ITGA8

Summary

ITGA8 (integrin subunit alpha 8, HGNC:6144) is a protein-coding gene on chromosome 10p13, encoding Integrin alpha-8 (P53708). Integrin alpha-8/beta-1 functions in the genesis of kidney and probably of other organs by regulating the recruitment of mesenchymal cells into epithelial structures.

Integrins are heterodimeric transmembrane receptor proteins that mediate numerous cellular processes including cell adhesion, cytoskeletal rearrangement, and activation of cell signaling pathways. Integrins are composed of alpha and beta subunits. This gene encodes the alpha 8 subunit of the heterodimeric integrin alpha8beta1 protein. The encoded protein is a single-pass type 1 membrane protein that contains multiple FG-GAP repeats. This repeat is predicted to fold into a beta propeller structure. This gene regulates the recruitment of mesenchymal cells into epithelial structures, mediates cell-cell interactions, and regulates neurite outgrowth of sensory and motor neurons. The integrin alpha8beta1 protein thus plays an important role in wound-healing and organogenesis. Mutations in this gene have been associated with renal hypodysplasia/aplasia-1 (RHDA1) and with several animal models of chronic kidney disease. Alternate splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 8516 — RefSeq curated summary.

At a glance

• Gene–disease (curated): renal hypodysplasia/aplasia 1 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 479 total — 12 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes
• MANE Select transcript: NM_003638

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6144
Approved symbol	ITGA8
Name	integrin subunit alpha 8
Location	10p13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000077943
Ensembl biotype	protein_coding
OMIM	604063
Entrez	8516

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000378076, ENST00000468882, ENST00000477064, ENST00000882526, ENST00000967017

RefSeq mRNA: 2 — MANE Select: NM_003638 NM_001291494, NM_003638

CCDS: CCDS31155

Canonical transcript exons

ENST00000378076 — 30 exons

Exon	Start	End
ENSE00000504035	15644030	15644221
ENSE00000504042	15604208	15604355
ENSE00000614390	15687938	15688038
ENSE00000614391	15684004	15684127
ENSE00000614392	15678722	15678783
ENSE00000614393	15677592	15677637
ENSE00000614394	15672624	15672749
ENSE00000614397	15658999	15659055
ENSE00000614398	15655354	15655406
ENSE00000691929	15605724	15605791
ENSE00000691950	15606285	15606422
ENSE00000691956	15607677	15607831
ENSE00000691960	15608235	15608290
ENSE00000691973	15646846	15647051
ENSE00000691979	15660879	15660922
ENSE00000691980	15671603	15671647
ENSE00000691987	15718766	15718899
ENSE00000925918	15613660	15613767
ENSE00000985524	15592225	15592304
ENSE00000985525	15586584	15586664
ENSE00000985526	15575489	15575594
ENSE00000985527	15572211	15572369
ENSE00000985528	15558074	15558202
ENSE00000985529	15548455	15548568
ENSE00000985530	15531050	15531151
ENSE00000985531	15519290	15519412
ENSE00001098640	15597207	15597299
ENSE00001476177	15513954	15517244
ENSE00001476256	15719563	15719922
ENSE00003572831	15616514	15616559

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 99.27.

