LTBP4

Summary

LTBP4 (latent transforming growth factor beta binding protein 4, HGNC:6717) is a protein-coding gene on chromosome 19q13.2, encoding Latent-transforming growth factor beta-binding protein 4 (Q8N2S1). Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space.

The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8425 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (Strong, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 1,300 total — 42 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 66
• MANE Select transcript: NM_001042545

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6717
Approved symbol	LTBP4
Name	latent transforming growth factor beta binding protein 4
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	LTBP-4, LTBP-4L, FLJ46318, FLJ90018
Ensembl gene	ENSG00000090006
Ensembl biotype	protein_coding
OMIM	604710
Entrez	8425

Gene structure

Transcript identifiers

Ensembl transcripts: 57 — 31 protein_coding, 22 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000204005, ENST00000243562, ENST00000308370, ENST00000318809, ENST00000396819, ENST00000546155, ENST00000593463, ENST00000593738, ENST00000594116, ENST00000594448, ENST00000594537, ENST00000595118, ENST00000595529, ENST00000595665, ENST00000596351, ENST00000597071, ENST00000597151, ENST00000597816, ENST00000598055, ENST00000598166, ENST00000598178, ENST00000598256, ENST00000598717, ENST00000599016, ENST00000599225, ENST00000599724, ENST00000600026, ENST00000600499, ENST00000601032, ENST00000601464, ENST00000602251, ENST00000610893, ENST00000612121, ENST00000612845, ENST00000617753, ENST00000618486, ENST00000622107, ENST00000622457, ENST00000622565, ENST00000908834, ENST00000908835, ENST00000908836, ENST00000908837, ENST00000908838, ENST00000908839, ENST00000908840, ENST00000969220, ENST00000969221, ENST00000969222, ENST00000969223, ENST00000969224, ENST00000969225, ENST00000969226, ENST00000969227, ENST00000969228, ENST00000969229, ENST00000969230

RefSeq mRNA: 3 — MANE Select: NM_001042545 NM_001042544, NM_001042545, NM_003573

CCDS: CCDS74368, CCDS74369, CCDS74370

Canonical transcript exons

ENST00000396819 — 30 exons

Exon	Start	End
ENSE00001138476	40617100	40617225
ENSE00003470864	40613065	40613196
ENSE00003471886	40616889	40617020
ENSE00003473771	40605405	40605652
ENSE00003479348	40622950	40623021
ENSE00003489371	40611152	40611394
ENSE00003502560	40613404	40613529
ENSE00003515432	40623604	40623732
ENSE00003525928	40608484	40608603
ENSE00003551867	40610532	40610657
ENSE00003555942	40612073	40612192
ENSE00003559698	40607365	40607529
ENSE00003560886	40626975	40627355
ENSE00003567471	40614315	40614446
ENSE00003575948	40605729	40605831
ENSE00003592264	40622401	40622667
ENSE00003603179	40609530	40609661
ENSE00003611456	40613916	40614038
ENSE00003613822	40608220	40608369
ENSE00003616156	40623936	40624082
ENSE00003618558	40605035	40605226
ENSE00003632322	40619347	40619493
ENSE00003647476	40611859	40611984
ENSE00003650113	40601369	40601637
ENSE00003652849	40609746	40609871
ENSE00003670911	40606233	40606307
ENSE00003677086	40606404	40606526
ENSE00003691115	40625857	40626009
ENSE00003738788	40627705	40627857
ENSE00003902211	40629396	40629818

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 99.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.2962 / max 704.9835, expressed in 1778 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175877	13.2237	1497
175866	11.6937	977
175862	5.5514	947
175869	3.8319	832
175873	3.5834	1071
175875	2.3821	1142
175876	1.3863	754
175874	1.1825	680
175864	1.1680	395
175865	0.9372	240

