INSL4

Summary

INSL4 (insulin like 4, HGNC:6087) is a protein-coding gene on chromosome 9p24.1, encoding Early placenta insulin-like peptide (Q14641). May play an important role in trophoblast development and in the regulation of bone formation.

INSL4 encodes the insulin-like 4 protein, a member of the insulin superfamily. INSL4 encodes a precursor that undergoes post-translational cleavage to produce 3 polypeptide chains, A-C, that form tertiary structures composed of either all three chains, or just the A and B chains. Expression of INSL4 products occurs within the early placental cytotrophoblast and syncytiotrophoblast.

Source: NCBI Gene 3641 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 43 total
• MANE Select transcript: NM_002195

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6087
Approved symbol	INSL4
Name	insulin like 4
Location	9p24.1
Locus type	gene with protein product
Status	Approved
Aliases	EPIL
Ensembl gene	ENSG00000120211
Ensembl biotype	protein_coding
OMIM	600910
Entrez	3641

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000239316

RefSeq mRNA: 1 — MANE Select: NM_002195 NM_002195

CCDS: CCDS6459

Canonical transcript exons

ENST00000239316 — 2 exons

Exon	Start	End
ENSE00000813146	5231419	5231719
ENSE00000813147	5233654	5235304

Expression profiles

Bgee: expression breadth broad, 21 present calls, max score 92.14.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3949 / max 179.4221, expressed in 54 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95935	0.3949	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	92.14	gold quality
pancreatic ductal cell	CL:0002079	59.37	silver quality
tibialis anterior	UBERON:0001385	58.90	silver quality
ileal mucosa	UBERON:0000331	57.52	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	57.08	silver quality
thymus	UBERON:0002370	52.33	gold quality
deltoid	UBERON:0001476	52.02	gold quality
epithelial cell of pancreas	CL:0000083	51.09	gold quality
hair follicle	UBERON:0002073	50.12	gold quality
quadriceps femoris	UBERON:0001377	50.07	gold quality
corpus epididymis	UBERON:0004359	49.32	silver quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
vastus lateralis	UBERON:0001379	49.20	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
layer of synovial tissue	UBERON:0007616	48.66	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
renal glomerulus	UBERON:0000074	48.08	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
upper leg skin	UBERON:0004262	48.04	silver quality
cervix epithelium	UBERON:0004801	48.04	gold quality
oviduct epithelium	UBERON:0004804	48.00	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-24	yes	3727.07
E-MTAB-6701	yes	3048.60
E-ANND-3	no	2.95

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

• We identified an INSL4 alternatively spliced mRNA species that encodes putative novel INSL4-like peptides. (PMID:12606452)
• Expression of the INSL4 gene was doubled in the placenta of the growth-restricted twin compared to the normally grown sibling, suggesting that it may be linked to a higher level of apoptosis and loss of cell viability (PMID:15958731)
• A tight interaction between HER-2 gene and EPIL in invasive breast cancer cells is probable. (PMID:18035692)
• Report decreased INSL4 gene expression in both the invasive and the noninvasive areas of villous trophoblast in patients with placenta accreta. (PMID:23302396)
• LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers. (PMID:30423141)

Cross-species orthologs

0 orthologs

Paralogs (3): RLN2 (ENSG00000107014), RLN1 (ENSG00000107018), INSL6 (ENSG00000120210)

Protein

Protein identifiers

Early placenta insulin-like peptide — Q14641 (reviewed: Q14641)

Alternative names: Insulin-like peptide 4, Placentin

All UniProt accessions (1): Q14641

UniProt curated annotations — full annotation on UniProt →

Function. May play an important role in trophoblast development and in the regulation of bone formation.

Subcellular location. Secreted.

Tissue specificity. Expressed in placenta, uterus and in fetal perichondrium. Expression levels were increased in both early placentas and molar pregnancies and were reduced in choriocarcinoma cells.

Similarity. Belongs to the insulin family.