FANTOM5 (CAGE): breadth broad, TPM avg 5.8862 / max 866.3195, expressed in 517 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108433	4.6778	490
108439	0.2364	111
108435	0.2231	94
108432	0.2124	62
108437	0.1506	54
108441	0.1309	46
108434	0.0779	37
108438	0.0779	35
108426	0.0331	9
108442	0.0264	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thoracic aorta	UBERON:0001515	99.27	gold quality
descending thoracic aorta	UBERON:0002345	99.27	gold quality
ascending aorta	UBERON:0001496	99.26	gold quality
urethra	UBERON:0000057	99.20	gold quality
right coronary artery	UBERON:0001625	99.14	gold quality
saphenous vein	UBERON:0007318	99.06	gold quality
mucosa of stomach	UBERON:0001199	99.03	gold quality
aorta	UBERON:0000947	98.28	gold quality
coronary artery	UBERON:0001621	97.69	gold quality
popliteal artery	UBERON:0002250	97.57	gold quality
tibial artery	UBERON:0007610	97.56	gold quality
left coronary artery	UBERON:0001626	97.53	gold quality
vena cava	UBERON:0004087	96.93	gold quality
blood vessel layer	UBERON:0004797	96.85	gold quality
superficial temporal artery	UBERON:0001614	95.15	gold quality
lower lobe of lung	UBERON:0008949	93.00	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.96	gold quality
right lung	UBERON:0002167	92.73	gold quality
visceral pleura	UBERON:0002401	92.39	gold quality
nipple	UBERON:0002030	91.62	gold quality
adrenal tissue	UBERON:0018303	90.18	gold quality
seminal vesicle	UBERON:0000998	89.71	gold quality
penis	UBERON:0000989	88.08	gold quality
cauda epididymis	UBERON:0004360	87.70	gold quality
lung	UBERON:0002048	87.63	gold quality
pericardium	UBERON:0002407	87.50	gold quality
cardia of stomach	UBERON:0001162	87.37	gold quality
upper lobe of lung	UBERON:0008948	86.99	gold quality
urinary bladder	UBERON:0001255	86.91	gold quality
upper lobe of left lung	UBERON:0008952	86.69	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	1532.27
E-HCAD-36	yes	1000.33
E-GEOD-124472	yes	521.41
E-HCAD-10	yes	49.64
E-CURD-119	yes	18.29
E-ANND-3	yes	6.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATM, HOXD11, MYOCD, SRF, ZFHX3

miRNA regulators (miRDB)

144 targeting ITGA8, 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-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-539-5P	99.93	70.30	2855

Literature-anchored findings (GeneRIF, showing 22)

• expressed in developing kidney (PMID:12060755)
• Role in regulation of mesangial cell phenotype. Seems to promote adhesion, but inhibit migration and proliferation of mesangial cells. Alpha8 integrin could play important role in maintaining tissue integrity in glomerulus during glomerular injury. (PMID:12787402)
• genomic analysis of the human integrin subunit alpha8 gene (PMID:15579315)
• Mammary carcinoma cells do express alpha8 integrin. (PMID:15592496)
• A polymorphism of the ITGA8 promoter modifies the progression of renal failure in ADPKD. (PMID:18277079)
• These results indicate that the specific high-affinity binding of nephronectin to alpha8beta1 integrin is achieved by bipartite interaction of the integrin with the RGD motif and LFEIFEIER sequence. (PMID:19342381)
• In intestinal crypt cells, integrin alpha8beta1 is closely involved in the regulation of adhesion, migration and cell proliferation via a predominant RhoA/ROCK-dependent mechanism. (PMID:19527220)
• alpha8beta1 is a prerequisite for the proper conduct of anoikis in normal human intestinal epithelial crypt cells, whereas its loss contributes to the illicit acquisition of anoikis resistance. (PMID:20678483)
• The mRNA levels of Integrinalpha8 were significantly lower in LSCC tissues than that in corresponding adjacent normal tissues. (PMID:20942236)
• Analysis of the data demonstrated that Itga8 expression is CArG box-serum response factor independent, but myocardin dependent through an as yet unknown sequence module that is distal from the promoter region. (PMID:23142384)
• the ITGA8 gene might have gender-specific roles in the development of schizophrenia. (PMID:23153507)
• Mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease. (PMID:24439109)
• In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. (PMID:24700879)
• ITGA2B and ITGA8 have roles in prognosis in clear cell renal cell carcinoma patients (PMID:26198048)
• Integrin alpha8beta1 is the most fibroblast specific integrin and its contribution to fibrosis remains controversial. Recently, we demonstrated that alpha8beta1 plays a role in liver fibrosis in 4 different settings of mouse models; 3 with a neutralizing monoclonal antibody and one with Tam-inducible knockout mice. The mechanisms for the pro-fibrotic roles are through myofibroblast differentiation and TGF-beta activation. (PMID:33433924)
• ITGA8 positive cells in the conventional outflow tissue exhibit Schlemm’s canal endothelial cell properties. (PMID:33961857)
• Glucocorticoids increase the risk of preterm premature rupture of membranes possibly by inducing ITGA8 gene expression in the amnion. (PMID:36088840)
• Bi-allelic pathogenic variants in ITGA8 cause slowly progressive renal disease of unknown etiology. (PMID:36089563)
• LINC01798/miR-17-5p axis regulates ITGA8 and causes changes in tumor microenvironment and stemness in lung adenocarcinoma. (PMID:36911684)
• Hypermethylated ITGA8 Facilitate Bladder Cancer Cell Proliferation and Metastasis. (PMID:37119505)
• M2 macrophage-derived exosomal circTMCO3 acts through miR-515-5p and ITGA8 to enhance malignancy in ovarian cancer. (PMID:38755265)
• Expression Profiles of ITGA8 and VANGL2 Are Altered in Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). (PMID:39064873)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	itga8	ENSDARG00000078717
mus_musculus	Itga8	ENSMUSG00000026768
rattus_norvegicus	Itga8	ENSRNOG00000016538
drosophila_melanogaster	if	FBGN0001250
drosophila_melanogaster	ItgaPS4	FBGN0034005
drosophila_melanogaster	ItgaPS5	FBGN0034880
drosophila_melanogaster	scb	FBGN0286785
caenorhabditis_elegans		WBGENE00003929

