INSL5

Summary

INSL5 (insulin like 5, HGNC:6088) is a protein-coding gene on chromosome 1p31.3, encoding Insulin-like peptide INSL5 (Q9Y5Q6). May have a role in gut contractility or in thymic development and regulation.

The protein encoded by this gene contains a classical signature of the insulin superfamily and is highly similar to relaxin 3 (RLN3/INSL7).

Source: NCBI Gene 10022 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 15 total
• MANE Select transcript: NM_005478

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6088
Approved symbol	INSL5
Name	insulin like 5
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000172410
Ensembl biotype	protein_coding
OMIM	606413
Entrez	10022

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000304526

RefSeq mRNA: 1 — MANE Select: NM_005478 NM_005478

CCDS: CCDS634

Canonical transcript exons

ENST00000304526 — 2 exons

Exon	Start	End
ENSE00001174208	66797740	66798245
ENSE00001174213	66801047	66801276

Expression profiles

Bgee: expression breadth broad, 89 present calls, max score 96.16.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	96.16	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.12	gold quality
colonic mucosa	UBERON:0000317	82.94	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.11	gold quality
mucosa of transverse colon	UBERON:0004991	72.71	gold quality
buccal mucosa cell	CL:0002336	65.53	gold quality
secondary oocyte	CL:0000655	59.37	gold quality
pancreatic ductal cell	CL:0002079	59.24	silver quality
oviduct epithelium	UBERON:0004804	56.43	silver quality
transverse colon	UBERON:0001157	54.99	gold quality
large intestine	UBERON:0000059	54.33	gold quality
myocardium	UBERON:0002349	53.71	gold quality
right uterine tube	UBERON:0001302	53.59	gold quality
ileal mucosa	UBERON:0000331	53.24	silver quality
colon	UBERON:0001155	53.19	gold quality
nasal cavity epithelium	UBERON:0005384	52.09	gold quality
male germ cell	CL:0000015	51.99	gold quality
sperm	CL:0000019	51.83	gold quality
epithelial cell of pancreas	CL:0000083	51.07	gold quality
hypothalamus	UBERON:0001898	51.07	gold quality
cranial nerve II	UBERON:0000941	50.91	silver quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
quadriceps femoris	UBERON:0001377	49.09	gold quality
deltoid	UBERON:0001476	49.05	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	8.70
E-ANND-3	no	1.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting INSL5, 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-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-1911-3P	99.15	66.17	528
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-6529-5P	97.85	66.47	673
HSA-MIR-6782-3P	97.60	67.75	931
HSA-MIR-212-5P	96.83	67.43	950

Literature-anchored findings (GeneRIF, showing 17)

• Insulin-like peptide 5 is an endogenous ligand for GPCR142 (PMID:15525639)
• The hydrogen-bond network and electrostatic interactions between charged groups in INSL5 by NMR-monitored temperature and pH titrations was characterized. (PMID:19178384)
• High INSL5 expression is associated with enteroendocrine cells of the neuroendocrine tumors. (PMID:23128569)
• INSL5 may be a unique marker of colorectal enteroendocrine cells, and INSL5-RXFP4 signaling might play a role in an autocrine/paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors. (PMID:23438439)
• Insl5 is an orexigenic hormone released from colonic L-cells, which promotes appetite during conditions of energy deprivation. (PMID:25028498)
• electrostatic interactions between INSL5 and RXFP4 (PMID:25043977)
• The C-terminus of the B-chain of human INSL5 is critical for cognate RXFP4 receptor activity. (PMID:26661035)
• High serum INSL5 is associated with obesity in men. (PMID:27355242)
• analysis of the interaction mechanism of INSL5 with its receptor RXFP4 (PMID:28274616)
• Mass spectral analysis of purified enteroendocrine cells and tissue homogenates identified the exact sequence of A and B chains of INSL5 endogenously expressed in L-cells. (PMID:28857318)
• The R27S (B5Ser) mutant variant of INSL5 was evaluated as a potential antagonist of the native RXFP4 receptor, yet was found to match the potency and maximal efficacy to the native hormone. This informs that the R27S phenotype is not directly linked to the receptor activity of the peptide, but likely affects endogenous hormone production or secretion. (PMID:29466617)
• This study provides novel insights into possible autocrine/paracrine roles of INSL5 in the intestinal tract. (PMID:29535183)
• High serum INLS5 levels are associated with metabolic diseases in women with polycystic ovary syndrome. (PMID:29956214)
• Autocrine INSL5 promotes tumor progression and glycolysis via activation of STAT5 signaling. (PMID:32657028)
• Expression of Cytokine-Coding Genes BMP8B, LEFTY1 and INSL5 Could Distinguish between Ulcerative Colitis and Crohn’s Disease. (PMID:34680872)
• Insulin-like peptide 5 (INSL5) positively correlates with anti-Mullerian hormone (AMH) in women with the polycystic ovary syndrome: a case-control study. (PMID:36303231)
• Insulin-like peptide 5 is associated with insulin resistance in women with polycystic ovary syndrome. (PMID:37207506)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	insl5b	ENSDARG00000069294
danio_rerio	insl5a	ENSDARG00000070966
mus_musculus	Insl5	ENSMUSG00000066090