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nerve	UBERON:0001021	99.61	gold quality
tibial nerve	UBERON:0001323	99.61	gold quality
right coronary artery	UBERON:0001625	99.54	gold quality
ascending aorta	UBERON:0001496	99.50	gold quality
thoracic aorta	UBERON:0001515	99.50	gold quality
descending thoracic aorta	UBERON:0002345	99.49	gold quality
left ovary	UBERON:0002119	99.43	gold quality
body of uterus	UBERON:0009853	99.42	gold quality
endocervix	UBERON:0000458	99.41	gold quality
left coronary artery	UBERON:0001626	99.36	gold quality
right ovary	UBERON:0002118	99.34	gold quality
coronary artery	UBERON:0001621	99.30	gold quality
mucosa of stomach	UBERON:0001199	99.26	gold quality
ectocervix	UBERON:0012249	99.19	gold quality
left uterine tube	UBERON:0001303	99.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.16	gold quality
right atrium auricular region	UBERON:0006631	99.15	gold quality
aorta	UBERON:0000947	99.14	gold quality
right lung	UBERON:0002167	99.10	gold quality
apex of heart	UBERON:0002098	99.09	gold quality
sural nerve	UBERON:0015488	99.04	gold quality
left lobe of thyroid gland	UBERON:0001120	98.99	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.97	gold quality
lower esophagus	UBERON:0013473	98.96	gold quality
popliteal artery	UBERON:0002250	98.90	gold quality
tibial artery	UBERON:0007610	98.90	gold quality
right lobe of thyroid gland	UBERON:0001119	98.88	gold quality
upper lobe of left lung	UBERON:0008952	98.83	gold quality
colonic epithelium	UBERON:0000397	98.82	gold quality
lower esophagus mucosa	UBERON:0035834	98.64	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	1824.73
E-HCAD-36	yes	989.43
E-MTAB-10287	yes	496.32
E-MTAB-8410	yes	70.50
E-CURD-114	yes	66.52
E-HCAD-10	yes	31.04
E-CURD-46	yes	26.73
E-GEOD-135922	yes	21.56
E-MTAB-9543	yes	18.09
E-MTAB-8142	yes	12.17
E-MTAB-10137	yes	5.26
E-MTAB-10553	yes	5.07
E-MTAB-8381	no	632.43
E-MTAB-10662	no	441.95
E-MTAB-6379	no	95.89

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, GATA1, SMAD3, SP1

miRNA regulators (miRDB)

6 targeting LTBP4, 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-3163	100.00	77.23	8605
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-876-3P	98.76	68.23	945
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6802-5P	94.94	65.95	366

Literature-anchored findings (GeneRIF, showing 31)