Paralogs (17): ITGAL (ENSG00000005844), ITGA3 (ENSG00000005884), ITGA2B (ENSG00000005961), ITGAE (ENSG00000083457), ITGA6 (ENSG00000091409), ITGA4 (ENSG00000115232), ITGA7 (ENSG00000135424), ITGA11 (ENSG00000137809), ITGAV (ENSG00000138448), ITGAX (ENSG00000140678), ITGA10 (ENSG00000143127), ITGA9 (ENSG00000144668), ITGAD (ENSG00000156886), ITGA5 (ENSG00000161638), ITGA2 (ENSG00000164171), ITGAM (ENSG00000169896), ITGA1 (ENSG00000213949)

Protein

Protein identifiers

Integrin alpha-8 — P53708 (reviewed: P53708)

All UniProt accessions (1): P53708

UniProt curated annotations — full annotation on UniProt →

Function. Integrin alpha-8/beta-1 functions in the genesis of kidney and probably of other organs by regulating the recruitment of mesenchymal cells into epithelial structures. It recognizes the sequence R-G-D in a wide array of ligands including TNC, FN1, SPP1 TGFB1, TGFB3 and VTN. NPNT is probably its functional ligand in kidney genesis. Neuronal receptor for TNC it mediates cell-cell interactions and regulates neurite outgrowth of sensory and motor neurons.

Subunit / interactions. Heterodimer of an alpha and a beta subunit. The alpha subunit is composed of a heavy and a light chain linked by a disulfide bond. Alpha-8 associates with beta-1.

Subcellular location. Membrane. Cell membrane.

Tissue specificity. Expressed in mesenchymal cells, including alveolar myofibroblasts, kidney mesangial cells and hepatic stellar cells and vascular and visceral smooth muscle (at protein level).

Disease relevance. Renal hypodysplasia/aplasia 1 (RHDA1) [MIM:191830] A perinatally lethal renal disease encompassing a spectrum of kidney development defects, including renal agenesis, bilateral renal aplasia, hypoplasia, (cystic) dysplasia, and severe obstructive uropathy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the integrin alpha chain family.

RefSeq proteins (2): NP_001278423, NP_003629* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000413	Integrin_alpha	Family
IPR013517	FG-GAP	Repeat
IPR013519	Int_alpha_beta-p	Repeat
IPR013649	Integrin_alpha_Ig-like_1	Domain
IPR018184	Integrin_alpha_C_CS	Conserved_site
IPR028994	Integrin_alpha_N	Homologous_superfamily
IPR032695	Integrin_dom_sf	Homologous_superfamily
IPR048285	Integrin_alpha_Ig-like_2	Domain
IPR048286	Integrin_alpha_Ig-like_3	Domain

Pfam: PF00357, PF01839, PF08441, PF20805, PF20806

UniProt features (72 total): binding site 19, glycosylation site 16, disulfide bond 9, sequence variant 9, repeat 7, sequence conflict 4, chain 3, topological domain 2, signal peptide 1, short sequence motif 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53708-F1	85.08	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.