RefSeq proteins (1): NP_002186* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022421	Relaxin	Family
IPR023258	Placentin	Family
IPR051042	Repro_Hormone_Insulin-like	Family

UniProt features (8 total): disulfide bond 3, peptide 2, signal peptide 1, chain 1, propeptide 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14641-F1	51.80	0.00

Functional residue map

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

Disulfide bonds (3): 31–125, 43–138, 124–129

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 64 (showing top): MODULE_92, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_CELL_CELL_SIGNALING, GOMF_INSULIN_LIKE_GROWTH_FACTOR_RECEPTOR_BINDING, KYNG_DNA_DAMAGE_BY_GAMMA_RADIATION, MODULE_99, GNF2_KISS1, HAN_SATB1_TARGETS_DN, GOMF_SIGNALING_RECEPTOR_BINDING, GOMF_HORMONE_ACTIVITY, GNF2_TIMP2, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, WOOD_EBV_EBNA1_TARGETS_DN, DAZARD_RESPONSE_TO_UV_NHEK_UP, KYNG_RESPONSE_TO_H2O2_VIA_ERCC6_UP

GO Biological Process (3): cell-cell signaling (GO:0007267), positive regulation of chorionic trophoblast cell proliferation (GO:1901384), signal transduction (GO:0007165)

GO Molecular Function (3): signaling receptor binding (GO:0005102), insulin-like growth factor receptor binding (GO:0005159), hormone activity (GO:0005179)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
signaling	2
positive regulation of cell population proliferation	1
chorionic trophoblast cell proliferation	1
regulation of chorionic trophoblast cell proliferation	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
protein binding	1
signaling receptor binding	1
receptor ligand activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

342 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INSL4	INSL6	Q9Y581	979
INSL4	RLN1	P04808	925
INSL4	RLN2	P04090	917
INSL4	INSL3	P51460	908
INSL4	RLN3	Q8WXF3	716
INSL4	INSL5	Q9Y5Q6	663
INSL4	RXFP4	Q8TDU9	599
INSL4	RXFP3	Q9NSD7	596
INSL4	RXFP1	Q9HBX9	582
INSL4	RXFP2	Q8WXD0	573
INSL4	INS	P01308	535
INSL4	IGF2	P01344	457
INSL4	SRY	Q05066	453
INSL4	MID1	O15344	401
INSL4	K7ELM3	K7ELM3	397

IntAct

3 interactions, top by confidence:

A	B	Type	Score
INSL4	SGSH	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): HMGCS1 (Affinity Capture-MS), UBR3 (Affinity Capture-MS), SGSH (Affinity Capture-MS), TESC (Affinity Capture-MS), GPR98 (Affinity Capture-MS), INSL4 (Proximity Label-MS), INSL4 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: B5DEL3, B5X8I6, E7F211, E7F5F0, E7FAP8, E9PVB5, O70514, O76061, O97561, P01586, P05305, P09558, P09916, P0DJK0, P13206, P13207, P16043, P17251, P17322, P20800, P22389, P23943, P29560, P47932, P51456, P52211, P58073, P58239, P83056, P83057, Q14641, Q1ZYL8, Q5CZK6, Q5JX71, Q5M889, Q5NRP8, Q5NRP9, Q5NRQ1, Q5RAT2, Q5VWQ0

Diamond homologs: P01347, P01348, P04090, P04808, P11184, P11185, P19884, P22969, P47932, P51453, P51454, P51455, P51456, Q14641, Q5CZK6, Q64171, Q7M3C4, Q9MYK8, Q9TRM8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

243 predictions. Top by Δscore:

