LTBP2

Summary

LTBP2 (latent transforming growth factor beta binding protein 2, HGNC:6715) is a protein-coding gene on chromosome 14q24.3, encoding Latent-transforming growth factor beta-binding protein 2 (Q14767). May play an integral structural role in elastic-fiber architectural organization and/or assembly.

The protein encoded by this gene belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. This protein is the largest member of the LTBP family possessing unique regions and with most similarity to the fibrillins. It has thus been suggested that it may have multiple functions: as a member of the TGF-beta latent complex, as a structural component of microfibrils, and a role in cell adhesion.

Source: NCBI Gene 4053 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glaucoma 3, primary congenital, D (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 3,286 total — 92 pathogenic, 53 likely-pathogenic
• MANE Select transcript: NM_000428

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6715
Approved symbol	LTBP2
Name	latent transforming growth factor beta binding protein 2
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000119681
Ensembl biotype	protein_coding
OMIM	602091
Entrez	4053

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000261978, ENST00000553939, ENST00000554861, ENST00000556206, ENST00000556690, ENST00000557425, ENST00000945197

RefSeq mRNA: 1 — MANE Select: NM_000428 NM_000428

CCDS: CCDS9831

Canonical transcript exons

ENST00000261978 — 36 exons

Exon	Start	End
ENSE00000808167	74503219	74503386
ENSE00000808168	74503469	74503606
ENSE00000808169	74503926	74504054
ENSE00000808170	74504778	74504861
ENSE00000808171	74504983	74505174
ENSE00000808172	74506048	74506191
ENSE00000808173	74506698	74506823
ENSE00000808174	74507179	74507310
ENSE00000808175	74507973	74508095
ENSE00000808176	74508604	74508729
ENSE00000808177	74508830	74508952
ENSE00000808178	74509238	74509363
ENSE00000808179	74509734	74509859
ENSE00000808180	74510091	74510213
ENSE00000808181	74511245	74511364
ENSE00000808191	74535926	74536000
ENSE00000808194	74552187	74552393
ENSE00000808195	74552892	74553062
ENSE00000808196	74555503	74555693
ENSE00000808197	74585854	74586118
ENSE00000808198	74603635	74603705
ENSE00000808199	74611451	74612237
ENSE00001097798	74516822	74516941
ENSE00001097800	74522790	74522918
ENSE00001097801	74528958	74529122
ENSE00001097802	74532426	74532548
ENSE00001097803	74527347	74527366
ENSE00001097805	74525124	74525225
ENSE00001097806	74521911	74522039
ENSE00001097809	74526075	74526114
ENSE00001310535	74498183	74501029
ENSE00001328221	74502653	74502934
ENSE00003468923	74528483	74528698
ENSE00003536505	74551064	74551350
ENSE00003543656	74549863	74549965
ENSE00003631662	74501441	74501590

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.8059 / max 133.5896, expressed in 922 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144065	6.6973	745
144064	3.2915	708
144063	3.2827	737
144066	1.0754	557
144043	0.7082	319
144062	0.5316	338
144067	0.3943	278
144061	0.3709	264
144057	0.3585	232
207293	0.2936	198

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
descending thoracic aorta	UBERON:0002345	99.08	gold quality
thoracic aorta	UBERON:0001515	99.01	gold quality
ascending aorta	UBERON:0001496	99.00	gold quality
stromal cell of endometrium	CL:0002255	98.80	gold quality
right coronary artery	UBERON:0001625	98.74	gold quality
tendon of biceps brachii	UBERON:0008188	98.32	gold quality
saphenous vein	UBERON:0007318	98.13	gold quality
aorta	UBERON:0000947	97.93	gold quality
pericardium	UBERON:0002407	97.65	gold quality
coronary artery	UBERON:0001621	97.34	gold quality
blood vessel layer	UBERON:0004797	97.28	gold quality
left coronary artery	UBERON:0001626	97.22	gold quality
popliteal artery	UBERON:0002250	97.17	gold quality
tibial artery	UBERON:0007610	97.16	gold quality
artery	UBERON:0001637	97.15	gold quality
hair follicle	UBERON:0002073	97.05	gold quality
tendon	UBERON:0000043	96.45	gold quality
visceral pleura	UBERON:0002401	96.11	gold quality
calcaneal tendon	UBERON:0003701	96.03	gold quality
right lobe of thyroid gland	UBERON:0001119	95.27	gold quality
thyroid gland	UBERON:0002046	95.19	gold quality
left lobe of thyroid gland	UBERON:0001120	95.16	gold quality
endocervix	UBERON:0000458	95.11	gold quality
mammary duct	UBERON:0001765	94.94	gold quality
periodontal ligament	UBERON:0008266	94.77	gold quality
urethra	UBERON:0000057	94.71	gold quality
synovial joint	UBERON:0002217	94.66	gold quality
epithelium of mammary gland	UBERON:0003244	94.54	gold quality
olfactory bulb	UBERON:0002264	94.09	silver quality
upper lobe of lung	UBERON:0008948	93.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-36	yes	1432.72
E-MTAB-11268	yes	1228.76
E-GEOD-135922	yes	61.18
E-GEOD-83139	yes	7.15
E-GEOD-130148	yes	4.25
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