• Extracellular matrix is an important site of deposition for LTBP-3 and LTBP-4. (PMID:16157329)
• Our findings suggest that variations in or near the HPN and LTBP4 genes do not play a role in the susceptibility to IA in the Dutch population. (PMID:18487557)
• Novel functions for LTBP-4 as an adhesion molecule. (PMID:18585707)
• Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. (PMID:19836010)
• Meta-analysis of abdominal aortic aneurysm size and growth rates demonstrated a significant association with the LTBP4 21011A>T genotype (a 2% decrease in AAA diameter, or a 0.53 mm/year reduction in AAA growth rate, per T allele [p=0.03, p=0.01]). (PMID:19897194)
• These data suggest that LTBP-4 functions are modified by tissue-specific expression of the two N-terminally distinct variants, which in addition exhibit significant differences in cellular processing and targeting. (PMID:20175115)
• The lack of LTBP4-mediated targeting in malignant mammary tumor tissues may lead to a possible modification of TGF-ss1 and BMP bioavailability and function. (PMID:21468687)
• the G1 and G3 domains of versican were upregulated and LTBP-4 was downregulated in breast cancer stroma (PMID:21505857)
• Data indicate mutations of FBLN4, FBLN5, and LTBP4 in 12 probands presenting with type 1 recessive cutis laxa. (PMID:22829427)
• LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of Duchenne muscular dystrophy patients. (PMID:23440719)
• Latent transforming growth factor beta-binding protein 4 is downregulated in esophageal cancer via promoter methylation. (PMID:23741501)
• In the mdx mouse model of Duchenne muscular dystrophy, the human LTBP4 transgene exacerbated muscular dystrophy symptoms and resulted in weaker muscles with an increased inflammatory infiltrate. (PMID:25338755)
• We show that corticosteroid treatment and the IAAM haplotype of the LTBP4 gene are significantly associated with prolonged ambulation in patients with Duchenne muscular dystrophy (PMID:25476005)
• In Caucasians with Duchenne muscular dystrophy and LTBP4 genotype there was a protective effect on age at loss of ambulation. (PMID:25641372)
• It recruits elastin to microfibrils via fibulin-5. (PMID:25675815)
• Our results show that LTBP4 interacts with TGFBR2 and stabilizes TGFbeta receptors by preventing their endocytosis and lysosomal degradation in a ligand-dependent and receptor kinase activity-dependent manner. (PMID:25882708)
• The LTBP4 VTTT allele is associated with increased risk of dilated cardiomyopathy in European Americans. LTBP4 protein with the IAAM residues bound more latent TGFbeta compared to the LTBP4 VTTT protein. (PMID:26918958)
• High LTBP4 expression is associated with recurrence in glioblastoma. (PMID:27270107)
• Studied the potential role of LTBP-4 in scleroderma through clinical, in vivo and in vitro studies. Results suggest that LTBP-4 protein level is increased in plasma and skin tissue of scleroderma patients; found LTBP-4 to be a potential biomarker to differentiate systemic scleroderma (SSc) from localized scleroderma (LSc) patients. (PMID:28263294)
• DMD gene mutations involving the hinge 3 region, actin-binding domain, and exons 45-49, as well as the LTBP4 IAAM haplotype, were not associated with age of left ventricular dysfunction onset inDuchenne muscular dystrophy. (PMID:29766838)
• an AMPK-LTBP4 axis in inflammatory macrophages controls the production of TGF-beta1, which is further activated by and acts on fibroblastic cells, leading to fibrosis in Duchenne muscular dystrophy. (PMID:30463013)
• Serum latent transforming growth factor-beta binding protein 4 as a novel biomarker for idiopathic pleuroparenchymal fibroelastosis. (PMID:32658840)
• Two novel compound heterozygous variants of LTBP4 in a Chinese infant with cutis laxa type IC and a review of the related literature. (PMID:33302946)
• LTBP4 affects renal fibrosis by influencing angiogenesis and altering mitochondrial structure. (PMID:34645813)
• Aberrant interaction between mutated ADAMTSL2 and LTBP4 is associated with adolescent idiopathic scoliosis. (PMID:34958866)
• Specific Overexpression of YAP in Vascular Smooth Muscle Attenuated Abdominal Aortic Aneurysm Formation by Activating Elastic Fiber Assembly via LTBP4. (PMID:35708897)
• LTBP4, SPP1, and CD40 Variants: Genetic Modifiers of Duchenne Muscular Dystrophy Analyzed in Serbian Patients. (PMID:36011296)
• Association of polymorphisms rs2303729, rs10880, and rs1131620 of LTBP4 with sarcopenia in elderly patients with type 2 diabetes mellitus. (PMID:36524797)
• LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts. (PMID:37232163)
• Novel indel variation of LTBP4 gene associates with risk of sudden cardiac death in Chinese populations with coronary artery disease. (PMID:38547642)
• Effect of decreased expression of latent TGF-beta binding proteins 4 on the pathogenesis of emphysema as an age-related disease. (PMID:39121531)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:cabz01070274.1	ENSDARG00000099137
mus_musculus	Ltbp4	ENSMUSG00000040488
rattus_norvegicus	Ltbp4	ENSRNOG00000020871

Paralogs (3): LTBP1 (ENSG00000049323), LTBP2 (ENSG00000119681), LTBP3 (ENSG00000168056)

Protein

Protein identifiers

Latent-transforming growth factor beta-binding protein 4 — Q8N2S1 (reviewed: Q8N2S1)

All UniProt accessions (15): Q8N2S1, A0A087WUU1, A0A087WVR1, A0A087WVV5, A0A087WWZ7, A0A087WXC2, A0A087WXJ2, A0A087WYX7, A0A087X0A7, A0A0C4DH07, F8WAA0, M0QXV3, M0QYE9, M0QZX0, M0R351

UniProt curated annotations — full annotation on UniProt →

Function. Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space. Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta.

