FEV

Summary

FEV (FEV transcription factor, ETS family member, HGNC:18562) is a protein-coding gene on chromosome 2q35, encoding Protein FEV (Q99581). Functions as a transcriptional regulator.

This gene belongs to the ETS transcription factor family. ETS family members have a highly conserved 85-amino acid ETS domain that binds purine-rich DNA sequences. The alanine-rich C-terminus of this gene indicates that it may act as a transcription repressor. This gene is exclusively expressed in neurons of the central serotonin (5-HT) system, a system implicated in the pathogeny of such psychiatric diseases as depression, anxiety, and eating disorders. In some types of Ewing tumors, this gene is fused to the Ewing sarcoma (EWS) gene following chromosome translocations.

Source: NCBI Gene 54738 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 44 total
• MANE Select transcript: NM_017521

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18562
Approved symbol	FEV
Name	FEV transcription factor, ETS family member
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	Pet-1
Ensembl gene	ENSG00000163497
Ensembl biotype	protein_coding
OMIM	607150
Entrez	54738

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000295727, ENST00000470119

RefSeq mRNA: 1 — MANE Select: NM_017521 NM_017521

CCDS: CCDS2428

Canonical transcript exons

ENST00000295727 — 3 exons

Exon	Start	End
ENSE00001075299	218984231	218984305
ENSE00001075302	218985024	218985184
ENSE00001075303	218981087	218982256

Expression profiles

Bgee: expression breadth broad, 90 present calls, max score 85.96.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9323 / max 392.4574, expressed in 66 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33996	0.3344	27
34005	0.1698	37
34004	0.0960	20
33998	0.0635	16
34003	0.0608	12
34000	0.0397	7
34002	0.0393	9
33999	0.0372	16
34006	0.0275	11
34007	0.0224	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	85.96	gold quality
diaphragm	UBERON:0001103	83.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.00	gold quality
olfactory bulb	UBERON:0002264	81.09	gold quality
islet of Langerhans	UBERON:0000006	76.04	gold quality
hair follicle	UBERON:0002073	69.49	gold quality
mucosa of transverse colon	UBERON:0004991	69.32	gold quality
duodenum	UBERON:0002114	67.16	gold quality
vastus lateralis	UBERON:0001379	66.82	gold quality
cardiac muscle of right atrium	UBERON:0003379	66.59	gold quality
left ventricle myocardium	UBERON:0006566	66.55	gold quality
rectum	UBERON:0001052	66.44	gold quality
quadriceps femoris	UBERON:0001377	65.92	gold quality
pituitary gland	UBERON:0000007	65.84	gold quality
mucosa of sigmoid colon	UBERON:0004993	65.21	gold quality
adenohypophysis	UBERON:0002196	64.88	gold quality
epithelium of nasopharynx	UBERON:0001951	63.35	gold quality
prostate gland	UBERON:0002367	62.71	gold quality
pancreas	UBERON:0001264	62.61	gold quality
putamen	UBERON:0001874	62.01	gold quality
CA1 field of hippocampus	UBERON:0003881	61.96	gold quality
nasal cavity epithelium	UBERON:0005384	61.38	gold quality
colonic mucosa	UBERON:0000317	61.17	gold quality
small intestine	UBERON:0002108	60.53	gold quality
superior vestibular nucleus	UBERON:0007227	60.40	silver quality
small intestine Peyer’s patch	UBERON:0003454	59.96	gold quality
inferior olivary complex	UBERON:0002127	59.76	gold quality
myocardium	UBERON:0002349	59.38	gold quality
heart right ventricle	UBERON:0002080	59.32	gold quality
Brodmann (1909) area 10	UBERON:0013541	59.20	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	907.22
E-MTAB-5061	yes	26.43
E-GEOD-81547	yes	21.96
E-ANND-3	no	3.10

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
DDC
GCH1	Unknown
GCHFR	Unknown
HTR1A	Activation
ICAM1	Repression
QDPR	Unknown
SLC6A4
TPH1

JASPAR motifs

Motif	Name	Family
MA0156.1	FEV	Ets-related
MA0156.2	FEV	Ets-related
MA0156.3	FEV	Ets-related
MA0156.4	FEV	Ets-related

JASPAR matrix evidence (PMIDs): PMID:17916232, PMID:20517297

miRNA regulators (miRDB)

