FOXN2

Summary

FOXN2 (forkhead box N2, HGNC:5281) is a protein-coding gene on chromosome 2p16.3, encoding Forkhead box protein N2 (P32314). Binds to the purine-rich region in HTLV-I LTR.

This gene encodes a forkhead domain binding protein and may function in the transcriptional regulation of the human T-cell leukemia virus long terminal repeat.

Source: NCBI Gene 3344 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 79 total
• MANE Select transcript: NM_002158

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5281
Approved symbol	FOXN2
Name	forkhead box N2
Location	2p16.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170802
Ensembl biotype	protein_coding
OMIM	143089
Entrez	3344

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000340553, ENST00000413569, ENST00000872826, ENST00000872827, ENST00000872828, ENST00000872829, ENST00000872830, ENST00000872831, ENST00000872832, ENST00000924484, ENST00000924485, ENST00000924486, ENST00000924487, ENST00000924488, ENST00000924489, ENST00000969510

RefSeq mRNA: 13 — MANE Select: NM_002158 NM_001375442, NM_001375443, NM_001375444, NM_001375445, NM_001375446, NM_001375447, NM_001375448, NM_001375449, NM_001375450, NM_001375451, NM_001375452, NM_001375781, NM_002158

CCDS: CCDS1838

Canonical transcript exons

ENST00000340553 — 7 exons

Exon	Start	End
ENSE00001163649	48373292	48373360
ENSE00001163653	48362643	48362707
ENSE00001166694	48359047	48359147
ENSE00001216231	48346201	48346751
ENSE00001371260	48374920	48379295
ENSE00001388977	48314682	48314814
ENSE00001390876	48328561	48328702

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 96.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.3092 / max 318.7360, expressed in 1803 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20178	26.3092	1803

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	96.15	gold quality
medial globus pallidus	UBERON:0002477	95.47	gold quality
corpus callosum	UBERON:0002336	95.46	gold quality
globus pallidus	UBERON:0001875	94.73	gold quality
trabecular bone tissue	UBERON:0002483	94.43	gold quality
inferior vagus X ganglion	UBERON:0005363	93.17	gold quality
subthalamic nucleus	UBERON:0001906	92.09	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.90	gold quality
biceps brachii	UBERON:0001507	91.80	gold quality
monocyte	CL:0000576	91.59	gold quality
superficial temporal artery	UBERON:0001614	91.26	gold quality
mononuclear cell	CL:0000842	90.75	gold quality
skin of hip	UBERON:0001554	90.67	gold quality
leukocyte	CL:0000738	90.49	gold quality
substantia nigra pars reticulata	UBERON:0001966	90.09	gold quality
parietal pleura	UBERON:0002400	89.97	gold quality
ganglionic eminence	UBERON:0004023	89.75	gold quality
visceral pleura	UBERON:0002401	89.71	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.71	gold quality
lateral globus pallidus	UBERON:0002476	89.64	gold quality
bone marrow	UBERON:0002371	89.43	gold quality
calcaneal tendon	UBERON:0003701	89.28	gold quality
pleura	UBERON:0000977	89.14	gold quality
tendon	UBERON:0000043	88.79	gold quality
jejunal mucosa	UBERON:0000399	88.66	gold quality
ventricular zone	UBERON:0003053	87.96	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.96	gold quality
upper leg skin	UBERON:0004262	87.87	gold quality
trigeminal ganglion	UBERON:0001675	87.59	gold quality
lower lobe of lung	UBERON:0008949	87.54	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

270 targeting FOXN2, 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-340-5P	100.00	72.50	4437
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-12121	99.99	66.64	255

Literature-anchored findings (GeneRIF, showing 9)