129 targeting LTBP2, 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-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-5580-3P	99.70	69.41	2052

Literature-anchored findings (GeneRIF, showing 40)

• LTBP-2 can play a role in melanoma cell adhesion (PMID:12716902)
• LTBP-2 specifically interacts with the amino-terminal region of fibrillin-1 and competes with LTBP-1 (PMID:17293099)
• These results suggest a novel regulatory mechanism of elastic fiber assembly in which LTBP-2 regulates targeting of DANCE on suitable microfibrils to form elastic fibers. (PMID:17581631)
• LTBP2 is a novel positional candidate gene in chromosome 14q quantitative trait locos for bone density variation and fracture. (PMID:18697872)
• LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone. (PMID:19361779)
• Loss of function mutations in LTBP2 cause the congenital glaucoma. (PMID:19656777)
• Extracellular matrix association of LTBP-2 in cultured human embryonic lung fibroblasts depends on a pre-formed fibrillin-1 network. (PMID:19681046)
• Biallelic null LTBP2 mutations cause the ocular phenotype in both families and could lead to Marfan-like features in older children. (PMID:20179738)
• Study suggests a role for LTBP2 in the structural stability of ciliary zonules, and growth and development of lens. (PMID:20617341)
• The authors reported that the isolated microspherophakia (MIM 251750) is caused by a mutation in the LTBP2 gene. The results suggested a role for LTBP2 in the growth and development of lens, and structural stability of ciliary zonules. (PMID:20617341)
• A susceptibility locus was identified on chromosome 14q24.3-31.2. The candidate functional gene is LTBP2. A suggestive linkage for mandibular prognathism in a Han Chinese pedigree. (PMID:21041550)
• Preliminary observations on compounds with mutations in both CYP1B1-LTBP2 suggest that the observed combinations are of no clinical significance and digenic inheritance is unlikely. (PMID:21081970)
• Demonstrate specific immunolocalization of fibrillin-1, MAGP-1, and LTBP-1 with elastin in the outer annulus fibrosus of the fetal human intravertebral disc. (PMID:21540769)
• A proteomic approach for identification and localization of the pericellular components of chondrocytes (PMID:21698479)
• Latent transforming growth factor beta-binding proteins-2 and -3 inhibit the proprotein convertase 5/6A. (PMID:21700711)
• This study provided evidence that the IL-17A-197 G/A and TGFR-beta2-875 A/G genotype is closely related to hemorrhage risk for patients with brain arteriovenous malformation. (PMID:21737283)
• Novel homozygous mutations in the LTBP-2 gene segregated with the phenotype in each affected consanguineous family cause congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma. (PMID:22025892)
• Data show that median level of latent TGF-beta binding protein (LTBP) in myocardial samples from heart failure patients was significantly elevated. (PMID:22515403)
• LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. (PMID:22539340)
• plasma levels of LTBP2 present a novel and powerful predictor of all-cause mortality, and particularly pulmonary death (PMID:22587491)
• Promoter hypermethylation was found to be involved in LTBP-2 silencing. (PMID:22743615)
• LTBP-2, in response to tension stress, may negatively control the function of fibulin-5, thereby modulating the mechanism of oxytalan fiber coalescence. (PMID:22827404)
• LTBP2 mutations were not found in the Turkish GLC3C-linked primary congenital glaucoma (PCG) family or in 94 British CYP1B1-negative PCG cases. (PMID:22924778)
• This study analyzed CYP1B1, LTBP2, and MYOC mutations in a cohort of primary congenital glaucoma patients from the United States, applying whole exome sequencing (PMID:23218701)
• No pathogenic variants are identified in the LTBP2 gene in a cohort of patients with primary congenital glaucoma. (PMID:23378721)
• Some LTBP2 sequence variations can contribute to the etiology of primary open angle glaucoma (POAG) and pseudoexfoliation (PEX) glaucoma syndrome. (PMID:23401661)
• Overall the results indicate that LTBP-2 may have a negative regulatory role during elastic fiber assembly, perhaps in displacing elastin microassemblies from complexes with fibulin-5 and/or cell surface heparan sulfate proteoglycans. (PMID:24148803)
• Increased plasma levels of LTBP2 and/or OPN are present in plasma up to 2 years prior to diagnosis of hepatocellular carcinoma. (PMID:24803312)
• perlecan HS was not essential for latent transforming growth factor-beta-1 binding protein-2 deposition (PMID:24867584)
• LTBP-2 is an essential component for the formation of microfibril bundles in ciliary zonules. (PMID:24908666)
• LTBP-1 and LTBP-2 are involved in the keratinization of oral epithelium. (PMID:25858550)
• LTBP2 was able to reduce phosphorylation of p65 at Serine 536, inhibit nuclear localization of active phosphorylated p65, and impair the p65 DNA-binding ability. This results in a consequential down-regulation of p65-related gene expression. (PMID:25974126)
• LTBP-2 is a potent inhibitor of FGF-2 that may influence FGF-2 bioactivity during wound repair particularly in fibrotic tissues. (PMID:26263555)
• LTBP-2 and FGF-2 are co-localized in fibrotic human keloid and hypertrophic scar. (PMID:26644005)
• Our data suggest that LTBP2 acts as an oncogene in head and neck squamous cell carcinoma development and progression (PMID:27281608)
• The results showed that no deleterious mutations were found in coding regions of LTBP2 in patients with PCG, suggesting that it is not a causal gene for primary congenital glaucoma in the Han Chinese population. (PMID:27293371)
• knockdown of LTBP2 inhibits invasion and tumorigenesis in thyroid carcinoma cells. (PMID:27712597)
• We identified one nonsense mutation (c.2421G>A, p.W807X) in LTBP2 in eight Indian families. Among the mutations identified W807X in LTBP2 represent novel mutations. (PMID:28384041)
• LTBP2 is a novel biomarker for the diagnosis of pancreatic cancer. (PMID:28669978)
• Study describes the first case of a microspherophakia phenotype associated with a novel homozygous mutation in the LTBP2 gene in a consanguineous Caucasian family. The insertion of an adenine in exon 36 of the LTBP2 gene (c.5439_5440insA) was associated with pathogenicity. (PMID:29751740)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ltbp2	ENSMUSG00000002020
rattus_norvegicus	Ltbp2	ENSRNOG00000012094