Ligand- & substrate-binding residues (19): 275; 277; 279; 283; 329; 331; 333; 335; 337; 395; 397; 399 …

Disulfide bonds (9): 96–106, 150–171, 187–200, 507–518, 524–580, 641–647, 713–726, 867–924, 929–934

Glycosylation sites (16): 81, 122, 177, 239, 302, 311, 504, 601, 605, 719, 737, 753, 780, 896, 923, 1005

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-2129379	Molecules associated with elastic fibres
R-HSA-216083	Integrin cell surface interactions
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-3000178	ECM proteoglycans
R-HSA-9830674	Formation of the ureteric bud
R-HSA-1266738	Developmental Biology
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
R-HSA-9830369	Kidney development

MSigDB gene sets: 337 (showing top): GOBP_MEMORY, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_COGNITION, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_BEHAVIOR, GOBP_METANEPHROS_DEVELOPMENT, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOCC_CELL_SURFACE, TAL1ALPHAE47_01, LHX3_01, AAAYRNCTG_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA_STIMULUS, GOBP_CELL_CELL_ADHESION

GO Biological Process (23): metanephros development (GO:0001656), kidney development (GO:0001822), cell-matrix adhesion (GO:0007160), transforming growth factor beta receptor signaling pathway (GO:0007179), integrin-mediated signaling pathway (GO:0007229), nervous system development (GO:0007399), memory (GO:0007613), cell projection organization (GO:0030030), extracellular matrix organization (GO:0030198), positive regulation of transforming growth factor beta receptor signaling pathway (GO:0030511), substrate adhesion-dependent cell spreading (GO:0034446), inner ear morphogenesis (GO:0042472), establishment of protein localization (GO:0045184), positive regulation of transcription by RNA polymerase II (GO:0045944), mesodermal cell differentiation (GO:0048333), smooth muscle tissue development (GO:0048745), smooth muscle cell differentiation (GO:0051145), cell-cell adhesion (GO:0098609), formation of primary germ layer (GO:0001704), cell adhesion (GO:0007155), tissue development (GO:0009888), cell differentiation (GO:0030154), cell-substrate adhesion (GO:0031589)

GO Molecular Function (2): signaling receptor activity (GO:0038023), metal ion binding (GO:0046872)

GO Cellular Component (12): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), focal adhesion (GO:0005925), integrin complex (GO:0008305), cell surface (GO:0009986), dendritic spine membrane (GO:0032591), integrin alpha8-beta1 complex (GO:0034678), perikaryon (GO:0043204), apical part of cell (GO:0045177), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Extracellular matrix organization	3
Elastic fibre formation	1
Signaling by TGF-beta Receptor Complex	1
Kidney development	1
Signaling by TGFB family members	1
Signal Transduction	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell-substrate adhesion	2
kidney development	1
animal organ development	1
renal system development	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
cell surface receptor signaling pathway	1
system development	1
learning or memory	1
cellular component organization	1
extracellular structure organization	1
external encapsulating structure organization	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
positive regulation of cellular response to transforming growth factor beta stimulus	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
establishment of localization	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
mesoderm formation	1
cell differentiation	1
muscle tissue development	1
muscle cell differentiation	1
cell adhesion	1
gastrulation	1
anatomical structure formation involved in morphogenesis	1
cellular process	1
molecular transducer activity	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
cell-substrate junction	1

Protein interactions and networks

STRING

1474 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITGA8	NPNT	Q6UXI9	995
ITGA8	ITGB1	P05556	953
ITGA8	VTN	P01141	901
ITGA8	FN1	P02751	776
ITGA8	SPP1	P10451	728
ITGA8	COL6A1	P12109	610
ITGA8	LAMA2	P24043	603
ITGA8	COL4A1	P02462	580
ITGA8	COL6A2	P12110	562
ITGA8	ITGB5	P18084	546
ITGA8	ITGB6	P18564	544
ITGA8	COL14A1	Q05707	539
ITGA8	EGFL6	Q8IUX8	536
ITGA8	ITGBL1	O95965	528
ITGA8	PCDH15	Q96QU1	525

