FERMT3

Summary

FERMT3 (FERM domain containing kindlin 3, HGNC:23151) is a protein-coding gene on chromosome 11q13.1, encoding Fermitin family homolog 3 (Q86UX7). Plays a central role in cell adhesion in hematopoietic cells.

Kindlins are a small family of proteins that mediate protein-protein interactions involved in integrin activation and thereby have a role in cell adhesion, migration, differentiation, and proliferation. The protein encoded by this gene has a key role in the regulation of hemostasis and thrombosis. This protein may also help maintain the membrane skeleton of erythrocytes. Mutations in this gene cause the autosomal recessive leukocyte adhesion deficiency syndrome-III (LAD-III). Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 83706 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukocyte adhesion deficiency 3 (Definitive, ClinGen)
• GWAS associations: 12
• Clinical variants (ClinVar): 625 total — 17 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 19
• MANE Select transcript: NM_031471

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23151
Approved symbol	FERMT3
Name	FERM domain containing kindlin 3
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	URP2, KIND3, MIG2B, MGC10966, UNC112C
Ensembl gene	ENSG00000149781
Ensembl biotype	protein_coding
OMIM	607901
Entrez	83706

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 18 protein_coding, 16 retained_intron, 10 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000279227, ENST00000345728, ENST00000540554, ENST00000540957, ENST00000541252, ENST00000541326, ENST00000544997, ENST00000545896, ENST00000546255, ENST00000698845, ENST00000698846, ENST00000698847, ENST00000698848, ENST00000698849, ENST00000698850, ENST00000698852, ENST00000698853, ENST00000698854, ENST00000698855, ENST00000698856, ENST00000698859, ENST00000698860, ENST00000698861, ENST00000698862, ENST00000698863, ENST00000698864, ENST00000698865, ENST00000698866, ENST00000698867, ENST00000698868, ENST00000698869, ENST00000698870, ENST00000698871, ENST00000698872, ENST00000698873, ENST00000698874, ENST00000698875, ENST00000698876, ENST00000698877, ENST00000698878, ENST00000698879, ENST00000698880, ENST00000962568, ENST00000962569, ENST00000962570

RefSeq mRNA: 7 — MANE Select: NM_031471 NM_001382361, NM_001382362, NM_001382363, NM_001382364, NM_001382448, NM_031471, NM_178443

CCDS: CCDS8059, CCDS8060, CCDS91497

Canonical transcript exons

ENST00000345728 — 15 exons

Exon	Start	End
ENSE00001316856	64211645	64211747
ENSE00002210136	64219251	64219358
ENSE00003578093	64210611	64210844
ENSE00003595112	64211052	64211171
ENSE00003628294	64211275	64211443
ENSE00003974951	64219740	64219789
ENSE00003974954	64223048	64223189
ENSE00003974975	64221016	64221140
ENSE00003974977	64220436	64220669
ENSE00003974979	64219891	64220015
ENSE00003974980	64220220	64220326
ENSE00003974982	64219524	64219658
ENSE00003975051	64207351	64207524
ENSE00003975053	64223313	64223891
ENSE00003975057	64206721	64206814

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 99.03.

FANTOM5 (CAGE): breadth broad, TPM avg 34.0965 / max 920.8468, expressed in 776 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114870	34.0965	776