Subunit / interactions. Forms part of the large latent transforming growth factor beta precursor complex; removal is essential for activation of complex. Interacts with LTBP1 and TGFB1. Interacts with EFEMP2; this interaction promotes fibrillar deposition of EFEMP2.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Highly expressed in heart, skeletal muscle, pancreas, uterus, and small intestine. Weakly expressed in placenta and lung.

Post-translational modifications. Contains hydroxylated asparagine residues.

Disease relevance. Urban-Rifkin-Davis syndrome (URDS) [MIM:613177] A syndrome characterized by disrupted pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial and dermal development. Clinical features include cutis laxa, mild cardiovascular lesions, respiratory distress with cystic and atelectatic changes in the lungs, and diverticulosis, tortuosity and stenosis at various levels of the intestinal tract. Craniofacial features include microretrognathia, flat midface, receding forehead and wide fontanelles. The disease is caused by variants affecting the gene represented in this entry. Duchenne muscular dystrophy (DMD) [MIM:310200] Most common form of muscular dystrophy; a sex-linked recessive disorder. It typically presents in boys aged 3 to 7 year as proximal muscle weakness causing waddling gait, toe-walking, lordosis, frequent falls, and difficulty in standing up and climbing up stairs. The pelvic girdle is affected first, then the shoulder girdle. Progression is steady and most patients are confined to a wheelchair by age of 10 or 12. Flexion contractures and scoliosis ultimately occur. About 50% of patients have a lower IQ than their genetic expectations would suggest. There is no treatment. The gene represented in this entry may act as a disease modifier. DMD patients homozygous for the IAAM haplotype consisting of Ile-194, Ala-787, Ala-820 and Met-1141 remain ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype consisting of Val-194, Thr-787, Thr-820 and Thr-1141. This may be due to increased binding to TGFB1, resulting in TGFB1 sequestration in the extracellular matrix and reduced TGFB1 signaling which has been linked to improved muscle function and regeneration.

Similarity. Belongs to the LTBP family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8N2S1-1	1, LTBP-4L	yes
Q8N2S1-2	2, LTBP-4S
Q8N2S1-3	3
Q8N2S1-4	4

RefSeq proteins (3): NP_001036009, NP_001036010, NP_003564 (=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
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: PF00683, PF07645, PF12661

UniProt features (130 total): disulfide bond 65, domain 20, sequence conflict 15, sequence variant 7, splice variant 6, compositionally biased region 6, glycosylation site 5, region of interest 4, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N2S1-F1	62.53	0.01

Functional residue map

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

Disulfide bonds (65): 1588–1602, 1604–1617, 153–163, 157–169, 171–180, 289–311, 298–324, 312–327, 361–372, 367–381, 383–396, 409–431, 418–444, 432–447, 433–459, 549–561, 556–570, 572–585, 591–603, 598–612 …

Glycosylation sites (5): 352, 425, 1055, 1200, 1339

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: 431 (showing top): GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, MORF_FLT1, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, MORF_MSH3, MORF_BRCA1, MORF_ATRX, GOBP_GROWTH, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_DN, GOBP_EXTRACELLULAR_MATRIX_ASSEMBLY, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, MORF_ESR1

GO Biological Process (6): regulation of cell growth (GO:0001558), protein folding (GO:0006457), transforming growth factor beta receptor signaling pathway (GO:0007179), regulation of transforming growth factor beta receptor signaling pathway (GO:0017015), hormone secretion (GO:0046879), elastic fiber assembly (GO:0048251)