Paralogs (1): RLN3 (ENSG00000171136)

Protein

Protein identifiers

Insulin-like peptide INSL5 — Q9Y5Q6 (reviewed: Q9Y5Q6)

All UniProt accessions (1): Q9Y5Q6

UniProt curated annotations — full annotation on UniProt →

Function. May have a role in gut contractility or in thymic development and regulation. Activates RXFP4 with high potency and appears to be the endogenous ligand for this receptor.

Subunit / interactions. Heterodimer of a B chain and an A chain linked by two disulfide bonds.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in rectum with lower levels in uterus and ascending and descending colon.

Similarity. Belongs to the insulin family.

RefSeq proteins (1): NP_005469* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016179	Insulin-like	Domain
IPR022353	Insulin_CS	Conserved_site
IPR036438	Insulin-like_sf	Homologous_superfamily
IPR051777	Insulin-like_neuro_ligands	Family

Pfam: PF00049

UniProt features (15 total): helix 3, disulfide bond 3, peptide 2, turn 2, signal peptide 1, propeptide 1, modified residue 1, sequence variant 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7YJ4	ELECTRON MICROSCOPY	3.19
2K1V	SOLUTION NMR
2KBC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5Q6-F1	63.74	0.23

Antibody-complex structures (SAbDab): 1 — 7YJ4

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 (1): 115

Disulfide bonds (3): 29–122, 41–135, 121–126

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-418594	G alpha (i) signalling events
R-HSA-444821	Relaxin receptors
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 77 (showing top): GOBP_BEHAVIOR, GOBP_POSITIVE_REGULATION_OF_BEHAVIOR, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_REGULATION_OF_BEHAVIOR, GOBP_REGULATION_OF_FEEDING_BEHAVIOR, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, SABATES_COLORECTAL_ADENOMA_DN, KANG_IMMORTALIZED_BY_TERT_DN, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_POSITIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_FEEDING_BEHAVIOR, GOMF_HORMONE_ACTIVITY, REACTOME_CLASS_A_1_RHODOPSIN_LIKE_RECEPTORS, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY

GO Biological Process (2): positive regulation of feeding behavior (GO:2000253), signal transduction (GO:0007165)

GO Molecular Function (3): G protein-coupled receptor binding (GO:0001664), hormone activity (GO:0005179), protein binding (GO:0005515)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by GPCR	2
GPCR downstream signalling	1
Peptide ligand-binding receptors	1
Signal Transduction	1
GPCR ligand binding	1
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
feeding behavior	1
positive regulation of behavior	1
regulation of feeding behavior	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signaling receptor binding	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

522 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INSL5	RXFP4	Q8TDU9	953
INSL5	RLN1	P04808	944
INSL5	RLN2	P04090	938
INSL5	RXFP3	Q9NSD7	868
INSL5	RXFP1	Q9HBX9	815
INSL5	RLN3	Q8WXF3	812
INSL5	RXFP2	Q8WXD0	753
INSL5	INSL6	Q9Y581	742
INSL5	INSL3	P51460	668
INSL5	INSL4	Q14641	663
INSL5	GPR142	Q7Z601	566
INSL5	GNG4	P50150	550
INSL5	PYY	P10082	542
INSL5	SST	P01166	530
INSL5	OR52A1	Q9UKL2	506

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ASPH	INSL5	psi-mi:“MI:0915”(physical association)	0.560
INSL5	COCH	psi-mi:“MI:0914”(association)	0.530
INSL5	LAMA5	psi-mi:“MI:0914”(association)	0.350

BioGRID (92): CTSF (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), ARSB (Affinity Capture-MS), AMZ2 (Affinity Capture-MS), FUT11 (Affinity Capture-MS), SEMA6A (Affinity Capture-MS), COL6A2 (Affinity Capture-MS), CERCAM (Affinity Capture-MS), EOGT (Affinity Capture-MS), TMEM2 (Affinity Capture-MS), ARSK (Affinity Capture-MS), SULF1 (Affinity Capture-MS), SUSD1 (Affinity Capture-MS), UBR2 (Affinity Capture-MS), LOXL2 (Affinity Capture-MS)

ESM2 similar proteins: E7F5F0, E7FAP8, F8W2C9, O15981, P01257, P01286, P0DUJ6, P18893, P19806, P29456, P46651, P47965, P49011, P51496, P51746, P56688, P68677, P68678, P70160, P70302, P79338, P84903, Q0Z972, Q13361, Q23247, Q25154, Q28022, Q28374, Q4RU86, Q58CP9, Q58T08, Q5CZK5, Q5Q0V6, Q60549, Q6AY06, Q6INW9, Q6UX71, Q6UXQ4, Q805D7, Q90WW4