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.03	gold quality
monocyte	CL:0000576	98.87	gold quality
leukocyte	CL:0000738	98.81	gold quality
spleen	UBERON:0002106	97.60	gold quality
bone marrow cell	CL:0002092	96.93	gold quality
vermiform appendix	UBERON:0001154	96.69	gold quality
blood	UBERON:0000178	96.31	gold quality
lymph node	UBERON:0000029	95.32	gold quality
bone marrow	UBERON:0002371	93.69	gold quality
upper lobe of left lung	UBERON:0008952	93.65	gold quality
right lung	UBERON:0002167	93.01	gold quality
upper lobe of lung	UBERON:0008948	92.90	gold quality
bone element	UBERON:0001474	91.33	gold quality
thymus	UBERON:0002370	91.11	gold quality
caecum	UBERON:0001153	90.36	gold quality
right coronary artery	UBERON:0001625	90.33	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.01	gold quality
trabecular bone tissue	UBERON:0002483	89.98	gold quality
omental fat pad	UBERON:0010414	89.21	gold quality
gall bladder	UBERON:0002110	89.20	gold quality
peritoneum	UBERON:0002358	89.14	gold quality
pancreatic ductal cell	CL:0002079	88.79	silver quality
adipose tissue of abdominal region	UBERON:0007808	88.20	gold quality
small intestine	UBERON:0002108	87.96	gold quality
left coronary artery	UBERON:0001626	87.94	gold quality
left uterine tube	UBERON:0001303	87.70	gold quality
lung	UBERON:0002048	87.24	gold quality
coronary artery	UBERON:0001621	86.89	gold quality
mucosa of stomach	UBERON:0001199	86.86	gold quality
transverse colon	UBERON:0001157	86.71	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	1873.62
E-HCAD-10	yes	1692.83
E-MTAB-7407	yes	1062.39
E-GEOD-130473	yes	1022.62
E-MTAB-9067	yes	968.38
E-ANND-5	yes	564.98
E-HCAD-4	yes	50.74
E-CURD-112	yes	39.45
E-HCAD-6	yes	26.51
E-CURD-122	yes	24.71
E-MTAB-9221	yes	23.00
E-HCAD-1	yes	7.09
E-MTAB-7606	no	803.16
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

52 targeting FERMT3, 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-6748-5P	100.00	65.81	1057
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514

Literature-anchored findings (GeneRIF, showing 40)