GO Molecular Function (8): transforming growth factor beta receptor activity (GO:0005024), integrin binding (GO:0005178), calcium ion binding (GO:0005509), glycosaminoglycan binding (GO:0005539), transforming growth factor beta binding (GO:0050431), extracellular matrix structural constituent (GO:0005201), protein binding (GO:0005515), growth factor binding (GO:0019838)

GO Cellular Component (4): microfibril (GO:0001527), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012)

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
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
cellular process	1
protein maturation	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
transforming growth factor beta receptor signaling pathway	1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of cellular response to transforming growth factor beta stimulus	1
hormone transport	1
signal release	1
extracellular matrix assembly	1
supramolecular fiber organization	1
transmembrane receptor protein serine/threonine kinase activity	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
metal ion binding	1
carbohydrate derivative binding	1
growth factor binding	1
cytokine binding	1
structural molecule activity	1
extracellular matrix	1
binding	1
protein binding	1
elastic fiber	1
supramolecular fiber	1
cellular anatomical structure	1
external encapsulating structure	1

Protein interactions and networks

STRING

1779 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LTBP4	TGFB1	P01137	990
LTBP4	TGFB2	P08112	798
LTBP4	TGFB3	P10600	708
LTBP4	EFEMP2	O95967	667
LTBP4	SMAD2	Q15796	624
LTBP4	MSTN	O14793	560
LTBP4	MFAP4	P55083	553
LTBP4	FBN1	P35555	545
LTBP4	ITGB6	P18564	541
LTBP4	ELN	P15502	531
LTBP4	FBLN5	Q9UBX5	524
LTBP4	SGCG	Q13326	483
LTBP4	LTBP1	P22064	462
LTBP4	IGF1	P01343	461
LTBP4	LTBP3	Q9NS15	457

IntAct

98 interactions, top by confidence:

A	B	Type	Score
ZNF8	TRIM28	psi-mi:“MI:0914”(association)	0.730
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
ZNF764	ZNF316	psi-mi:“MI:0914”(association)	0.640
HRG	PLSCR1	psi-mi:“MI:0914”(association)	0.590
ZNF707	ZNF316	psi-mi:“MI:0914”(association)	0.530
ZNF169	ZNF316	psi-mi:“MI:0914”(association)	0.530
ZNF324B	ZNF316	psi-mi:“MI:0914”(association)	0.530
VWCE	ZNF316	psi-mi:“MI:0914”(association)	0.530
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
ZNF331	USP9Y	psi-mi:“MI:0914”(association)	0.530
E4F1	ZBTB24	psi-mi:“MI:0914”(association)	0.530
ZNF563	LRP4	psi-mi:“MI:0914”(association)	0.530
ZFP41	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF669	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF408	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF517	GGPS1	psi-mi:“MI:0914”(association)	0.530
ZNF764	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
EMILIN3	ZZEF1	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
ATXN7	LTBP4	psi-mi:“MI:0915”(physical association)	0.510
LTBP4	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
LTBP4	ATXN7	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	LTBP4	psi-mi:“MI:0915”(physical association)	0.510
LTBP4	gB	psi-mi:“MI:0915”(physical association)	0.370
	LTBP4	psi-mi:“MI:0915”(physical association)	0.370
LTBP4	NEC1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (107): LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS), LTBP4 (Affinity Capture-MS)

ESM2 similar proteins: A2A9Q0, A5A8Y8, A5PKD8, F1SAM7, O00468, O60500, O75325, P0C7J6, P12843, P13384, P18065, P24853, P49705, P50895, P60827, P60882, Q16270, Q24JP5, Q29400, Q2WF71, Q50LG9, Q5W7P8, Q61581, Q641Q3, Q6IQX7, Q6UKI2, Q6UWL6, Q75ZP3, Q7TSU7, Q7Z7M0, Q80W15, Q8BHA1, Q8BJ66, Q8IZ52, Q8N2S1, Q8NDA2, Q8WX77, Q91ZV8, Q96I82, Q96MS0