Variant	Effect	Δscore
9:5233645:A:AG	acceptor_gain	1.0000
9:5233646:C:G	acceptor_gain	1.0000
9:5233651:C:G	acceptor_gain	1.0000
9:5233651:CA:C	acceptor_loss	1.0000
9:5233652:A:AG	acceptor_gain	1.0000
9:5233653:G:GA	acceptor_gain	1.0000
9:5233653:GA:G	acceptor_gain	1.0000
9:5233653:GAA:G	acceptor_gain	1.0000
9:5233653:GAAAT:G	acceptor_gain	1.0000
9:5233650:A:AG	acceptor_gain	0.9900
9:5233653:GAAA:G	acceptor_gain	0.9900
9:5231715:CAAAG:C	donor_loss	0.9600
9:5231716:AAAGG:A	donor_loss	0.9600
9:5231717:AAGG:A	donor_loss	0.9600
9:5231718:AGG:A	donor_loss	0.9600
9:5231719:GGTGA:G	donor_loss	0.9600
9:5231720:G:C	donor_loss	0.9600
9:5231721:T:G	donor_loss	0.9600
9:5233655:A:AG	acceptor_gain	0.9200
9:5231687:G:GT	donor_gain	0.8900
9:5231722:G:GT	donor_loss	0.8900
9:5231688:A:T	donor_gain	0.8300
9:5231720:G:GG	donor_gain	0.8300
9:5233652:A:C	acceptor_gain	0.8300
9:5233632:A:AG	acceptor_gain	0.8200
9:5231793:T:TA	donor_gain	0.8100
9:5231794:A:AA	donor_gain	0.8100
9:5233653:G:C	acceptor_gain	0.8100
9:5231708:G:GT	donor_gain	0.7800
9:5233651:CAGAA:C	acceptor_gain	0.7800

AlphaMissense

873 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:5233842:T:A	C129S	0.945
9:5233843:G:C	C129S	0.945
9:5231626:T:C	F35L	0.932
9:5231628:T:A	F35L	0.932
9:5231628:T:G	F35L	0.932
9:5233830:T:A	C125S	0.930
9:5233831:G:C	C125S	0.930
9:5233843:G:A	C129Y	0.913
9:5233842:T:C	C129R	0.907
9:5233869:T:A	C138S	0.905
9:5233870:G:C	C138S	0.905
9:5231572:A:C	S17R	0.895
9:5231574:C:A	S17R	0.895
9:5231574:C:G	S17R	0.895
9:5233831:G:A	C125Y	0.890
9:5233871:T:G	C138W	0.886
9:5233844:T:G	C129W	0.880
9:5231650:T:A	C43S	0.877
9:5231651:G:C	C43S	0.877
9:5233869:T:C	C138R	0.875
9:5233830:T:C	C125R	0.873
9:5231652:C:G	C43W	0.865
9:5233832:T:G	C125W	0.855
9:5231560:T:A	W13R	0.847
9:5231560:T:C	W13R	0.847
9:5233831:G:T	C125F	0.841
9:5231627:T:G	F35C	0.833
9:5231614:T:A	C31S	0.830
9:5231615:G:C	C31S	0.830
9:5231650:T:C	C43R	0.828

dbSNP variants (sampled 300 via entrez): RS1000154028 (9:5230543 G>A), RS1000910067 (9:5233043 A>G), RS1000935491 (9:5229450 G>C), RS1001038738 (9:5229828 T>A,C), RS1001449884 (9:5229604 C>T), RS1001569721 (9:5231408 A>G,T), RS1001699087 (9:5235556 A>C,G), RS1002069285 (9:5235469 C>A,G), RS1002171605 (9:5230946 G>A), RS1002541376 (9:5235703 A>C), RS1003247063 (9:5230775 G>A,C,T), RS1003812553 (9:5234685 C>T), RS1004042540 (9:5230140 G>C), RS1004323663 (9:5232606 C>G), RS1004725877 (9:5234784 C>A)

Disease associations

OMIM: gene MIM:600910 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000529_4	Ulcerative colitis	1.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases expression	3
beta-Naphthoflavone	decreases expression	2
Esketamine	decreases expression	1
propionaldehyde	decreases expression	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Atrazine	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Lipopolysaccharides	affects expression, affects response to substance	1
Silicon Dioxide	decreases expression	1
Thiram	increases expression	1
Valproic Acid	decreases methylation	1
Vanadium	increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	decreases expression	1

Clinical trials (associated diseases)

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