IntAct

47 interactions, top by confidence:

A	B	Type	Score
SCGB1D4	EGFR	psi-mi:“MI:0914”(association)	0.530
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
TAFA4	NRP1	psi-mi:“MI:0914”(association)	0.530
ITGA8	CKMT1A	psi-mi:“MI:0915”(physical association)	0.400
ITGA8	H1-4	psi-mi:“MI:0915”(physical association)	0.400
BTNL8	TMEM131L	psi-mi:“MI:0914”(association)	0.350
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
SUSD4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
PTPRK	MANBA	psi-mi:“MI:0914”(association)	0.350
TAZ	MANBA	psi-mi:“MI:0914”(association)	0.350
ST8SIA4	NRP1	psi-mi:“MI:0914”(association)	0.350
TMEM25	FUZ	psi-mi:“MI:0914”(association)	0.350
CLU	TOR1A	psi-mi:“MI:0914”(association)	0.350
CCL22	HSPA12A	psi-mi:“MI:0914”(association)	0.350
	HSPA12A	psi-mi:“MI:0914”(association)	0.350
CALR3	CLN5	psi-mi:“MI:0914”(association)	0.350
PNLIPRP1	ITGA8	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
BST1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
PSCA	METTL15	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
GPIHBP1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
TAFAZZIN	MANBA	psi-mi:“MI:0914”(association)	0.350

BioGRID (92): ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS)

ESM2 similar proteins: A2ARA8, B0S5N4, B8JK39, F1MMS9, O08665, P05555, P06756, P08514, P08648, P11215, P11688, P13612, P17301, P17852, P18564, P20701, P23229, P24063, P26006, P26007, P26008, P26009, P38570, P43406, P53708, P53710, P53711, P61622, P61625, P80746, Q00651, Q06274, Q13683, Q13797, Q60677, Q61738, Q61739, Q62469, Q62470, Q63258

Diamond homologs: A2ARA8, O70362, P06756, P08514, P08648, P11688, P12080, P26008, P26009, P34446, P43406, P53708, P53711, P80108, P80109, P80746, Q06274, Q27977, Q61739, Q86AV9, Q8R2H5, Q9QUM0, F1MMS9, O75578, P20701, P23229, P26006, P26007, P38570, Q00651, Q13683, Q13797, Q24247, Q60677, Q61738, Q63258, Q91687, Q9W1M8, A8X3A7, P20702

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ITGA8	“form complex”	“A8/b1 integrin”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	9
Uncertain significance	214
Likely benign	113
Benign	102

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
126499	NM_003638.3(ITGA8):c.1622_1626del (p.Glu541fs)	Pathogenic
126500	NM_003638.3(ITGA8):c.1219G>A (p.Gly407Arg)	Pathogenic
1706540	NM_003638.3(ITGA8):c.2804dup (p.Val936fs)	Pathogenic
2424712	NC_000010.10:g.(?15686009)(15686240_?)del	Pathogenic
3356710	NM_003638.3(ITGA8):c.1780C>T (p.Arg594Ter)	Pathogenic
3372139	NM_003638.3(ITGA8):c.360dup (p.Val121fs)	Pathogenic
3900017	NM_003638.3(ITGA8):c.467G>A (p.Trp156Ter)	Pathogenic
450375	NM_003638.3(ITGA8):c.2174dup (p.Cys726fs)	Pathogenic
4688183	NM_003638.3(ITGA8):c.2812C>T (p.Arg938Ter)	Pathogenic
4694107	NM_003638.3(ITGA8):c.2683C>T (p.Arg895Ter)	Pathogenic
4715342	NM_003638.3(ITGA8):c.3003G>A (p.Trp1001Ter)	Pathogenic
4778227	NM_003638.3(ITGA8):c.410del (p.Gly137fs)	Pathogenic
1012552	NM_003638.3(ITGA8):c.1123dup (p.Gln375fs)	Likely pathogenic
1012553	NM_003638.3(ITGA8):c.722C>A (p.Ser241Ter)	Likely pathogenic
1324596	NM_003638.3(ITGA8):c.2626C>T (p.Gln876Ter)	Likely pathogenic
2627439	NM_003638.3(ITGA8):c.1764+1G>A	Likely pathogenic
3065947	NM_003638.3(ITGA8):c.1970+1G>A	Likely pathogenic
3382277	NM_003638.3(ITGA8):c.158del (p.Lys53fs)	Likely pathogenic
3647486	NM_003638.3(ITGA8):c.2118_2118+3del	Likely pathogenic
4278106	NM_003638.3(ITGA8):c.562C>T (p.Arg188Trp)	Likely pathogenic
4761540	NM_003638.3(ITGA8):c.1445+1G>A	Likely pathogenic