Diamond homologs: A0A087WV53, A1KZ92, A2AJ76, A4IFW2, A4IGL7, A6NDA9, B0BNK7, B0V2N1, D2HFT7, D3YXG0, D4A1J9, D4ABX8, F1NWE3, G5EG78, O15146, O73775, O75325, O94898, P07722, P15364, P20916, P20917, P23468, P43146, P48960, P53813, P70193, P70211, Q03142, Q08761, Q08879, Q13332, Q13449, Q1ENI8, Q1RMS4, Q1WIM1, Q21038, Q24372, Q26474, Q2Q421

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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
Molecules associated with elastic fibres	7	33.2×	3e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

1300 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	20
Uncertain significance	534
Likely benign	520
Benign	81

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323255	NM_003573.2(LTBP4):c.76-1G>A	Pathogenic
1458473	NM_001042545.2(LTBP4):c.4023dup (p.Ala1342fs)	Pathogenic
1970671	NM_001042545.2(LTBP4):c.1965_1966dup (p.Pro656fs)	Pathogenic
2035317	NM_003573.2(LTBP4):c.202_203del (p.Gln68fs)	Pathogenic
2419168	NM_001042545.2(LTBP4):c.2071C>T (p.Arg691Ter)	Pathogenic
2744609	NM_001042545.2(LTBP4):c.3994G>T (p.Glu1332Ter)	Pathogenic
2750551	NM_001042545.2(LTBP4):c.3694G>T (p.Glu1232Ter)	Pathogenic
2770690	NM_001042545.2(LTBP4):c.3035_3036insA (p.Tyr1013fs)	Pathogenic
2789934	NM_001042545.2(LTBP4):c.349dup (p.Ser117fs)	Pathogenic
2842177	NM_001042545.2(LTBP4):c.3497C>A (p.Ser1166Ter)	Pathogenic
3004450	NM_001042545.2(LTBP4):c.3159del (p.Asn1053fs)	Pathogenic
3069146	NM_001042545.2(LTBP4):c.113del (p.Pro38fs)	Pathogenic
3623504	NM_001042545.2(LTBP4):c.2037_2050del (p.Gly680fs)	Pathogenic
3649189	NM_001042545.2(LTBP4):c.1860C>A (p.Cys620Ter)	Pathogenic
3651178	NM_001042545.2(LTBP4):c.1397_1401del (p.Ala466fs)	Pathogenic
3651368	NM_001042545.2(LTBP4):c.2877del (p.Gly960fs)	Pathogenic
3678185	NM_001042545.2(LTBP4):c.2004_2005del (p.Ala669fs)	Pathogenic
3679723	NM_001042545.2(LTBP4):c.2854dup (p.Ala952fs)	Pathogenic
3683759	NM_003573.2(LTBP4):c.312_324dup (p.Ala109fs)	Pathogenic
3696513	NM_001042545.2(LTBP4):c.3205C>T (p.Arg1069Ter)	Pathogenic
3721658	NM_003573.2(LTBP4):c.284_285del (p.Gly95fs)	Pathogenic
40002	NM_001042545.2(LTBP4):c.1252C>T (p.Arg418Ter)	Pathogenic
40003	NM_001042545.2(LTBP4):c.4025dup (p.Tyr1343fs)	Pathogenic
40004	NM_001042545.2(LTBP4):c.4039C>T (p.Arg1347Ter)	Pathogenic
4695056	NM_001042545.2(LTBP4):c.383del (p.Pro128fs)	Pathogenic
4717678	NM_001042545.2(LTBP4):c.3016C>T (p.Gln1006Ter)	Pathogenic
4717923	NM_001042545.2(LTBP4):c.2401dup (p.Ala801fs)	Pathogenic
4720225	NM_001042545.2(LTBP4):c.2248C>T (p.Gln750Ter)	Pathogenic
4722970	NM_001042545.2(LTBP4):c.4254dup (p.Ser1419fs)	Pathogenic
4723119	NM_001042545.2(LTBP4):c.3650_3651insTGCAG (p.Tyr1218fs)	Pathogenic