• expressed preferentially in B cells; MIG2B is in a highly conserved and defined gene family containing two plasma-membrane-binding ezrin/radixin/moesin domains and a pleckstrin homology domain (PMID:12886250)
• our data show for the first time that URP2SF may act as a transcriptional repressor in NF-kappaB signaling pathway and regulate cell apoptotic pathway. (PMID:18280249)
• the LAD-III phenotype could manifest a combined defect in both upstream and downstream integrin regulatory effectors CalDAG-GEFI and Kindlin-3 (PMID:18779414)
• Mutations in FERMT3 is associated with Leukocyte adhesion deficiency syndrome. (PMID:19064721)
• Kindlin-3 is essential to activate the beta1, beta2 and beta3 integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III-like phenotype in mice (PMID:19234461)
• identify mutations in the KINDLIN3 (official symbol FERMT3) gene specifying the KINDLIN-3 protein as the cause of leukocyte adhesion deficiency-III in Maltese and Turkish subjects (PMID:19234463)
• Kindlin-1 and -2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects (PMID:19240021)
• Kindlin-3 is more critical to LFA-1 than to VLA-4-adhesive functions in human lymphocytes. (PMID:19617577)
• Studies indicate that LAD I is due to the mutations in beta2-integrin essential for firm adhesion. (PMID:19647987)
• cellular functions and possible clinical relevance of kindlin-3 [REVIEW] (PMID:19854292)
• in two brothers with LAD-III syndrome homozygous mutation 1717C>T causes integrin-dependent platelet dysfunction in siblings with leukocyte adhesion deficiency-III (PMID:20216991)
• LAD-III patient mutations have highlighted functionally important regions of kindlin-3 that alter leukocyte integrin-dependent function in 2 distinct ways. (PMID:20357244)
• integrin co-activator Kindlin-3 is expressed and functional in a non-hematopoietic cell, the endothelial cell (PMID:20378539)
• investigation into roles of kindlin-3 in activated T-cells: facilitates multimerization of LFA-1/ICAM-1; increases stability of focal LFA-1 contacts (presumably at immunological synapses)and anchors to cytoskeleton; facilitates T-cell spreading (PMID:21536861)
• TIIICBP and kindlin-3 could be the same protein and propose a key role for kindlin-3 in platelet activation by type III collagen. (PMID:21871525)
• We investigated the role of talin-1, kindlin-3, and alpha-actinin-1 in the upregulation of alpha(4)beta(1) integrin affinity and consequent inflammatory leukocyte adhesive events (PMID:21911599)
• LAD-III syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells that is involved in the regulation of beta integrin conformation. (Review) (PMID:22134107)
• A new mutation in codon 476 of exon 12, CAG–>TAG was found in 2 siblings with Leukocyte adhesion deficiency-I variant syndrome. (PMID:22139635)
• integrin alphaLbeta2 engagement by its ligand ICAM-1 promotes the association of kindlin-3 with RACK1 (PMID:22334666)
• Kindlin-3 deficiency impairs integrin function, including activation of beta(1) integrin. Abnormalities in glycoprotein Ib-IX function in Kindlin-3-deficient platelets are secondary to integrin defects (PMID:22564402)
• kindlin-3 lowers the threshold for NK cell activation. Loss of kindlin-3 has a pronounced effect on NK cell-mediated cytotoxicity triggered by single activating receptors. (PMID:22983444)
• cleavage of Kindlin-3 by calpain controls the dynamics of integrin-Kindlin-3 interaction and as a result, integrin-dependent adhesion and migration of hematopoietic cells. (PMID:23012377)
• Agonist stimulation, talin-1, and kindlin-3 are crucial for alpha(IIb)beta(3) activation in a human megakaryoblastic cell line, CMK. (PMID:23022222)
• Multivalent LFA-1/ICAM-1 bonds serve as mechanosensors that direct PMN cytoskeletal activity by transmission of tensile force to a supramolecular complex that triggers Ca2+ influx at sites of adhesive contact. (PMID:23144497)
• kindlin-3 is required for the integrin alphaMbeta2-Syk-Vav1 signaling axis that regulates Rac1 and Cdc42 activities. These findings reinforce a role for kindlin-3 in integrin outside-in signaling. (PMID:23437269)
• the correct functioning of the kindlin 3 PH domain is central to the role that kindlin 3 performs in guiding lymphocyte adhesion and motility behavior, which in turn is required for a successful immune response. (PMID:23595985)
• the beta-2-integrin-kindlin-3 interaction is particularly important in adhesion strengthening under shear flow, and for T-cell homing to lymph nodes, but dispensable for T cell activation which occurs in a shear-free environment (PMID:23823319)
• kindlin-3-mediated high-affinity LFA-1 controls both the early transient integrin-dependent adhesions in addition to the final stable adhesions made under flow conditions (PMID:24010654)
• Kindlin 2 expression was significantly increased in luteinized granulosa cells from patients with polycystic ovary syndrome. (PMID:24336678)
• Kindlin-3 influences breast cancer progression by influencing the crosstalk between beta1 integrins and Twist to increase VEGF production, which enhances breast cancer cell invasion and tumor angiogenesis and metastasis (PMID:24469992)
• ADAP interacts with talin and kindlin-3 to promote platelet Integrin alphaIIbbeta3 activation and stable fibrinogen binding. (PMID:24523237)
• While Kindlin-2 was highly expressed in control tissues, a drastic low expression of Kindlin-2 was found in the tumor tissues of serous epithelial ovarian cancer, especially in high-grade serous epithelial ovarian cancer. (PMID:24583125)
• Direct activation of RhoA with recombinant bacterial cytotoxic necrotizing factor y reverted the abnormal phenotype and barrier function of kindlin-2-deficient keratinocytes and skin equivalents. (PMID:24615351)
• Mig-2 significantly attenuates the antitumor action of cisplatin. (PMID:25152024)
• kindlin-2 tyrosine phosphorylation and interaction with Src serve as a regulatable switch downstream of focal adhesion kinase in the integrin outside-in signaling circuit controlling cell migration and proliferation (PMID:25237194)
• The data uncover a novel and unexpected tumor suppressor role of Kindlin-3 which can influence integrins targeted therapies development. (PMID:25344860)
• These data identify a role of kindlin-3 phosphorylation in integrin b3 activation and provide a basis for functional differences between kindlin-3 and the two other kindlin paralogs. (PMID:25609252)
• High Kindlin-2 expression promotes pancreatic ductal adenocarcinoma progression. (PMID:25724625)
• A new C>T point mutation was found in exon 13 in the FERMT3 gene in an infant diagnosed with LAD-III. KINDLIN-3 expression is required for platelet aggregation and leukocyte function, but also osteoclast-mediated bone resorption. (PMID:25854317)
• Kindlin-3/FERMT3 is upregulated in atherosclerotic, mainly in cells of monocytic origin and of M2 type. Simultaneous upregulation of ITGB2 suggests a synergistic effect on leukocyte adherence and transmigration into the vessel wall. (PMID:26188538)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	fermt3b	ENSDARG00000030938
danio_rerio	fermt3a	ENSDARG00000079267
mus_musculus	Fermt3	ENSMUSG00000024965
rattus_norvegicus	Fermt3	ENSRNOG00000021161
drosophila_melanogaster	Fit1	FBGN0035498
drosophila_melanogaster	Fit2	FBGN0036688
caenorhabditis_elegans		WBGENE00006836

