Not specified	ENROLLING_BY_INVITATION	Endovascular Treatment of Thoracic Aortic Disease
NCT00597870	Not specified	COMPLETED	Physician-Sponsored IDE for the Talent Endoluminal Stent Graft System for the Treatment of Thoracic Lesions
NCT00805948	Not specified	TERMINATED	Post-Approval Clinical Study of the Talent Thoracic Stent Graft to Treat Thoracic Aortic Aneurysms (THRIVE)
NCT01082172	Not specified	COMPLETED	South American Thoracic Stent-Graft Study
NCT01327742	Not specified	APPROVED_FOR_MARKETING	Phase II Clinical Study of the Safety and Efficacy of the Relay Thoracic Stent-Graft
NCT01390181	Not specified	TERMINATED	The Effect of Losartan in Bicuspid Aortic Valve Patients
NCT01480206	Not specified	COMPLETED	Overlay of 3D Scans on Live Fluoroscopy for Endovascular Procedures in the Hybrid OR
NCT01839695	Not specified	COMPLETED	Safety and Efficacy of Valiant Mona LSA Stent Graft System
NCT02010892	Not specified	UNKNOWN	Effective Treatments for Thoracic Aortic Aneurysms (ETTAA Study): A Prospective Cohort Study
NCT02164201	Not specified	COMPLETED	Post Market Surveillance Study Evaluating BioFoam Surgical Matrix in Cardiovascular Surgery
NCT02256163	Not specified	COMPLETED	Identification of Genes and Pathogenesis Involved in Familial Thoracic Aortic Aneurysm
NCT02365454	Not specified	COMPLETED	NEXUS™ Aortic Arch Stent Graft System First In Man Study
NCT02735720	Not specified	TERMINATED	The CardiOvascular Remodeling Following Endovascular Aortic Repair (CORE) Study
NCT03142074	Not specified	RECRUITING	Biomechanical and Microstructural Properties of Ascending Aortic Aneurysms
NCT03440697	Not specified	ACTIVE_NOT_RECRUITING	Pathogenetic Basis of Aortopathy and Aortic Valve Disease
NCT03824626	Not specified	UNKNOWN	Biomechanical Reappraisal of Planning for Thoracic Endovascular Aortic Repair
NCT04083118	Not specified	COMPLETED	Assessment of Risk in Thoracic Aortopathy Using 18F-Sodium Fluoride
NCT04100499	Not specified	UNKNOWN	Evaluation of Adjunctive EndoAnchors for EVAR and TEVAR
NCT04197648	Not specified	RECRUITING	Effects of Exercise on Thoracic Aneurysms
NCT04246463	Not specified	RECRUITING	Terumo Aortic Global Endovascular Registry
NCT04523909	Not specified	RECRUITING	Trajectory of Neuroinflammatory Markers in Cerebrospinal Fluid Prior to and After Thoracic Aortic Surgery
NCT04663074	Not specified	COMPLETED	Intravascular Ultrasound (IVUS) in Complex Aortic Endovascular Interventions
NCT04747626	Not specified	RECRUITING	B-SAFER: Branched Stented Anastomosis Frozen Elephant Trunk Repair
NCT04756778	Not specified	COMPLETED	Indexed Aortic Area in Bicuspid Aortic Valve Aortopathy
NCT05137366	Not specified	UNKNOWN	Transthoracic Ultrasound Evaluation of Thoracic Aortic Aneurysms
NCT05143138	Not specified	ACTIVE_NOT_RECRUITING	Real-World Data Collection of the GORE® VIABAHN® VBX Balloon Expandable Endoprosthesis When Used as a Bridging Stent With Branched and Fenestrated Endografts in the Treatment of Aortic Aneurysms Involving the Renal-Mesenteric Arteries
NCT05146375	Not specified	UNKNOWN	Genes Modulating the Severity of Aortic Aneurysms (MSF1-TGFBR2)
NCT05155956	Not specified	ACTIVE_NOT_RECRUITING	Cerebral Hemodynamics and Microemboli During Placement of Relay®Branch Thoracic Stent-Graft System
NCT05309707	Not specified	RECRUITING	ENDOBARC-S Study: Endovascular Branched Stent-grafts for Aortic ARCh Pathologies in Spain
NCT05395598	Not specified	RECRUITING	Incidence of Major Complication in Case of Thoracic Aortic Aneurysm