26 targeting FEV, 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-4283	100.00	66.42	2097
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-514A-5P	96.94	65.49	801
HSA-MIR-597-5P	96.82	67.57	732
HSA-MIR-3189-3P	96.80	66.34	896
HSA-MIR-6839-5P	96.74	68.29	1088
HSA-MIR-378J	96.44	66.20	1020
HSA-MIR-3675-5P	95.90	65.80	474
HSA-MIR-6796-5P	95.37	66.08	1120
HSA-MIR-769-5P	94.45	64.56	603
HSA-MIR-6820-5P	94.04	61.13	161

Literature-anchored findings (GeneRIF, showing 14)

• FEV acts as a transcriptional repressor through its DNA-binding ETS domain and alanine-rich domain. (PMID:12761502)
• We showed that fev is exclusively expressed in the midline part of the human brainstem containing raphe nuclei, which also specifically expressed 5-HT transporter (sert) and tryptophan hydroxylase (tph), two markers of the 5-HT neurotransmitter system. (PMID:15003288)
• Analysis of transgene expression in Pet-1 null mice indicates that Pet-1 is required to maintain the activity of the Pet-1 enhancer region in a subset of serotonin (5-HT) neurons. (PMID:15758173)
• Variation in FEV gene observed exclusively in a subset of African American sudden infant death syndrome cases may help explain the observed abnormalities of this system in some SIDS cases and the ethnic disparity. (PMID:17597646)
• Serotonin-related FEV gene variant in the sudden infant death syndrome is a common polymorphism in the African-American population. (PMID:19707175)
• FEV identifies serotonin-producing cells in normal and neoplastic small intestine. (PMID:20048018)
• our data argue against an exclusive role of FEV in the adult human brain serotonergic system and genetic analyses did not suggest that FEV variation adds to the genetic liability towards affective disorders (PMID:20480378)
• Fev-ERK signaling is essential for hemogenic endothelium-based hematopoietic stem cell development. (PMID:23591790)
• novel evidence for the role of Pet-1 in human amygdala threat processing extends literature demonstrating the influence of genetic variation in the serotonin system on emotional regulation (PMID:24100022)
• Genetic variation in FEV1 was associated with serum 25-Hydroxyvitamin D status. (PMID:26122139)
• identified FEV is unique to fetal HSCs and stably expressed in leukemic cells of prenatal origin (PMID:27807368)
• This study adds to the growing evidence on the association of single- and multiple-risk variants in DRD3, DRD4, and FEV with aggressive behavior in Chinese adolescents. (PMID:28846959)
• Ewing sarcoma with FEV gene rearrangements is a rare subset with predilection for extraskeletal locations and aggressive behavior. (PMID:31756779)
• Tumor Suppressor Role and Clinical Significance of the FEV Gene in Prostate Cancer. (PMID:35548776)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fev	ENSDARG00000009242
mus_musculus	Fev	ENSMUSG00000055197
rattus_norvegicus	Fev	ENSRNOG00000017856

Paralogs (28): ETV1 (ENSG00000006468), ETV7 (ENSG00000010030), SPI1 (ENSG00000066336), ELF4 (ENSG00000102034), ETV2 (ENSG00000105672), ERF (ENSG00000105722), ELF2 (ENSG00000109381), ELK3 (ENSG00000111145), ETV3 (ENSG00000117036), ELF1 (ENSG00000120690), SPDEF (ENSG00000124664), ELK1 (ENSG00000126767), ETS1 (ENSG00000134954), EHF (ENSG00000135373), ELF5 (ENSG00000135374), ETV6 (ENSG00000139083), FLI1 (ENSG00000151702), GABPA (ENSG00000154727), ERG (ENSG00000157554), ETS2 (ENSG00000157557), ELK4 (ENSG00000158711), ELF3 (ENSG00000163435), SPIC (ENSG00000166211), ETV4 (ENSG00000175832), ETV5 (ENSG00000244405), ETV3L (ENSG00000253831), ERFL (ENSG00000268041), SPIB (ENSG00000269404)

Protein

Protein identifiers

Protein FEV — Q99581 (reviewed: Q99581)

Alternative names: Fifth Ewing variant protein, PC12 ETS domain-containing transcription factor 1

All UniProt accessions (1): Q99581

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a transcriptional regulator. According to PubMed:12761502, it functions as a transcriptional repressor. Functions in the differentiation and the maintenance of the central serotonergic neurons. May play a role in cell growth.

Subcellular location. Nucleus.

Tissue specificity. In brain, exclusively expressed in the major serotonergic neurons of the dorsal and median raphe nuclei located in the midbrain and pons. Also detected in prostate and small intestine.