Paralogs (2): FERMT2 (ENSG00000073712), FERMT1 (ENSG00000101311)

Protein

Protein identifiers

Fermitin family homolog 3 — Q86UX7 (reviewed: Q86UX7)

Alternative names: Kindlin-3, MIG2-like protein, Unc-112-related protein 2

All UniProt accessions (15): Q86UX7, A0A8V8TMB3, A0A8V8TMD7, A0A8V8TME2, A0A8V8TMS8, A0A8V8TMT4, A0A8V8TMT7, A0A8V8TMU1, A0A8V8TNT4, A0A8V8TNT9, A0A8V8TP41, A0A8V8TP46, F5H1C6, F5H3I6, H0YFT5

UniProt curated annotations — full annotation on UniProt →

Function. Plays a central role in cell adhesion in hematopoietic cells. Acts by activating the integrin beta-1-3 (ITGB1, ITGB2 and ITGB3). Required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells. Required for activation of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes (PMNs). Isoform 2 may act as a repressor of NF-kappa-B and apoptosis.

Subunit / interactions. Interacts with ITGB1, ITGB2 and ITGB3 (via cytoplasmic tails).

Subcellular location. Cell projection. Podosome.

Tissue specificity. Highly expressed in lymph node. Expressed in thymus, spleen and leukocytes. Weakly expressed in placenta, small intestine, stomach, testis and lung. Overexpressed in B-cell malignancies.

Disease relevance. Leukocyte adhesion deficiency 3 (LAD3) [MIM:612840] A disorder characterized by recurrent bacterial infections without pus formation, leukocytosis and major bleeding disorders. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The FERM domain is not correctly detected by PROSITE or Pfam techniques because it contains the insertion of a PH domain.

Similarity. Belongs to the kindlin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86UX7-1	1, Long, URP2LF	yes
Q86UX7-2	2, Short, URP2SF

RefSeq proteins (7): NP_001369290, NP_001369291, NP_001369292, NP_001369293, NP_001369377, NP_113659, NP_848537 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR035963	FERM_2	Homologous_superfamily
IPR037837	PH_Kindlin/fermitin	Domain
IPR037843	Kindlin/fermitin	Family
IPR040790	Kindlin_2_N	Domain

Pfam: PF00169, PF00373, PF18124

UniProt features (63 total): strand 21, helix 20, turn 11, modified residue 4, domain 2, sequence conflict 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6V9G	X-RAY DIFFRACTION	2.35
6V97	X-RAY DIFFRACTION	2.38
7C3M	X-RAY DIFFRACTION	3.6
2YS3	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UX7-F1	83.80	0.50

Functional residue map

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

Post-translational modifications (4): 8, 11, 504, 591

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation

MSigDB gene sets: 226 (showing top): GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_PLATELET_ACTIVATION, chr11q13, GOBP_WOUND_HEALING, GOBP_CELL_CELL_ADHESION, MARTINEZ_RB1_TARGETS_DN, GOBP_REGULATION_OF_CELL_ADHESION_MEDIATED_BY_INTEGRIN, TGANTCA_AP1_C, GOBP_SUBSTRATE_ADHESION_DEPENDENT_CELL_SPREADING, WANG_TARGETS_OF_MLL_CBP_FUSION_UP, GOBP_LEUKOCYTE_CELL_CELL_ADHESION, RYTTCCTG_ETS2_B, GOBP_HOMOTYPIC_CELL_CELL_ADHESION, GOBP_HEMOSTASIS