Paralogs (3): LTBP1 (ENSG00000049323), LTBP4 (ENSG00000090006), LTBP3 (ENSG00000168056)

Protein

Protein identifiers

Latent-transforming growth factor beta-binding protein 2 — Q14767 (reviewed: Q14767)

All UniProt accessions (4): Q14767, G3V3X5, G3V511, H0YJ20

UniProt curated annotations — full annotation on UniProt →

Function. May play an integral structural role in elastic-fiber architectural organization and/or assembly.

Subunit / interactions. Forms part of the large latent transforming growth factor beta precursor complex; removal is essential for activation of complex. Interacts with SDC4. Interacts (via C-terminal domain) with FBN1 (via N-terminal domain) in a Ca(+2)-dependent manner.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in the aorta (at protein level). Expressed in lung, weakly expressed in heart, placenta, liver and skeletal muscle.

Post-translational modifications. N-Glycosylated. Contains hydroxylated asparagine residues.

Disease relevance. Glaucoma 3, primary congenital, D (GLC3D) [MIM:613086] An autosomal recessive form of primary congenital glaucoma (PCG). PCG is characterized by marked increase of intraocular pressure at birth or early childhood, large ocular globes (buphthalmos) and corneal edema. It results from developmental defects of the trabecular meshwork and anterior chamber angle of the eye that prevent adequate drainage of aqueous humor. The disease is caused by variants affecting the gene represented in this entry. Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma (MSPKA) [MIM:251750] A rare disease characterized by smaller and more spherical lenses than normal bilaterally, an increased anteroposterior thickness of the lens, and highly myopic eyes. Lens dislocation or subluxation may occur, leading to defective accommodation. The disease is caused by variants affecting the gene represented in this entry. Weill-Marchesani syndrome 3 (WMS3) [MIM:614819] A rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and eye abnormalities including microspherophakia, ectopia lentis, severe myopia and glaucoma. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the LTBP family.

RefSeq proteins (1): NP_000419* (*=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
IPR017878	TB_dom	Domain
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR036773	TB_dom_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain
IPR050751	ECM_structural_protein	Family

Pfam: PF00008, PF00683, PF07645

UniProt features (135 total): disulfide bond 75, domain 24, glycosylation site 9, region of interest 8, compositionally biased region 6, sequence variant 4, sequence conflict 3, signal peptide 1, chain 1, mutagenesis site 1, short sequence motif 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14767-F1	58.33	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.