Diamond homologs: P01349, P11184, P11185, P11952, P11953, Q5CZK2, Q5CZK5, Q6X7V3, Q8BFS3, Q8CHK2, Q8HY17, Q8WXF3, Q9Y5Q6, Q9WUG6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	14
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

149 predictions. Top by Δscore:

Variant	Effect	Δscore
1:66798246:C:CC	acceptor_gain	1.0000
1:66801041:TGTTA:T	donor_loss	1.0000
1:66801043:TTA:T	donor_loss	1.0000
1:66801044:TA:T	donor_loss	1.0000
1:66801045:A:AG	donor_loss	1.0000
1:66801046:CCTTG:C	donor_gain	1.0000
1:66798241:CTCAG:C	acceptor_gain	0.9900
1:66798242:TCAG:T	acceptor_gain	0.9900
1:66798243:CAG:C	acceptor_gain	0.9900
1:66798243:CAGC:C	acceptor_gain	0.9900
1:66798245:GCT:G	acceptor_loss	0.9900
1:66798247:T:A	acceptor_loss	0.9900
1:66798248:G:C	acceptor_gain	0.9900
1:66798248:G:GC	acceptor_gain	0.9900
1:66798250:A:AC	acceptor_gain	0.9900
1:66798250:A:C	acceptor_gain	0.9900
1:66801039:A:AC	donor_gain	0.9900
1:66801040:C:CC	donor_gain	0.9900
1:66801081:TCTCC:T	donor_gain	0.9900
1:66798244:AG:A	acceptor_gain	0.9800
1:66801045:A:AC	donor_gain	0.9600
1:66801046:C:CC	donor_gain	0.9600
1:66800285:C:CT	donor_gain	0.9500
1:66801036:G:C	donor_gain	0.9500
1:66798246:CT:C	acceptor_gain	0.9300
1:66798242:TCA:T	acceptor_gain	0.9200
1:66798245:GCTGT:G	acceptor_gain	0.9200
1:66798244:AGCTG:A	acceptor_gain	0.8900
1:66798247:T:G	acceptor_gain	0.8900
1:66798243:CAGCT:C	acceptor_gain	0.8800

AlphaMissense

878 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:66801084:C:A	W46C	0.978
1:66801084:C:G	W46C	0.978
1:66798018:A:G	C135R	0.941
1:66798044:C:G	C126S	0.934
1:66798045:A:T	C126S	0.934
1:66798016:G:C	C135W	0.928
1:66798017:C:G	C135S	0.927
1:66798018:A:T	C135S	0.927
1:66798029:A:G	L131S	0.925
1:66801100:C:G	C41S	0.925
1:66801101:A:T	C41S	0.925
1:66801101:A:G	C41R	0.916
1:66801100:C:T	C41Y	0.913
1:66801136:C:G	C29S	0.912
1:66801137:A:T	C29S	0.912
1:66798056:C:G	C122S	0.910
1:66798057:A:T	C122S	0.910
1:66801118:C:G	R35P	0.909
1:66798045:A:G	C126R	0.904
1:66798017:C:T	C135Y	0.902
1:66801087:C:A	R45S	0.891
1:66801087:C:G	R45S	0.891
1:66801093:G:C	S43R	0.886
1:66801093:G:T	S43R	0.886
1:66801095:T:G	S43R	0.886
1:66801124:T:G	Y33S	0.886
1:66801124:T:C	Y33C	0.883
1:66801125:A:G	Y33H	0.882
1:66801097:G:T	A42D	0.880
1:66798059:C:G	C121S	0.879

dbSNP variants (sampled 300 via entrez): RS1000508800 (1:66801013 A>C,T), RS1001043163 (1:66802091 T>A), RS1001202243 (1:66800186 C>T), RS1001254372 (1:66800469 G>A,T), RS1002880552 (1:66798818 T>A,C), RS1002929848 (1:66799090 A>T), RS1002974314 (1:66798076 T>C), RS1003311564 (1:66797833 A>G), RS1004337580 (1:66801591 G>A), RS1004481226 (1:66798413 G>A), RS1006347244 (1:66798778 A>T), RS1006687384 (1:66798491 T>A), RS1006894375 (1:66800502 A>G,T), RS1007065865 (1:66799472 G>T), RS1007404477 (1:66798204 A>G)

Disease associations

OMIM: gene MIM:606413 | 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
GCST004131_16	Inflammatory bowel disease	5.000000e-111
GCST004132_7	Crohn’s disease	6.000000e-93
GCST004133_2	Ulcerative colitis	4.000000e-41
GCST006585_2660	Blood protein levels	4.000000e-07

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	decreases expression	1
CGP 52608	increases reaction, affects binding	1
Benzo(a)pyrene	affects methylation	1
Tobacco Smoke Pollution	increases expression	1
Vanadium	increases expression	1

Clinical trials (associated diseases)

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