GO Biological Process (9): leukocyte cell-cell adhesion (GO:0007159), cell-matrix adhesion (GO:0007160), integrin-mediated signaling pathway (GO:0007229), positive regulation of cell migration (GO:0030335), integrin activation (GO:0033622), regulation of cell-cell adhesion mediated by integrin (GO:0033632), substrate adhesion-dependent cell spreading (GO:0034446), platelet aggregation (GO:0070527), cell adhesion (GO:0007155)

GO Molecular Function (3): integrin binding (GO:0005178), lipid binding (GO:0008289), protein binding (GO:0005515)

GO Cellular Component (8): podosome (GO:0002102), extracellular region (GO:0005576), membrane (GO:0016020), cell-substrate junction (GO:0030055), platelet alpha granule lumen (GO:0031093), extracellular exosome (GO:0070062), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell-substrate adhesion	2
binding	2
cell-cell adhesion	1
cell surface receptor signaling pathway	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
protein-containing complex assembly	1
regulation of cell-cell adhesion	1
regulation of cell adhesion mediated by integrin	1
cell-cell adhesion mediated by integrin	1
platelet activation	1
homotypic cell-cell adhesion	1
cellular process	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
actin-based cell projection	1
anchoring junction	1
platelet alpha granule	1
secretory granule lumen	1
extracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

1508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FERMT3	APBB1IP	Q7Z5R6	941
FERMT3	TLN1	Q9Y490	938
FERMT3	ITGB2	P05107	934
FERMT3	FBLIM1	Q8WUP2	929
FERMT3	RASGRP2	Q7LDG7	898
FERMT3	ITGB3	P05106	890
FERMT3	TLN2	Q9Y4G6	817
FERMT3	RASGRP1	O95267	794
FERMT3	PXN	P49023	779
FERMT3	FLNB	O75369	771
FERMT3	FLNC	Q14315	757
FERMT3	PLEK2	Q9NYT0	716
FERMT3	PLEK	P08567	715
FERMT3	FLNA	P21333	711
FERMT3	SKAP1	Q86WV1	698

IntAct

27 interactions, top by confidence:

A	B	Type	Score
ZNF398	LRP4	psi-mi:“MI:0914”(association)	0.530
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
FERMT3	H2BC12L	psi-mi:“MI:0915”(physical association)	0.400
TINF2	FERMT3	psi-mi:“MI:0915”(physical association)	0.370
NLRP12	FERMT3	psi-mi:“MI:0915”(physical association)	0.370
FERMT3	rep	psi-mi:“MI:0915”(physical association)	0.370
FERMT3	BLTP3B	psi-mi:“MI:0914”(association)	0.350
PB2		psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
FERMT1	TARS3	psi-mi:“MI:0914”(association)	0.350
FERMT3	FERMT2	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
MAVS	CHMP2A	psi-mi:“MI:0914”(association)	0.350
VCAM1		psi-mi:“MI:0914”(association)	0.350
FN1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
CDH5	MYO1C	psi-mi:“MI:2364”(proximity)	0.270
ugpC	FERMT3	psi-mi:“MI:0915”(physical association)	0.000
EXOSC10	FERMT3	psi-mi:“MI:0915”(physical association)	0.000
LSM8	FERMT3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (65): PARVB (Co-fractionation), NCBP1 (Affinity Capture-MS), PRDX1 (Affinity Capture-MS), RBBP5 (Affinity Capture-MS), STXBP1 (Affinity Capture-MS), PKP4 (Affinity Capture-MS), TAF1B (Affinity Capture-MS), COX5A (Affinity Capture-MS), EIF4E2 (Affinity Capture-MS), KEAP1 (Affinity Capture-MS), USP15 (Affinity Capture-MS), PDCD6 (Affinity Capture-MS), SPEN (Affinity Capture-MS), SNRNP200 (Affinity Capture-MS), UHRF1BP1L (Affinity Capture-MS)