• HLTF methylation may exist in gastric cardia dysplasia stages and may play important role in the development of gastric cardia adenocarcinoma. (PMID:21531217)
• HTLF is a RUNX1 target whose down-regulation promotes genomic instability and correlates with complex cytogenetic abnormalities in acute myeloid leukemia patients. (PMID:26802049)
• The Ser365 and Ser369 sites in a conserved DSGYAS motif are critical for the degradation of FOXN2 by beta-Trcp and RSK2. Moreover, gain-of-function and loss-of-function studies show that FOXN2 impairs cell proliferation in vitro and in vivo and enhances the radiosensitivity of lung cancer. (PMID:29396548)
• The WT1-AS was under-expressed in cervical carcinoma and suppresses cervical cancer cell growth and aggressiveness via a miR-203a-5p/FOXN2 axis. (PMID:30720155)
• FOXN2 suppresses the proliferation and invasion of human hepatocellular carcinoma cells. (PMID:33577027)
• HOXC6-Mediated miR-188-5p Expression Induces Cell Migration through the Inhibition of the Tumor Suppressor FOXN2. (PMID:35008435)
• Hsa_circ_0001741 Suppresses Ovarian Cancer Cell Proliferations Through Adsorption of miR-188-5p and Promotion of FOXN2 Expression. (PMID:37318741)
• Bmi1 facilitates the progression of cholangiocarcinoma by inhibiting Foxn2 expression dependent on a histone H2A ubiquitination manner. (PMID:38705565)
• FOXN2, identified as a novel biomarker in serum, modulates the transforming growth factor-beta signaling pathway through its interaction with partitioning defective 6 homolog alpha, contributing to the pathogenesis of gastric cancer. (PMID:38954805)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxn2b	ENSDARG00000045105
danio_rerio	FOXN2	ENSDARG00000055574
mus_musculus	Foxn2	ENSMUSG00000034998
rattus_norvegicus	Foxn2	ENSRNOG00000040110

Paralogs (2): FOXN3 (ENSG00000053254), FOXN4 (ENSG00000139445)

Protein

Protein identifiers

Forkhead box protein N2 — P32314 (reviewed: P32314)

Alternative names: Human T-cell leukemia virus enhancer factor

All UniProt accessions (2): P32314, C9JTA7

UniProt curated annotations — full annotation on UniProt →

Function. Binds to the purine-rich region in HTLV-I LTR.

Subcellular location. Nucleus.

Isoforms (2)

UniProt ID	Names	Canonical?
P32314-1	1	yes
P32314-2	2

RefSeq proteins (13): NP_001362371, NP_001362372, NP_001362373, NP_001362374, NP_001362375, NP_001362376, NP_001362377, NP_001362378, NP_001362379, NP_001362380, NP_001362381, NP_001362710, NP_002149* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR018122	TF_fork_head_CS_1	Conserved_site
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR047119	FOXN2/3-like	Family
IPR047403	FH_FOXN2	Domain

Pfam: PF00250

UniProt features (5 total): splice variant 2, chain 1, DNA-binding region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P32314-F1	61.00	0.20

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 247 (showing top): GOBP_MUSCLE_TISSUE_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GCAAGGA_MIR502, CAGCTG_AP4_Q5, AGTCTTA_MIR499, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_SKELETAL_MUSCLE_ORGAN_DEVELOPMENT, MORF_EPHA7, MORF_RAB3A, MORF_WNT1, CUI_TCF21_TARGETS_2_DN, GOBP_SKELETAL_MUSCLE_CELL_DIFFERENTIATION, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, MORF_IL9

GO Biological Process (3): regulation of DNA-templated transcription (GO:0006355), skeletal muscle cell differentiation (GO:0035914), regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (7): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
skeletal muscle tissue development	1
cell differentiation	1
transcription by RNA polymerase II	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1147 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXN2	ETS1	P14921	709
FOXN2	SHPRH	Q149N8	667
FOXN2	HLTF	Q14527	618
FOXN2	UBE2V2	Q15819	553
FOXN2	UBE2N	P61088	546
FOXN2	SMARCAL1	Q9NZC9	526
FOXN2	PPP1R21	Q6ZMI0	513
FOXN2	ZRANB3	Q5FWF4	506
FOXN2	FBXO11	Q86XK2	500
FOXN2	RAD18	Q9NS91	498
FOXN2	CDKN2A	P42771	492
FOXN2	FBH1	Q8NFZ0	477
FOXN2	LHCGR	P22888	437
FOXN2	HABP2	Q14520	419
FOXN2	GABPB1	Q06547	418