Ligand- & substrate-binding residues (1): 344–354

Post-translational modifications (1): 506

Disulfide bonds (75): 1289–1301, 1307–1319, 1313–1328, 1330–1343, 1349–1361, 1356–1370, 1372–1386, 1413–1436, 1423–1448, 1437–1451, 1438–1463, 1489–1502, 1497–1511, 1513–1526, 1532–1542, 1537–1551, 1553–1566, 1586–1609, 1595–1621, 1610–1624 …

Glycosylation sites (9): 181, 343, 421, 616, 811, 1170, 1309, 1430, 1568

Mutagenesis-validated functional residues (1):

Position	Phenotype
1449–1450	gain-of-function. forms a complex with tgfb1.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2129379	Molecules associated with elastic fibres
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-1474244	Extracellular matrix organization
R-HSA-1566948	Elastic fibre formation
R-HSA-162582	Signal Transduction
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 735 (showing top): RNGTGGGC_UNKNOWN, MODULE_92, BENPORATH_ES_WITH_H3K27ME3, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_PROTEIN_TARGETING, TGACCTY_ERR1_Q2, CHX10_01, chr11q13, HUMMERICH_SKIN_CANCER_PROGRESSION_DN

GO Biological Process (5): protein targeting (GO:0006605), transforming growth factor beta receptor signaling pathway (GO:0007179), protein secretion (GO:0009306), supramolecular fiber organization (GO:0097435), establishment of protein localization to extracellular region (GO:0035592)

GO Molecular Function (6): calcium ion binding (GO:0005509), heparin binding (GO:0008201), growth factor binding (GO:0019838), microfibril binding (GO:0050436), extracellular matrix structural constituent (GO:0005201), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Elastic fibre formation	1
Signaling by TGF-beta Receptor Complex	1
Extracellular matrix organization	1
Signaling by TGFB family members	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
establishment of protein localization	2
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
cellular component organization	1
metal ion binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
protein binding	1
extracellular matrix binding	1
structural molecule activity	1
extracellular matrix	1
binding	1
cellular anatomical structure	1
external encapsulating structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

2541 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LTBP2	TGFB1	P01137	954
LTBP2	TGFB2	P08112	936
LTBP2	MSTN	O14793	855
LTBP2	FBN1	P35555	842
LTBP2	LOXL1	Q08397	823
LTBP2	FBLN5	Q9UBX5	809
LTBP2	CYP1B1	Q16678	788
LTBP2	ADAMTS10	Q9H324	787
LTBP2	WNT10A	Q9GZT5	741
LTBP2	TGFB3	P10600	713
LTBP2	PAX9	P55771	700
LTBP2	CLU	P10909	699
LTBP2	ELN	P15502	695
LTBP2	WDR36	Q8NI36	667
LTBP2	MYOC	Q99972	658

IntAct

32 interactions, top by confidence:

A	B	Type	Score
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
ZNF764	ZNF316	psi-mi:“MI:0914”(association)	0.640
LTBP2	FBLN5	psi-mi:“MI:0915”(physical association)	0.560
EGFL8	MPO	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
FOXD4	PPP2R1B	psi-mi:“MI:0914”(association)	0.530
EDN3	MGRN1	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
ZNF785	TRIO	psi-mi:“MI:0914”(association)	0.530
LTBP2	ABL1	psi-mi:“MI:0915”(physical association)	0.400
LTBP2	FYN	psi-mi:“MI:0915”(physical association)	0.400
LTBP2	ZNF320	psi-mi:“MI:0914”(association)	0.350
CER1	PC	psi-mi:“MI:0914”(association)	0.350
DEFA5	PDE2A	psi-mi:“MI:0914”(association)	0.350
EGFL7	LAMA5	psi-mi:“MI:0914”(association)	0.350
EMID1	NDUFS4	psi-mi:“MI:0914”(association)	0.350
FBLN2	AURKA	psi-mi:“MI:0914”(association)	0.350
FBLN5	CYTH3	psi-mi:“MI:0914”(association)	0.350
FBXO6	TMEM131L	psi-mi:“MI:0914”(association)	0.350
FRMD1	TRIM37	psi-mi:“MI:0914”(association)	0.350
MRPS12	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
NTN5	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
PATE1	AGRN	psi-mi:“MI:0914”(association)	0.350
PRG2	RB1	psi-mi:“MI:0914”(association)	0.350
PRG3	IGLL5	psi-mi:“MI:0914”(association)	0.350
RNASE3	RNASEH1	psi-mi:“MI:0914”(association)	0.350
WNT10B	VWA8	psi-mi:“MI:0914”(association)	0.350
WNT3A	LRP5	psi-mi:“MI:0914”(association)	0.350
WNT9A	ZSWIM8	psi-mi:“MI:0914”(association)	0.350