ESM2 similar proteins: A1L2W9, B2RQE8, B5XG43, G9CGD6, O08969, O88387, P59113, Q0V987, Q0VC85, Q1KKW7, Q1KKZ1, Q32LP0, Q3UUV5, Q3ZBA3, Q4V7G1, Q503L1, Q53GA4, Q5FVW6, Q5PQT7, Q5R8M5, Q5U597, Q5XGP7, Q5ZL23, Q6P0G8, Q6PG29, Q7Z628, Q7Z6J4, Q80VL0, Q80YS6, Q86UX7, Q86WV1, Q8AW35, Q8BY35, Q8IZC4, Q8K1B8, Q8N556, Q8VH46, Q91ZM9, Q91ZT5, Q925E0

Diamond homologs: F1Q8X5, P59113, Q18685, Q32LP0, Q5R8M5, Q86UX7, Q8CIB5, Q8K1B8, Q96AC1, Q9BQL6, Q9VZI3, A0A3G2LGI8, P0CE94, P0CE95, P26039, P54939, Q71LX4, Q9Y490, Q9Y4G6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PRKCA	“up-regulates activity”	FERMT3	phosphorylation
FERMT3	“up-regulates activity”	ITGB1	binding
FERMT3	“up-regulates activity”	ITGB3	binding
FERMT3	“up-regulates activity”	FBLIM1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	6
Uncertain significance	255
Likely benign	288
Benign	31

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1453537	NM_031471.6(FERMT3):c.540del (p.Met181fs)	Pathogenic
1686803	NM_031471.6(FERMT3):c.921del (p.Ser307fs)	Pathogenic
2023047	NM_031471.6(FERMT3):c.847_853del (p.Glu283fs)	Pathogenic
2584467	NM_031471.6(FERMT3):c.1601_1602del (p.Glu534fs)	Pathogenic
2708	NM_031471.6(FERMT3):c.1671-2A>G	Pathogenic
2709	NM_031471.6(FERMT3):c.48G>A (p.Trp16Ter)	Pathogenic
2711	NM_031471.6(FERMT3):c.687G>A (p.Trp229Ter)	Pathogenic
2712	NM_031471.6(FERMT3):c.1525C>T (p.Arg509Ter)	Pathogenic
30687	NM_031471.6(FERMT3):c.1275del (p.Glu426fs)	Pathogenic
31528	NM_031471.6(FERMT3):c.161-2A>C	Pathogenic
3721047	NM_031471.6(FERMT3):c.1426C>T (p.Gln476Ter)	Pathogenic
4707843	NM_031471.6(FERMT3):c.1462del (p.His488fs)	Pathogenic
4726349	NM_031471.6(FERMT3):c.224del (p.Gln75fs)	Pathogenic
4732996	NM_031471.6(FERMT3):c.1295_1296insACTGCGGTGCCAGGATGTGAGTGAGATCTA (p.Tyr432Ter)	Pathogenic
643472	NM_031471.6(FERMT3):c.664_665del (p.Lys222fs)	Pathogenic
646802	NM_031471.6(FERMT3):c.1029+2T>C	Pathogenic
652864	NM_031471.6(FERMT3):c.814dup (p.Tyr272fs)	Pathogenic
2068172	NM_031471.6(FERMT3):c.684-1G>A	Likely pathogenic
2800615	NM_031471.6(FERMT3):c.1671-4_1671del	Likely pathogenic
3004277	NM_031471.6(FERMT3):c.786+1G>T	Likely pathogenic
3660341	NM_031471.6(FERMT3):c.1204+1G>T	Likely pathogenic
3680800	NM_031471.6(FERMT3):c.787-14_788del	Likely pathogenic
947116	NM_031471.6(FERMT3):c.1312-2A>C	Likely pathogenic

SpliceAI

2643 predictions. Top by Δscore:

Variant	Effect	Δscore
11:64207520:GATCA:G	donor_gain	1.0000
11:64207521:A:G	donor_gain	1.0000
11:64207525:G:GG	donor_gain	1.0000
11:64210845:G:GG	donor_gain	1.0000
11:64211132:G:GT	donor_gain	1.0000
11:64211168:GGGG:G	donor_gain	1.0000
11:64211169:GGG:G	donor_gain	1.0000
11:64211169:GGGG:G	donor_gain	1.0000
11:64211170:GGG:G	donor_gain	1.0000
11:64211637:C:CA	acceptor_gain	1.0000
11:64211748:G:A	donor_loss	1.0000
11:64219249:A:AG	acceptor_gain	1.0000
11:64219250:G:GA	acceptor_gain	1.0000
11:64219250:GACA:G	acceptor_gain	1.0000
11:64219329:G:GT	donor_gain	1.0000
11:64219356:CAG:C	donor_loss	1.0000
11:64219357:AGG:A	donor_loss	1.0000
11:64219359:G:T	donor_loss	1.0000
11:64219735:CATAG:C	acceptor_loss	1.0000
11:64219737:TAGGA:T	acceptor_loss	1.0000
11:64219738:A:AG	acceptor_gain	1.0000
11:64219739:G:GG	acceptor_gain	1.0000
11:64219739:GGACA:G	acceptor_gain	1.0000
11:64219790:G:GG	donor_gain	1.0000
11:64220011:CAAGG:C	donor_gain	1.0000
11:64220012:AAGG:A	donor_gain	1.0000
11:64220013:AGG:A	donor_gain	1.0000
11:64220013:AGGG:A	donor_loss	1.0000
11:64220014:GG:G	donor_gain	1.0000
11:64220014:GGG:G	donor_gain	1.0000

AlphaMissense

4333 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:64223163:T:A	W600R	1.000
11:64223163:T:C	W600R	1.000
11:64219348:C:A	A295D	0.999
11:64219354:T:C	L297P	0.999
11:64220454:T:A	W448R	0.999
11:64220454:T:C	W448R	0.999
11:64223095:G:C	R577P	0.999
11:64223164:G:C	W600S	0.999
11:64223165:G:C	W600C	0.999
11:64223165:G:T	W600C	0.999
11:64207412:G:C	W16C	0.998
11:64207412:G:T	W16C	0.998
11:64210625:T:A	W59R	0.998
11:64210625:T:C	W59R	0.998
11:64210664:T:A	W72R	0.998
11:64210664:T:C	W72R	0.998
11:64210834:C:G	C128W	0.998
11:64211717:G:C	K252N	0.998
11:64211717:G:T	K252N	0.998
11:64219351:C:A	A296D	0.998
11:64220261:T:C	F420L	0.998
11:64220263:C:A	F420L	0.998
11:64220263:C:G	F420L	0.998
11:64220274:T:C	L424P	0.998
11:64220318:T:C	C439R	0.998
11:64220445:T:G	Y445D	0.998
11:64220449:C:A	A446D	0.998
11:64221086:T:C	F543S	0.998
11:64223098:T:C	L578P	0.998
11:64223139:T:A	W592R	0.998

dbSNP variants (sampled 300 via entrez): RS1000020701 (11:64207753 C>T), RS1000064093 (11:64213846 G>C), RS1000071395 (11:64222798 A>C), RS1000080876 (11:64222520 G>A), RS1000657179 (11:64212505 C>T), RS1000663787 (11:64217473 C>T), RS1000698758 (11:64207131 G>T), RS1000709075 (11:64212213 T>C), RS1000733934 (11:64206025 G>C), RS1001027391 (11:64208820 C>G), RS1001227185 (11:64204685 A>G), RS1001380732 (11:64208537 G>C), RS1001382865 (11:64207301 G>A,T), RS1001410415 (11:64208303 C>T), RS1001670676 (11:64206790 C>T)

Disease associations

OMIM: gene MIM:607901 | disease phenotypes: MIM:612840

GenCC curated gene-disease

Disease	Classification	Inheritance
leukocyte adhesion deficiency 3	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
leukocyte adhesion deficiency 3	Definitive	AR

Mondo (2): leukocyte adhesion deficiency 3 (MONDO:0013016), leukocyte adhesion deficiency (MONDO:0017570)