SpliceAI

4471 predictions. Top by Δscore:

Variant	Effect	Δscore
19:40597376:GCCAG:G	donor_gain	1.0000
19:40597381:G:C	donor_loss	1.0000
19:40597381:G:GG	donor_gain	1.0000
19:40597382:T:G	donor_loss	1.0000
19:40605033:A:AG	acceptor_gain	1.0000
19:40605034:G:GA	acceptor_gain	1.0000
19:40605034:GTC:G	acceptor_gain	1.0000
19:40605034:GTCCT:G	acceptor_gain	1.0000
19:40605101:C:A	acceptor_gain	1.0000
19:40605222:GCACG:G	donor_gain	1.0000
19:40605653:G:GG	donor_gain	1.0000
19:40606542:G:GT	donor_gain	1.0000
19:40607363:A:AG	acceptor_gain	1.0000
19:40607364:G:GA	acceptor_gain	1.0000
19:40607364:GCCCA:G	acceptor_gain	1.0000
19:40608218:A:AG	acceptor_gain	1.0000
19:40608218:AGAG:A	acceptor_gain	1.0000
19:40608219:G:GG	acceptor_gain	1.0000
19:40608219:GAGG:G	acceptor_gain	1.0000
19:40608368:AGGT:A	donor_loss	1.0000
19:40608369:GGTG:G	donor_loss	1.0000
19:40608370:G:GC	donor_loss	1.0000
19:40609742:TCAGA:T	acceptor_loss	1.0000
19:40609743:CAGAT:C	acceptor_loss	1.0000
19:40609744:A:AG	acceptor_gain	1.0000
19:40609744:AGA:A	acceptor_loss	1.0000
19:40609745:G:GA	acceptor_loss	1.0000
19:40609745:G:GG	acceptor_gain	1.0000
19:40609745:GAT:G	acceptor_gain	1.0000
19:40610530:A:AG	acceptor_gain	1.0000

AlphaMissense

10046 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:40605426:T:A	V222D	1.000
19:40607397:T:C	C409R	1.000
19:40607399:C:G	C409W	1.000
19:40607463:T:C	C431R	1.000
19:40607464:G:A	C431Y	1.000
19:40607465:C:G	C431W	1.000
19:40607492:G:C	W440C	1.000
19:40607492:G:T	W440C	1.000
19:40607511:T:A	C447S	1.000
19:40607511:T:C	C447R	1.000
19:40607512:G:A	C447Y	1.000
19:40607512:G:C	C447S	1.000
19:40607513:C:G	C447W	1.000
19:40608237:T:C	C459R	1.000
19:40622624:G:C	W1214C	1.000
19:40622624:G:T	W1214C	1.000
19:40625879:G:C	W1352C	1.000
19:40625879:G:T	W1352C	1.000
19:40605052:T:A	C157S	0.999
19:40605052:T:C	C157R	0.999
19:40605053:G:A	C157Y	0.999
19:40605053:G:C	C157S	0.999
19:40605054:T:G	C157W	0.999
19:40605070:T:A	C163S	0.999
19:40605070:T:C	C163R	0.999
19:40605071:G:C	C163S	0.999
19:40605088:T:A	C169S	0.999
19:40605088:T:C	C169R	0.999
19:40605089:G:C	C169S	0.999
19:40605094:T:C	C171R	0.999

dbSNP variants (sampled 300 via entrez): RS1000017606 (19:40620246 A>AT,ATT), RS1000194183 (19:40599842 A>C), RS1000268080 (19:40598289 G>A), RS1000284571 (19:40621938 C>G,T), RS1000347438 (19:40604456 GA>G), RS1000483036 (19:40606207 G>A), RS1000490468 (19:40591960 G>A), RS1000512477 (19:40627725 G>A,C), RS1000643091 (19:40597927 G>A,C,T), RS1000656859 (19:40615714 G>A,C), RS1000815406 (19:40604776 G>A), RS1000863672 (19:40610950 G>A,C), RS1000931842 (19:40598176 C>A,T), RS1000947948 (19:40593857 G>A,T), RS1001085649 (19:40622338 T>A,C)