BioGRID (85): MCCC1 (Co-fractionation), RPL10 (Affinity Capture-MS), NUFIP2 (Affinity Capture-MS), ZNF12 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), ZNF282 (Affinity Capture-MS), SENP5 (Affinity Capture-MS), ZNF92 (Affinity Capture-MS), FBN2 (Affinity Capture-MS), ZNF316 (Affinity Capture-MS), ZNF77 (Affinity Capture-MS), ZNF768 (Affinity Capture-MS), RBAK (Affinity Capture-MS), ZNF57 (Affinity Capture-MS), ZNF664 (Affinity Capture-MS)

ESM2 similar proteins: A1L0T3, A1L4H1, A6QNY1, D3YZF7, O95428, P28698, P30203, P55068, P55106, P59222, P98162, Q04756, Q14767, Q28019, Q28062, Q28256, Q28343, Q28670, Q3U515, Q4G0T1, Q5F378, Q5HZW5, Q61003, Q61361, Q6H9L7, Q6KF10, Q6PGE4, Q6QNF4, Q7TQH7, Q7Z4F1, Q86T13, Q86VR7, Q86VZ4, Q8BV57, Q8BZE1, Q8CB67, Q8VCP9, Q8WTU2, Q91V98, Q96DN2

Diamond homologs: A0A1D5NSM8, A1A5Y0, A2AVA0, A2VCU8, A5A8Y8, B8JI71, O08999, O35806, O75095, P0C6B8, P10040, P25723, P41990, P98118, Q00918, Q08761, Q09165, Q14393, Q14766, Q14767, Q28019, Q2VWQ2, Q4LDE5, Q5RBP1, Q61592, Q62919, Q63772, Q6AZ60, Q6GUQ1, Q6MG84, Q6UXI9, Q75N90, Q7ZXL5, Q8AVH7, Q8CG19, Q8IUX8, Q8NDA2, Q91V88, Q92832, Q99944

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
LTBP2	“up-regulates activity”	FBN1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

3286 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	92
Likely pathogenic	53
Uncertain significance	1496
Likely benign	1299
Benign	134

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032352	NM_000428.3(LTBP2):c.2931del (p.Gly978fs)	Pathogenic
126952	NM_000428.3(LTBP2):c.1642C>T (p.Arg548Ter)	Pathogenic
126959	NM_000428.3(LTBP2):c.5376del (p.Cys1793fs)	Pathogenic
1327506	NM_001130144.3(LTBP3):c.2017G>T (p.Gly673Cys)	Pathogenic
1327507	NM_001130144.3(LTBP3):c.1721-2A>G	Pathogenic
1387276	NM_001130144.3(LTBP3):c.536_537del (p.Val179fs)	Pathogenic
1416583	NM_000428.3(LTBP2):c.972del (p.Asp325fs)	Pathogenic
1417406	NM_001130144.3(LTBP3):c.1735C>T (p.Arg579Ter)	Pathogenic
1418711	NM_000428.3(LTBP2):c.2327del (p.Val776fs)	Pathogenic
1441073	NM_001130144.3(LTBP3):c.932G>A (p.Trp311Ter)	Pathogenic
1445505	NM_001130144.3(LTBP3):c.2542dup (p.Tyr848fs)	Pathogenic
1451121	NM_000428.3(LTBP2):c.304G>T (p.Glu102Ter)	Pathogenic
1451240	NM_000428.3(LTBP2):c.1107_1108del (p.Ala370fs)	Pathogenic
1452054	NM_001130144.3(LTBP3):c.1160_1161insGTGT (p.Gly388fs)	Pathogenic
1452258	NM_000428.3(LTBP2):c.744del (p.Ser249fs)	Pathogenic
1455225	NM_000428.3(LTBP2):c.3856_3857del (p.Val1286fs)	Pathogenic
1722765	NM_001130144.3(LTBP3):c.3629-1G>T	Pathogenic
1909521	NM_000428.3(LTBP2):c.112del (p.Asp38fs)	Pathogenic
1925448	NM_000428.3(LTBP2):c.3776-1G>C	Pathogenic
1950571	NM_001130144.3(LTBP3):c.1854_1860dup (p.Glu621fs)	Pathogenic
1975426	NM_000428.3(LTBP2):c.4869del (p.Cys1624fs)	Pathogenic
1982594	NM_000428.3(LTBP2):c.4667dup (p.Leu1557fs)	Pathogenic
1994635	NM_000428.3(LTBP2):c.3833_3840dup (p.Gly1281fs)	Pathogenic
2005613	NM_001130144.3(LTBP3):c.2821G>T (p.Glu941Ter)	Pathogenic
2009579	NM_001130144.3(LTBP3):c.1483del (p.Glu495fs)	Pathogenic
2015794	NM_000428.3(LTBP2):c.129C>G (p.Tyr43Ter)	Pathogenic
2022494	NM_001130144.3(LTBP3):c.1569del (p.Val524fs)	Pathogenic
2026372	NM_001130144.3(LTBP3):c.2553_2554del (p.Cys852fs)	Pathogenic
2033728	NM_000428.3(LTBP2):c.3509del (p.Asn1170fs)	Pathogenic
2035901	NM_001130144.3(LTBP3):c.3615dup (p.Lys1206fs)	Pathogenic