Disease relevance. Sudden infant death syndrome (SIDS) [MIM:272120] SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. Disease susceptibility may be associated with variants affecting the gene represented in this entry. A chromosomal aberration involving FEV is found in Ewing tumors. Translocation t(2;21;22)(q23;q22;q12) that forms a EWSR1-FEV fusion protein with a potential oncogenic activity.

Similarity. Belongs to the ETS family.

RefSeq proteins (1): NP_059991* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000418	Ets_dom	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR046328	ETS_fam	Family

Pfam: PF00178

UniProt features (15 total): helix 5, strand 4, turn 2, chain 1, DNA-binding region 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3ZP5	X-RAY DIFFRACTION	2
2YPR	X-RAY DIFFRACTION	2.64

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99581-F1	68.03	0.39

Functional residue map

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

Catalytic / active sites (1): 18–19 (breakpoint for insertion to form ews-fev fusion protein)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 140 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_NEURON_MATURATION, SP3_Q3, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_NEUROGENESIS, MODULE_16, LHX3_01, SP1_Q2_01, GCM_PRKCG, MODULE_66, GOBP_ANATOMICAL_STRUCTURE_MATURATION, IRF7_01, GCM_RING1, GGAANCGGAANY_UNKNOWN

GO Biological Process (10): regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of gene expression (GO:0010628), cell differentiation (GO:0030154), neuron maturation (GO:0042551), maternal behavior (GO:0042711), neuron fate specification (GO:0048665), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nuclear speck (GO:0016607)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
regulation of gene expression	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
DNA binding	2
gene expression	1
positive regulation of macromolecule biosynthetic process	1
cellular developmental process	1
cell maturation	1
neuron development	1
parental behavior	1
cell fate specification	1
neuron fate commitment	1
regulation of RNA biosynthetic process	1
system development	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FEV	SLC6A4	P31645	632
FEV	TPH2	Q8IWU9	548
FEV	RFX6	Q8HWS3	498
FEV	LMX1B	O60663	485
FEV	INSM1	Q01101	478
FEV	NEUROG3	Q9Y4Z2	476
FEV	BTBD17	A6NE02	466
FEV	NKX2-2	O95096	443
FEV	HCRTR1	O43613	437
FEV	PAX4	O43316	436
FEV	SLC17A7	Q9P2U7	433
FEV	ABR	Q12979	419
FEV	SLC18A2	Q05940	418
FEV	SLC17A8	Q8NDX2	415
FEV	TPH1	P17752	404

IntAct

3 interactions, top by confidence:

A	B	Type	Score
FEV	PSMB4	psi-mi:“MI:0914”(association)	0.350
FEV	TAF4	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (202): FEV (Affinity Capture-MS), FOXP2 (Proximity Label-MS), ELF1 (Proximity Label-MS), SOX5 (Proximity Label-MS), MNX1 (Proximity Label-MS), FOXK1 (Proximity Label-MS), ARID2 (Proximity Label-MS), ZNF521 (Proximity Label-MS), FOXP1 (Proximity Label-MS), ZNF644 (Proximity Label-MS), TAF4 (Proximity Label-MS), BCL9 (Proximity Label-MS), NFIB (Proximity Label-MS), ARID1A (Proximity Label-MS), KMT2D (Proximity Label-MS)

ESM2 similar proteins: A2WY46, A6BLW4, B8A9B2, G0SB31, G4MRQ6, G4N3L5, M2TF54, O54772, O65001, O70132, P17208, P20264, P20265, P20266, P20267, P21952, P25209, P31360, P31361, P53784, P56222, Q01851, Q02516, Q03052, Q0JGS5, Q13164, Q60764, Q60EQ4, Q63262, Q655V5, Q69J40, Q69TW5, Q6EU10, Q75IZ7, Q8L4B2, Q8LCG7, Q8LH59, Q8QZW2, Q92925, Q960X8

Diamond homologs: A0A1W2PQ73, A0JN51, A1A4L6, A1YF15, A1YG61, A1YG91, A2D4Z7, A2T737, A2T762, A3FEM2, A4GTP4, A8WFJ9, O00321, O01519, O70132, O70273, O95238, P01105, P10157, P11308, P11536, P13474, P14921, P15036, P15037, P15062, P18755, P18756, P19102, P19419, P20105, P26323, P27577, P28322, P28324, P29773, P29774, P29775, P29776, P32519

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FEV	“down-regulates quantity by repression”	ICAM1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

688 predictions. Top by Δscore:

Variant	Effect	Δscore
2:218984227:TCACC:T	donor_loss	1.0000
2:218984229:A:C	donor_loss	1.0000
2:218984230:CCTTT:C	donor_gain	1.0000
2:218984302:GGAT:G	acceptor_gain	1.0000
2:218984302:GGATC:G	acceptor_loss	1.0000
2:218984303:GATC:G	acceptor_loss	1.0000
2:218984304:ATCT:A	acceptor_loss	1.0000
2:218984305:TCT:T	acceptor_loss	1.0000
2:218984306:C:CA	acceptor_loss	1.0000
2:218984306:C:CC	acceptor_gain	1.0000
2:218984307:T:A	acceptor_loss	1.0000
2:218984977:C:A	donor_gain	1.0000
2:218982253:CTGC:C	acceptor_gain	0.9900
2:218982255:GCCTG:G	acceptor_loss	0.9900
2:218982257:C:CC	acceptor_gain	0.9900
2:218984301:GGGAT:G	acceptor_gain	0.9900
2:218984303:GAT:G	acceptor_gain	0.9900
2:218984313:C:CT	acceptor_gain	0.9900
2:218984314:A:T	acceptor_gain	0.9900
2:218984443:T:TA	donor_gain	0.9900
2:218984976:T:TA	donor_gain	0.9900
2:218982254:TGC:T	acceptor_gain	0.9800
2:218984304:AT:A	acceptor_gain	0.9800
2:218984309:C:CT	acceptor_gain	0.9800
2:218984446:T:TA	donor_gain	0.9800
2:218984447:C:CA	donor_gain	0.9800
2:218984431:C:CT	donor_gain	0.9700
2:218984440:T:TA	donor_gain	0.9700
2:218984996:C:CT	donor_gain	0.9700
2:218985019:GGTAC:G	donor_loss	0.9700

AlphaMissense

1535 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:218982001:A:G	F128S	1.000
2:218982006:G:C	F126L	1.000
2:218982006:G:T	F126L	1.000
2:218982007:A:C	F126C	1.000
2:218982007:A:G	F126S	1.000
2:218982008:A:C	F126V	1.000
2:218982008:A:G	F126L	1.000
2:218982008:A:T	F126I	1.000
2:218982013:T:C	Y124C	1.000
2:218982014:A:C	Y124D	1.000
2:218982014:A:G	Y124H	1.000
2:218982014:A:T	Y124N	1.000
2:218982016:G:T	A123D	1.000
2:218982019:T:C	Y122C	1.000
2:218982020:A:C	Y122D	1.000
2:218982020:A:G	Y122H	1.000
2:218982023:G:A	R121C	1.000
2:218982023:G:T	R121S	1.000
2:218982024:C:A	K120N	1.000
2:218982024:C:G	K120N	1.000
2:218982028:C:A	G119V	1.000
2:218982028:C:T	G119D	1.000
2:218982029:C:A	G119C	1.000
2:218982029:C:G	G119R	1.000
2:218982036:C:A	K116N	1.000
2:218982036:C:G	K116N	1.000
2:218982037:T:A	K116M	1.000
2:218982038:T:C	K116E	1.000
2:218982038:T:G	K116Q	1.000
2:218982043:A:C	M114R	1.000

dbSNP variants (sampled 300 via entrez): RS1000192283 (2:218981525 C>A,G), RS1000582709 (2:218983001 C>A), RS1000644750 (2:218983273 T>A,C), RS1000710909 (2:218981697 T>C,G), RS1000931914 (2:218982964 G>A), RS1001548966 (2:218983984 C>A,T), RS1002618909 (2:218985461 C>G,T), RS1002661498 (2:218985676 C>G), RS1002736096 (2:218984487 T>C), RS1002936093 (2:218985455 C>A,G,T), RS1003383616 (2:218981182 A>C), RS1004149928 (2:218986944 A>G), RS1004393209 (2:218981013 G>A,C), RS1004462712 (2:218981360 C>A,T), RS1004512011 (2:218980702 T>C,G)

Disease associations

OMIM: gene MIM:607150 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000175_19	Height	1.000000e-06
GCST001491_18	Immune response to smallpox vaccine (IL-6)	2.000000e-06
GCST006661_114	Male-pattern baldness	2.000000e-16
GCST010002_409	Refractive error	2.000000e-17

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases expression	2
MT19c compound	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Sarin	decreases expression, increases expression	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

5 cell lines: 3 embryonic stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_4Z31	TC-205	Cancer cell line
CVCL_9682	STA-ET-10	Cancer cell line	Female
CVCL_A1R7	SEES3-1V human FEV, clone1	Embryonic stem cell	Male
CVCL_A1R8	SEES3-1V human FEV, clone2	Embryonic stem cell	Male
CVCL_A1R9	SEES3-1V human FEV, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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