Disease associations

OMIM: gene MIM:604710 | disease phenotypes: MIM:613177

GenCC curated gene-disease

Disease	Classification	Inheritance
cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies	Strong	Autosomal recessive

Mondo (2): cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (MONDO:0013170), cutis laxa (MONDO:0016175)

Orphanet (2): Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (Orphanet:221145), Cutis laxa (Orphanet:209)

HPO phenotypes

66 total (30 of 66 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000126	Hydronephrosis
HP:0000239	Large fontanelles
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000340	Sloping forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000431	Wide nasal bridge
HP:0000750	Delayed speech and language development
HP:0000778	Hypoplasia of the thymus
HP:0000835	Adrenal hypoplasia
HP:0000938	Osteopenia
HP:0000954	Single transverse palmar crease
HP:0000973	Cutis laxa
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001328	Specific learning disability
HP:0001371	Flexion contracture
HP:0001382	Joint hypermobility
HP:0001510	Growth delay
HP:0001522	Death in infancy
HP:0001537	Umbilical hernia
HP:0001541	Ascites
HP:0001582	Redundant skin
HP:0001601	Laryngomalacia

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST007429_80	Lung function (FVC)	4.000000e-07
GCST007430_5	Peak expiratory flow	4.000000e-10
GCST007431_135	Lung function (FEV1/FVC)	2.000000e-47
GCST008481_10	Lung function (FEV1/FVC)	1.000000e-12
GCST009921_7	Carotid intima media thickness (mean)	1.000000e-10
GCST90000025_567	Appendicular lean mass	3.000000e-13
GCST90000026_27	Appendicular lean mass	8.000000e-07
GCST90000027_1	Appendicular lean mass	2.000000e-07
GCST90002383_280	Hematocrit	5.000000e-13
GCST90002384_464	Hemoglobin	4.000000e-11
GCST90002403_295	Red blood cell count	1.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity
EFO:0009718	peak expiratory flow
EFO:0004713	FEV/FVC ratio
EFO:0004980	appendicular lean mass
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003483	Cutis Laxa	C16.320.850.180; C17.300.230; C17.800.827.180
C567716	Cutis Laxa With Severe Pulmonary, Gastrointestinal, And Urinary Abnormalities (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
sodium arsenite	increases abundance, increases expression, affects cotreatment, decreases expression	3
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Particulate Matter	increases expression, affects cotreatment, increases abundance	2
GSK-J4	decreases expression	1
TAK-243	increases sumoylation	1
aminomethylphosphonic acid (AMPA)	decreases expression	1
bisphenol A	affects cotreatment, affects methylation, decreases methylation	1
beta-lapachone	increases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, affects cotreatment, decreases expression	1
manganese chloride	increases abundance, increases expression	1
bathocuproine sulfonate	decreases reaction, affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Troglitazone	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Ethanol	increases expression, affects cotreatment, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	affects expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Hydrogen Peroxide	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03887208	PHASE1/PHASE2	COMPLETED	Therapy of Scars and Cutis Laxa With Autologous Adipose Derived Mesenchymal Stem Cells
NCT01293864	Not specified	TERMINATED	Structural Analysis of Human Tissue
NCT01658163	Not specified	COMPLETED	Use of 2-octyl-cyanoacrylate Together With a Self-adhering Mesh
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07614997	Not specified	NOT_YET_RECRUITING	Effectiveness and Safety of the Ulthera® System for Skin Laxity in the Lower Face, Submentum and Neck