SpliceAI

10440 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65539238:G:GC	acceptor_gain	1.0000
11:65539326:A:AC	donor_gain	1.0000
11:65539327:C:CC	donor_gain	1.0000
11:65539327:CCCA:C	donor_gain	1.0000
11:65539460:C:CC	acceptor_gain	1.0000
11:65539470:C:CT	acceptor_gain	1.0000
11:65539543:CTCA:C	donor_loss	1.0000
11:65539544:TCACC:T	donor_loss	1.0000
11:65539545:CA:C	donor_loss	1.0000
11:65539546:A:AC	donor_gain	1.0000
11:65539547:C:CA	donor_loss	1.0000
11:65539547:C:CC	donor_gain	1.0000
11:65539547:CCT:C	donor_gain	1.0000
11:65539627:CC:C	acceptor_gain	1.0000
11:65539628:CC:C	acceptor_gain	1.0000
11:65539628:CCTGG:C	acceptor_loss	1.0000
11:65539629:C:CA	acceptor_loss	1.0000
11:65539629:C:CC	acceptor_gain	1.0000
11:65539629:C:T	acceptor_gain	1.0000
11:65539630:T:A	acceptor_loss	1.0000
11:65539714:CCTTA:C	donor_loss	1.0000
11:65539715:CTTA:C	donor_loss	1.0000
11:65539716:TTA:T	donor_loss	1.0000
11:65539717:TACCC:T	donor_loss	1.0000
11:65539718:A:AC	donor_gain	1.0000
11:65539718:A:AG	donor_loss	1.0000
11:65539718:AC:A	donor_gain	1.0000
11:65539719:C:CC	donor_gain	1.0000
11:65539719:CC:C	donor_gain	1.0000
11:65539719:CCCG:C	donor_gain	1.0000

AlphaMissense

11902 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:74603669:C:A	W177C	1.000
14:74603669:C:G	W177C	1.000
14:74503256:C:A	W1617C	0.999
14:74503256:C:G	W1617C	0.999
14:74503346:C:A	W1587C	0.999
14:74503346:C:G	W1587C	0.999
14:74586031:C:G	C218S	0.999
14:74586032:A:T	C218S	0.999
14:74528995:C:A	W705C	0.998
14:74528995:C:G	W705C	0.998
14:74501518:C:G	C1748S	0.997
14:74501519:A:T	C1748S	0.997
14:74502916:C:G	C1636S	0.997
14:74502917:A:T	C1636S	0.997
14:74503236:C:G	C1624S	0.997
14:74503237:A:T	C1624S	0.997
14:74503282:A:G	C1609R	0.997
14:74503323:C:G	C1595S	0.997
14:74503324:A:T	C1595S	0.997
14:74503564:C:G	C1542S	0.997
14:74503565:A:T	C1542S	0.997
14:74529088:G:C	C674W	0.997
14:74529089:C:G	C674S	0.997
14:74529090:A:G	C674R	0.997
14:74529090:A:T	C674S	0.997
14:74586032:A:G	C218R	0.997
14:74603643:C:G	C186S	0.997
14:74603644:A:T	C186S	0.997
14:74503237:A:G	C1624R	0.996
14:74503277:G:C	C1610W	0.996

dbSNP variants (sampled 300 via entrez): RS1000014604 (14:74558074 G>A), RS1000036288 (14:74533752 C>T), RS1000053715 (14:74586770 C>T), RS1000147693 (14:74541190 C>T), RS1000163196 (14:74508474 C>G), RS1000210520 (14:74582820 C>A), RS1000215988 (14:74540330 G>A,T), RS1000238644 (14:74570507 G>A), RS1000261555 (14:74585075 A>G), RS1000315853 (14:74505324 C>A,T), RS1000325577 (14:74505071 C>A,T), RS1000368523 (14:74589303 C>A,T), RS1000373027 (14:74553126 C>G,T), RS1000408721 (14:74534015 C>T), RS1000442075 (14:74554868 C>G)