IntAct

10 interactions, top by confidence:

A	B	Type	Score
FOXN2	RFX1	psi-mi:“MI:0915”(physical association)	0.710
FOXN2	RFX1	psi-mi:“MI:0914”(association)	0.710
FBXW11	EEF2K	psi-mi:“MI:0914”(association)	0.640
FBXW11	FOXN2	psi-mi:“MI:0915”(physical association)	0.620
FOXA2	FOXN2	psi-mi:“MI:0914”(association)	0.350
FOXN2	FOXN2	psi-mi:“MI:0914”(association)	0.350
FOXN2	DHX16	psi-mi:“MI:0914”(association)	0.350

BioGRID (29): FOXN2 (Affinity Capture-MS), FOXN2 (Affinity Capture-MS), RFX1 (Affinity Capture-MS), FBXW11 (Affinity Capture-MS), HCFC1 (Affinity Capture-MS), SKP1 (Affinity Capture-MS), BTRC (Affinity Capture-MS), PSMD8 (Affinity Capture-MS), RFX1 (Affinity Capture-MS), RFX2 (Affinity Capture-MS), BTRC (Affinity Capture-MS), FBXW11 (Affinity Capture-MS), FOXN2 (Affinity Capture-MS), FOXN2 (Affinity Capture-Western), BTRC (Affinity Capture-Western)

ESM2 similar proteins: A8E5T6, O35437, O43680, O57598, O73615, O93507, O96642, P13349, P13903, P13904, P15375, P16075, P16076, P17667, P19335, P23409, P24699, P24700, P32314, P57101, P57102, P59101, P70661, P79782, P79920, P97831, Q02576, Q10574, Q18277, Q23579, Q32PV5, Q4ZHW1, Q5E9S3, Q62282, Q6GNB7, Q6NYU3, Q6PUV5, Q6SYV5, Q7YS80, Q7ZSX3

Diamond homologs: A0A8V0YY16, A1L1S5, A2BGM5, A8MTJ6, B5RHS5, D3Z120, O00358, O00409, O15353, O54743, O60129, O70220, O88470, O93529, P32027, P32028, P32030, P32314, P42128, P55316, P56260, P58012, Q00939, Q12946, Q12947, Q12948, Q12951, Q13461, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q28BS5, Q28D67, Q28F43, Q28G71, Q28H65, Q28HT3

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RPS6KA3	“down-regulates quantity by destabilization”	FOXN2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	66
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1571 predictions. Top by Δscore:

Variant	Effect	Δscore
2:48328543:A:G	acceptor_gain	1.0000
2:48344359:T:G	donor_gain	1.0000
2:48346199:A:AG	acceptor_gain	1.0000
2:48346200:G:GG	acceptor_gain	1.0000
2:48346200:GAACT:G	acceptor_gain	1.0000
2:48359041:TTCTA:T	acceptor_loss	1.0000
2:48359042:TCTA:T	acceptor_loss	1.0000
2:48359043:CTA:C	acceptor_loss	1.0000
2:48359044:TA:T	acceptor_loss	1.0000
2:48359045:A:AT	acceptor_loss	1.0000
2:48359145:AAA:A	donor_gain	1.0000
2:48359146:AA:A	donor_gain	1.0000
2:48359148:G:GG	donor_gain	1.0000
2:48362641:A:AG	acceptor_gain	1.0000
2:48362642:G:GG	acceptor_gain	1.0000
2:48373286:TTTCA:T	acceptor_loss	1.0000
2:48373287:TTCA:T	acceptor_loss	1.0000
2:48373288:TCA:T	acceptor_loss	1.0000
2:48373289:CAGAA:C	acceptor_loss	1.0000
2:48373290:A:AG	acceptor_gain	1.0000
2:48373290:A:G	acceptor_loss	1.0000
2:48373291:G:GT	acceptor_gain	1.0000
2:48373291:G:T	acceptor_loss	1.0000
2:48373291:GA:G	acceptor_gain	1.0000
2:48373291:GAA:G	acceptor_gain	1.0000
2:48373291:GAAT:G	acceptor_gain	1.0000
2:48373291:GAATC:G	acceptor_gain	1.0000
2:48373356:AGAAT:A	donor_gain	1.0000
2:48373357:GAAT:G	donor_gain	1.0000
2:48373357:GAATG:G	donor_gain	1.0000