SpliceAI

5375 predictions. Top by Δscore:

Variant	Effect	Δscore
10:15531048:A:AC	donor_gain	1.0000
10:15531049:C:CC	donor_gain	1.0000
10:15531049:CT:C	donor_gain	1.0000
10:15531049:CTA:C	donor_gain	1.0000
10:15531049:CTACT:C	donor_gain	1.0000
10:15531059:T:TA	donor_gain	1.0000
10:15558068:ACTC:A	donor_loss	1.0000
10:15558069:CTC:C	donor_loss	1.0000
10:15558070:TCACC:T	donor_loss	1.0000
10:15558071:CACCA:C	donor_loss	1.0000
10:15558072:A:AC	donor_gain	1.0000
10:15558072:A:C	donor_loss	1.0000
10:15558073:C:A	donor_loss	1.0000
10:15558073:C:CC	donor_gain	1.0000
10:15558198:GCAGG:G	acceptor_gain	1.0000
10:15558199:CAGG:C	acceptor_gain	1.0000
10:15558199:CAGGC:C	acceptor_gain	1.0000
10:15558200:AGG:A	acceptor_gain	1.0000
10:15558201:GG:G	acceptor_gain	1.0000
10:15558202:GC:G	acceptor_loss	1.0000
10:15558203:C:CC	acceptor_gain	1.0000
10:15558203:CTGCA:C	acceptor_loss	1.0000
10:15586576:CTA:C	donor_gain	1.0000
10:15586579:CTTA:C	donor_loss	1.0000
10:15586580:TTA:T	donor_loss	1.0000
10:15586581:TACCC:T	donor_loss	1.0000
10:15586582:A:AC	donor_gain	1.0000
10:15586582:AC:A	donor_gain	1.0000
10:15586583:C:A	donor_loss	1.0000
10:15586583:C:CC	donor_gain	1.0000

AlphaMissense

6994 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:15597242:A:G	C726R	0.999
10:15605754:C:G	C647S	0.999
10:15605755:A:G	C647R	0.999
10:15605755:A:T	C647S	0.999
10:15655390:C:T	G322E	0.999
10:15660883:C:T	G296E	0.999
10:15672749:C:T	G226E	0.999
10:15677592:C:G	G226R	0.999
10:15677592:C:T	G226R	0.999
10:15678752:G:C	C200W	0.999
10:15678753:C:T	C200Y	0.999
10:15684009:C:G	R188P	0.999
10:15684011:G:C	C187W	0.999
10:15684012:C:G	C187S	0.999
10:15684013:A:G	C187R	0.999
10:15684013:A:T	C187S	0.999
10:15684059:G:C	C171W	0.999
10:15684061:A:G	C171R	0.999
10:15684122:A:C	C150W	0.999
10:15684123:C:T	C150Y	0.999
10:15684124:A:G	C150R	0.999
10:15687989:T:A	K131N	0.999
10:15687989:T:G	K131N	0.999
10:15517236:G:C	F1038L	0.998
10:15517236:G:T	F1038L	0.998
10:15517238:A:G	F1038L	0.998
10:15519339:A:T	I1019K	0.998
10:15597241:C:G	C726S	0.998
10:15597241:C:T	C726Y	0.998
10:15597242:A:T	C726S	0.998