Disease associations

OMIM: gene MIM:602091 | disease phenotypes: MIM:601216, MIM:617809, MIM:613086, MIM:614819, MIM:154700, MIM:251750, MIM:277600, MIM:137760, MIM:129600, MIM:600975, MIM:231300, MIM:231050, MIM:104500

GenCC curated gene-disease

Disease	Classification	Inheritance
microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma	Definitive	Autosomal recessive
brachyolmia-amelogenesis imperfecta syndrome	Definitive	Autosomal recessive
geleophysic dysplasia 3	Strong	Autosomal dominant
glaucoma 3, primary congenital, D	Strong	Autosomal recessive
Weill-Marchesani syndrome 3	Moderate	Autosomal recessive
glaucoma secondary to spherophakia/ectopia lentis and megalocornea	Supportive	Autosomal recessive
Weill-Marchesani syndrome	Supportive	Autosomal dominant
congenital glaucoma	Supportive	Autosomal dominant
geleophysic dysplasia	Supportive	Autosomal dominant
Acromicric dysplasia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
glaucoma 3, primary congenital, D	Definitive	AR

Mondo (22): brachyolmia-amelogenesis imperfecta syndrome (MONDO:0011018), geleophysic dysplasia 3 (MONDO:0054722), glaucoma 3, primary congenital, D (MONDO:0013122), Weill-Marchesani syndrome 3 (MONDO:0013899), Marfan syndrome (MONDO:0007947), exfoliation syndrome (MONDO:0008327), microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma (MONDO:0009633), Weill-Marchesani syndrome (MONDO:0018096), OPTN-related open angle glaucoma (MONDO:0100553), ectopia lentis 1, isolated, autosomal dominant (MONDO:0007514), glaucoma 3, primary infantile, B (MONDO:0010968), glaucoma 3A (MONDO:0009277), geleophysic dysplasia 1 (MONDO:0009269), intellectual disability (MONDO:0001071), amelogenesis imperfecta (MONDO:0019507)