AlphaMissense

2844 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:48346563:T:C	F117L	1.000
2:48346564:T:G	F117C	1.000
2:48346565:T:A	F117L	1.000
2:48346565:T:G	F117L	1.000
2:48346573:T:C	L120P	1.000
2:48346585:C:A	A124D	1.000
2:48346618:T:A	V135D	1.000
2:48346659:T:C	F149L	1.000
2:48346660:T:C	F149S	1.000
2:48346660:T:G	F149C	1.000
2:48346661:T:A	F149L	1.000
2:48346661:T:G	F149L	1.000
2:48346678:G:A	G155D	1.000
2:48346680:T:A	W156R	1.000
2:48346680:T:C	W156R	1.000
2:48346681:G:C	W156S	1.000
2:48346682:G:C	W156C	1.000
2:48346682:G:T	W156C	1.000
2:48346685:G:C	K157N	1.000
2:48346685:G:T	K157N	1.000
2:48346688:T:A	N158K	1.000
2:48346688:T:G	N158K	1.000
2:48346690:C:T	S159F	1.000
2:48346693:T:A	V160D	1.000
2:48346695:C:G	R161G	1.000
2:48346696:G:C	R161P	1.000
2:48346698:C:A	H162N	1.000
2:48346698:C:G	H162D	1.000
2:48346699:A:C	H162P	1.000
2:48346699:A:G	H162R	1.000

dbSNP variants (sampled 300 via entrez): RS1000015861 (2:48312205 T>C), RS1000083464 (2:48359370 T>C), RS1000149699 (2:48345584 A>G), RS1000199145 (2:48356264 A>G), RS1000203022 (2:48370251 G>A,C), RS1000223434 (2:48365011 C>A,G), RS1000250036 (2:48345826 A>G), RS1000272372 (2:48324902 T>A,C), RS1000313536 (2:48364939 G>A), RS1000322315 (2:48340241 G>T), RS1000356301 (2:48354575 G>C), RS1000385343 (2:48375919 C>G), RS1000393676 (2:48335454 T>A,C), RS1000471779 (2:48335344 T>C), RS1000517914 (2:48320400 C>G,T)

Disease associations

OMIM: gene MIM:143089 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST004861_40	Itch intensity from mosquito bite	3.000000e-08
GCST004862_174	Itch intensity from mosquito bite adjusted by bite size	2.000000e-07
GCST004865_59	Itch intensity from mosquito bite adjusted by bite size	8.000000e-08
GCST006976_66	Macular thickness	5.000000e-10
GCST007576_189	Chronotype	2.000000e-08
GCST007954_15	Glycated hemoglobin levels	2.000000e-08
GCST008522_8	Bitter alcoholic beverage consumption	6.000000e-08
GCST010242_125	HDL cholesterol levels	2.000000e-08
GCST011769_10	Schizophrenia	6.000000e-09
GCST90000025_743	Appendicular lean mass	3.000000e-15
GCST90011899_3	Aspartate aminotransferase levels	5.000000e-12
GCST90011900_138	Serum alkaline phosphatase levels	4.000000e-09
GCST90013405_96	Liver enzyme levels (alanine transaminase)	2.000000e-13
GCST90013407_104	Liver enzyme levels (gamma-glutamyl transferase)	3.000000e-30
GCST90013421_2	Left-handedness	2.000000e-11

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0008328	chronotype measurement
EFO:0004541	HbA1c measurement
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004980	appendicular lean mass
EFO:0004736	aspartate aminotransferase measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0009902	handedness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	increases abundance, increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
jinfukang	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	increases methylation	1
Carcinogens	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Indomethacin	increases expression, affects cotreatment	1
Manganese	increases abundance, increases expression	1
Mutagens	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Zinc	affects cotreatment, increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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