dbSNP variants (sampled 300 via entrez): RS1000041388 (10:15609818 T>A), RS1000041792 (10:15669617 C>T), RS1000065590 (10:15675127 C>G,T), RS1000069087 (10:15590387 T>C), RS1000070233 (10:15548312 C>T), RS1000098363 (10:15590717 A>C,G), RS1000100339 (10:15516074 C>A,T), RS1000122157 (10:15552734 T>C,G), RS1000143417 (10:15529091 C>G), RS1000152026 (10:15668600 G>A,C,T), RS1000152127 (10:15568871 C>A,T), RS1000157841 (10:15704111 T>C), RS1000162263 (10:15569164 G>T), RS1000179949 (10:15553573 T>C,G), RS1000180523 (10:15631709 G>C)

Disease associations

OMIM: gene MIM:604063 | disease phenotypes: MIM:191830

GenCC curated gene-disease

Disease	Classification	Inheritance
renal hypodysplasia/aplasia 1	Strong	Autosomal recessive
bilateral renal agenesis	Supportive	Autosomal recessive

Mondo (2): renal hypodysplasia/aplasia 1 (MONDO:0024519), bilateral renal agenesis (MONDO:0015986)

Orphanet (1): Renal agenesis (Orphanet:411709)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000093	Proteinuria
HP:0000104	Renal agenesis
HP:0000110	Renal dysplasia
HP:0000148	Vaginal atresia
HP:0000175	Cleft palate
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000457	Depressed nasal ridge
HP:0000786	Primary amenorrhea
HP:0000813	Bicornuate uterus
HP:0000822	Hypertension
HP:0001562	Oligohydramnios
HP:0001563	Fetal polyuria
HP:0001762	Talipes equinovarus
HP:0001958	Nonketotic hypoglycemia
HP:0002009	Potter facies
HP:0002089	Pulmonary hypoplasia
HP:0002242	Abnormal intestine morphology
HP:0002575	Tracheoesophageal fistula
HP:0003577	Congenital onset
HP:0005107	Abnormal sacrum morphology
HP:0010497	Sirenomelia
HP:0010958	Bilateral renal agenesis
HP:0025700	Anhydramnios
HP:0030680	Abnormal cardiovascular system morphology
HP:0100335	Non-midline cleft of the upper lip

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000337_11	Quantitative traits	6.000000e-06
GCST000528_3	Parkinson’s disease	5.000000e-06
GCST002126_9	Periodontitis (CDC/AAP)	9.000000e-06
GCST002875_15	Diisocyanate-induced asthma	1.000000e-06
GCST004490_19	Cerebrospinal fluid t-tau:AB1-42 ratio	2.000000e-08
GCST004490_20	Cerebrospinal fluid t-tau:AB1-42 ratio	2.000000e-08
GCST004490_21	Cerebrospinal fluid t-tau:AB1-42 ratio	2.000000e-08
GCST008667_9	Smoking status (heavy vs never)	1.000000e-07
GCST009325_1	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	3.000000e-13
GCST010584_4	Autism spectrum disorders (social interaction)	3.000000e-06
GCST010991_34	Parkinson’s disease	3.000000e-07

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0006995	response to diisocyanate
EFO:0007708	t-tau:beta-amyloid 1-42 ratio measurement
EFO:0006527	smoking status measurement
EFO:0005426	autism spectrum disorder symptom

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL6066569 (PROTEIN COMPLEX), CHEMBL6066586 (PROTEIN COMPLEX)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Integrins

Binding affinities (BindingDB)