Orphanet (2): Leukocyte adhesion deficiency (Orphanet:2968), Leukocyte adhesion deficiency type III (Orphanet:99844)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000421	Epistaxis
HP:0000967	Petechiae
HP:0001433	Hepatosplenomegaly
HP:0001482	Subcutaneous nodule
HP:0001581	Recurrent skin infections
HP:0001744	Splenomegaly
HP:0001872	Abnormality of thrombocytes
HP:0001892	Abnormal bleeding
HP:0001903	Anemia
HP:0001974	Increased total leukocyte count
HP:0001978	Extramedullary hematopoiesis
HP:0002240	Hepatomegaly
HP:0002718	Recurrent bacterial infections
HP:0002733	Abnormal lymph node morphology
HP:0003593	Infantile onset
HP:0011002	Osteopetrosis
HP:0012531	Pain
HP:0100806	Sepsis

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001154_1	Attention deficit hyperactivity disorder	1.000000e-06
GCST004132_98	Crohn’s disease	5.000000e-06
GCST004611_179	High light scatter reticulocyte count	1.000000e-16
GCST004612_117	High light scatter reticulocyte percentage of red cells	5.000000e-17
GCST004628_46	Immature fraction of reticulocytes	1.000000e-26
GCST007930_151	Medication use (agents acting on the renin-angiotensin system)	6.000000e-10
GCST007931_37	Medication use (HMG CoA reductase inhibitors)	2.000000e-11
GCST010136_47	Fruit consumption	9.000000e-10
GCST90002385_204	High light scatter reticulocyte count	2.000000e-17
GCST90002386_354	High light scatter reticulocyte percentage of red cells	1.000000e-17
GCST90002387_372	Immature fraction of reticulocytes	2.000000e-36
GCST90002395_88	Mean platelet volume	4.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0008111	diet measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567555	Leukocyte Adhesion Deficiency, Type III (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1011219	FERMT3		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Cisplatin	decreases expression, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Tretinoin	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
benzo(e)pyrene	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
entinostat	decreases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression, affects cotreatment	1
Arsenic	affects methylation	1
Calcitriol	decreases expression	1
Catechin	affects cotreatment, decreases expression	1
Diuron	affects expression	1
Methapyrilene	decreases methylation	1
Nickel	increases expression	1
Potassium Chloride	decreases response to substance, increases expression	1
Smoke	decreases expression	1
Dronabinol	decreases response to substance, increases expression	1
Triclosan	increases methylation	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	affects expression	1
Acrylamide	increases expression	1

Cellosaurus cell lines

10 cell lines: 10 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_VP08	LAD-III LCL family 1 father	Transformed cell line	Male
CVCL_VP09	LAD-III LCL family 1 mother	Transformed cell line	Female
CVCL_VP10	LAD-III LCL family 1 sibling	Transformed cell line	Female
CVCL_VP11	LAD-III LCL family 1 subject	Transformed cell line	Female
CVCL_VP12	LAD-III LCL family 3 father	Transformed cell line	Male
CVCL_VP13	LAD-III LCL family 3 subject	Transformed cell line	Female
CVCL_VP14	LAD-III LCL family 2 father	Transformed cell line	Male
CVCL_VP15	LAD-III LCL family 2 mother	Transformed cell line	Female
CVCL_VP16	LAD-III LCL family 2 sibling	Transformed cell line	Female
CVCL_VP17	LAD-III LCL family 2 subject	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05462587	PHASE3	RECRUITING	A Study to Evaluate Efficacy and Safety of AVTX-803 in Patients With Leukocyte Adhesion Deficiency Type II
NCT05754450	PHASE3	RECRUITING	An Extension Study Assessing the Safety and Efficacy of AVTX-803 in Subjects With Leukocyte Adhesion Deficiency Type II
NCT01998633	PHASE2	COMPLETED	Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT06282432	Not specified	ACTIVE_NOT_RECRUITING	Long-Term Follow-Up (LTFU) for Gene Therapy of Leukocyte Adhesion Deficiency-I (LAD-I)