Orphanet (12): Brachyolmia-amelogenesis imperfecta syndrome (Orphanet:2899), Congenital glaucoma (Orphanet:98976), Weill-Marchesani syndrome (Orphanet:3449), Marfan syndrome type 1 (Orphanet:284963), Marfan syndrome (Orphanet:558), Glaucoma secondary to spherophakia/ectopia lentis and megalocornea (Orphanet:238763), Isolated ectopia lentis (Orphanet:1885), Juvenile glaucoma (Orphanet:98977), Geleophysic dysplasia (Orphanet:2623), Amelogenesis imperfecta (Orphanet:88661), NON RARE IN EUROPE: Exfoliation syndrome (Orphanet:529819), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000766_7	Non-alcoholic fatty liver disease histology (lobular)	9.000000e-07
GCST001791_43	Urate levels	3.000000e-13
GCST002481_8	Acne (severe)	3.000000e-11
GCST006926_4	Osteoarthritis (hip)	8.000000e-10
GCST006979_800	Heel bone mineral density	7.000000e-26
GCST009724_77	Vertical cup-disc ratio (multi-trait analysis)	1.000000e-25
GCST010002_240	Refractive error	3.000000e-11
GCST90002381_513	Eosinophil count	4.000000e-10
GCST90002388_541	Lymphocyte count	2.000000e-10
GCST90011900_69	Serum alkaline phosphatase levels	8.000000e-09
GCST90020028_1998	Hip circumference adjusted for BMI	5.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0006939	cup-to-disc ratio measurement
EFO:0004842	eosinophil count
EFO:0004587	lymphocyte count
EFO:0004533	alkaline phosphatase measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D000567	Amelogenesis Imperfecta	C07.650.800.295.250; C07.793.700.295.250; C16.131.850.800.295.250
D017889	Exfoliation Syndrome	C11.941.375.285
D006871	Hydrophthalmos	C11.250.480; C11.525.381.407.480; C16.131.384.480; C16.614.438
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008382	Marfan Syndrome	C05.116.099.674; C14.240.400.725; C14.280.400.725; C16.131.077.550; C16.131.240.400.720; C16.320.540; C17.300.500
D056846	Weill-Marchesani Syndrome	C05.116.099.343.957; C11.270.921; C16.131.077.941; C16.320.290.842; C17.300.899
C535662	Acromicric dysplasia (supp.)
C567765	Glaucoma 3, Primary Congenital, D (supp.)
C536824	Glaucoma 3, primary infantile, B (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Doxorubicin	decreases expression, affects response to substance	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
Cadmium Chloride	increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
sotorasib	affects cotreatment, decreases expression	1
deoxynivalenol	decreases expression	1
lead acetate	increases expression	1
titanium dioxide	decreases methylation, increases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
seocalcitol	increases expression	1
chloropicrin	decreases expression	1
entinostat	increases expression	1
monomethylarsonous acid	decreases expression	1
dimethylarsinous acid	decreases expression	1
bisphenol B	increases expression	1
NSC 689534	increases expression, affects binding	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01295047	PHASE4	COMPLETED	Comparison of Medical Therapies in Marfan Syndrome.
NCT00273442	PHASE4	COMPLETED	Assessing Cosopt Switch Patients
NCT07228221	PHASE4	RECRUITING	Standalone iStent Infinite and iDose TR for Management of Moderate to Severe Open Angle Glaucoma
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00429364	PHASE3	COMPLETED	Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome
NCT00485368	PHASE3	COMPLETED	Angiotensin Converting Enzyme Inhibitors in Marfan Syndrome
NCT00683124	PHASE3	UNKNOWN	Nebivolol Versus Losartan Versus Nebivolol+Losartan Against Aortic Root Dilation in Genotyped Marfan Patients
NCT00723801	PHASE3	COMPLETED	Effects of Losartan Versus Atenolol on Aortic and Cardiac Muscle Stiffness in Adults With Marfan Syndrome
NCT00763893	PHASE3	TERMINATED	Study of the Efficacy of Losartan on Aortic Dilatation in Patients With Marfan Syndrome
NCT00782327	PHASE3	COMPLETED	Randomized, Double-blind Study for the Evaluation of the Effect of Losartan Versus Placebo on Aortic Root Dilatation in Patients With Marfan Syndrome Under Treatment With Beta-blockers
NCT01145612	PHASE3	UNKNOWN	Atenolol Versus Losartan in the Prevention of Progressive Dilation of the Aorta in Marfan Syndrome
NCT01361087	PHASE3	WITHDRAWN	Circulating Transforming Growth Factor Beta (TGF-β) in Individuals With Marfan Syndrome
NCT01715207	PHASE3	COMPLETED	Comparison of Aliskiren vs Negative Controls on Aortic Stiffness in Patients With MFS
NCT00331240	PHASE3	COMPLETED	24-Hour Intraocular Pressure (IOP) Control With Travoprost/Timolol Fixed Combination
NCT01126203	PHASE3	COMPLETED	Randomized Prospective Study of Selective Laser Trabeculoplasty (SLT) Versus Argon Trabeculoplasty (ALT) in Patients With Pseudoexfoliation Glaucoma and Ocular Hypertension
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT04947124	PHASE2	COMPLETED	A Study to Determine the Safety and Tolerability of 2 Concentrations of QLS-101
NCT00593710	PHASE2	COMPLETED	Losartan Versus Atenolol for the Treatment of Marfan Syndrome
NCT00651235	PHASE2	UNKNOWN	A Randomized, Open-label, LOSARTAN Therapy on the Progression of Aortic Root Dilation in Patients With Marfan Syndrome
NCT01949233	PHASE2	UNKNOWN	The Oxford Marfan Trial
NCT01936389	PHASE2	COMPLETED	A Prospective Study to Assess the Hypotensive Efficacy of Rho-Kinase Inhibitor AR-12286 Ophthalmic Solution 0.5% and 0.7% in Patients With Exfoliation Syndrome and Ocular Hypertension or Glaucoma
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01460017	PHASE1	UNKNOWN	Comparison Between Deep Sclerectomy and Traditional Trabeculotomy & Trabeculectomy in Congenital Glaucoma
NCT02121171	PHASE1	UNKNOWN	Combined Trab+Trab Versus Combined Trab+Trab With Subconjunctival Implantation of Ologen for Primary Congenital Glaucoma
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01020721	Not specified	UNKNOWN	The Genetic Characteristics in South Korean Patients With Primary Congenital Glaucoma
NCT01136460	Not specified	UNKNOWN	Genetic Testing in Primary Congenital Glaucoma Patients
NCT02945176	Not specified	COMPLETED	Safety and Performance Study of the ARGOS-IO System in Patients Undergoing Boston Keratoprosthesis Implantation
NCT03077789	Not specified	COMPLETED	Prospective Study of the Diagnostic and Therapeutic Management of Congenital Glaucoma in France
NCT03541551	Not specified	COMPLETED	Ologen® Collagen Matrix in Patients With Primary Congenital Glaucoma Undergoing Trabeculectomy