17 measured of 17 human assays (17 total across all organisms); most potent 17 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(3S)-3-[3-bromo-5-(trifluoromethyl)phenyl]-3-[[2-[[5-[(5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino]pyridine-3-carbonyl]amino]acetyl]amino]propanoic acid	IC50	0.3 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3-chloro-5-(difluoromethyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido]propanoic acid	IC50	0.5 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3-bromo-5-methyl-phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid	IC50	0.5 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3-bromo-5-chloro-phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido]propanoic acid	IC50	0.6 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-(3-bromo-5-chloro-phenyl)-3-[[2-[[5-[(5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino]pyridine-3-carbonyl]amino]acetyl]amino]propanoic acid	IC50	0.6 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3-bromo-5-fluoro-phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid	IC50	0.6 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-(3,5-dibromophenyl)-3-[[2-[[5-[(5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino]pyridine-3-carbonyl]amino]acetyl]amino]propanoic acid	IC50	0.6 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3-bromo-5-(difluoromethyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido]propanoic acid	IC50	0.7 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3-chloro-5-(trifluoromethyl)phenyl]3-[[2-[[5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino]pyridine-3-carbonyl]amino]acetyl]amino]propanoic acid	IC50	0.7 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid	IC50	0.8 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido]propanoic acid	IC50	0.8 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-(3,5-dibromophenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid	IC50	1 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3,5-bis(trifluoromethyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido]propanoic acid	IC50	1 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3,5-dichloro-phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid	IC50	1 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3-chloro-5-(trifluoromethoxy)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid	IC50	1 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-(3-bromo-5-(trifluoromethoxy)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid	IC50	1 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
(3S)-3-[3-chloro-5-methyl-phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid	IC50	2 nM	US-10035778: Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists

ChEMBL bioactivities

46 potent at pChembl≥5 of 46 total, top 29 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.40	IC50	0.4	nM	CHEMBL5914164
9.30	IC50	0.5	nM	CHEMBL5802710
9.30	IC50	0.5	nM	CHEMBL5786200
9.30	IC50	0.5	nM	CHEMBL5770209
9.22	IC50	0.6	nM	CHEMBL5974146
9.22	IC50	0.6	nM	CHEMBL5920684
9.22	IC50	0.6	nM	CHEMBL5889173
9.22	IC50	0.6	nM	CHEMBL5951981
9.15	IC50	0.7	nM	CHEMBL5790208
9.15	IC50	0.7	nM	CHEMBL5980310
9.10	IC50	0.8	nM	CHEMBL5819051
9.05	IC50	0.9	nM	CHEMBL5964326
9.05	IC50	0.9	nM	CHEMBL5975238
8.96	IC50	1.1	nM	CHEMBL5748399
8.92	IC50	1.2	nM	CHEMBL5802648
8.89	IC50	1.3	nM	CHEMBL5781301
8.82	IC50	1.5	nM	CHEMBL5766697
8.52	IC50	3	nM	CHEMBL6027181
8.10	IC50	8	nM	CHEMBL244013
8.00	IC50	10	nM	CHEMBL242061
7.85	IC50	14	nM	CHEMBL5784734
7.77	IC50	17	nM	CHEMBL6050248
7.77	IC50	17	nM	CHEMBL5798185
7.58	IC50	26	nM	CHEMBL5981351
7.40	IC50	40	nM	CHEMBL5946569
7.20	IC50	63	nM	CHEMBL5982261
6.42	IC50	383	nM	CHEMBL5828678
6.23	IC50	594	nM	CHEMBL5766817
5.23	IC50	5888	nM	CHEMBL3892042

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-1-(benzenesulfonyl)pyrrolidine-2-carbonyl]amino]-3-[4-[5-(diaminomethylideneamino)pentanoylamino]phenyl]propanoic acid	2065312: Inhibition of recombinant human Integrin alpha8beta1 mediated cellular adhesion expressed in HEK cells incubated for 24 hrs in presence of Ca2+ and Mg2+ by real-time cell analysis	ic50	5.8884	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
bisphenol A	increases expression, decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Vorinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Aflatoxin B1	decreases expression, increases methylation	2
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
arsenite	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
Arsenic	affects methylation	1
Estradiol	affects cotreatment, decreases expression	1
Phenytoin	increases expression	1
Progesterone	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5734881	Binding	Solid Phase Receptor Assay (SPRA) for alpha8beta1 Function: Recombinant mouse nephronectin protein (R&D Systems, Inc, 4298-NP) diluted to 1 μg/mL in TBS+ buffer (25 mM Tris pH 7.4, 137 mM NaCl, 2.7 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 1 mM MnCl2	Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9HG	Ubigene HEK293 ITGA8 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06728228	Not specified	RECRUITING	Amnioinfusion for Fetal Renal Failure