RLN3

Summary

RLN3 (relaxin 3, HGNC:17135) is a protein-coding gene on chromosome 19p13.12, encoding Relaxin-3 (Q8WXF3). May play a role in neuropeptide signaling processes.

This gene encodes a member of the relaxin family of insulin-like hormones that is expressed predominantly in the brain and plays a role in physiological processes such as stress, memory and appetite regulation. The encoded protein is a precursor that is proteolytically processed to generate a heterodimeric mature form consisting A and B chains interlinked by disulfide bonds. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 117579 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 26 total
• MANE Select transcript: NM_080864

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17135
Approved symbol	RLN3
Name	relaxin 3
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Aliases	ZINS4, RXN3, H3
Ensembl gene	ENSG00000171136
Ensembl biotype	protein_coding
OMIM	606855
Entrez	117579

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000431365, ENST00000585987

RefSeq mRNA: 2 — MANE Select: NM_080864 NM_001311197, NM_080864

CCDS: CCDS12302, CCDS82304

Canonical transcript exons

ENST00000431365 — 2 exons

Exon	Start	End
ENSE00001681039	14030710	14031551
ENSE00001687869	14028148	14028394

Expression profiles

Bgee: expression breadth broad, 78 present calls, max score 89.83.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.83	gold quality
granulocyte	CL:0000094	74.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	60.11	gold quality
blood	UBERON:0000178	59.91	gold quality
right testis	UBERON:0004534	58.57	gold quality
testis	UBERON:0000473	58.35	gold quality
left testis	UBERON:0004533	58.22	gold quality
right lung	UBERON:0002167	52.61	gold quality
leukocyte	CL:0000738	51.33	gold quality
monocyte	CL:0000576	50.37	gold quality
spleen	UBERON:0002106	48.68	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	47.57	gold quality
right adrenal gland cortex	UBERON:0035827	47.23	gold quality
bone marrow cell	CL:0002092	45.84	gold quality
right adrenal gland	UBERON:0001233	45.47	gold quality
left adrenal gland	UBERON:0001234	41.47	gold quality
lymph node	UBERON:0000029	40.86	gold quality
prostate gland	UBERON:0002367	40.70	gold quality
adrenal gland	UBERON:0002369	40.68	gold quality
vermiform appendix	UBERON:0001154	40.40	gold quality
upper lobe of left lung	UBERON:0008952	40.02	gold quality
small intestine Peyer’s patch	UBERON:0003454	38.89	gold quality
subcutaneous adipose tissue	UBERON:0002190	38.83	gold quality
adipose tissue	UBERON:0001013	38.71	gold quality
omental fat pad	UBERON:0010414	38.55	gold quality
left adrenal gland cortex	UBERON:0035825	38.44	gold quality
tonsil	UBERON:0002372	38.27	silver quality
sural nerve	UBERON:0015488	37.92	gold quality
bone marrow	UBERON:0002371	37.90	gold quality
small intestine	UBERON:0002108	37.88	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting RLN3, 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-6740-5P	100.00	65.64	932
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-122-5P	97.23	64.92	1024
HSA-MIR-6131	97.22	66.72	960
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-1202	97.19	66.43	827
HSA-MIR-3972	97.19	66.46	808
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-3194-5P	96.80	64.90	1027
HSA-MIR-3135A	96.41	65.30	494
HSA-MIR-4515	95.70	65.73	716
HSA-MIR-1915-5P	95.25	65.78	571
HSA-MIR-1238-5P	94.82	67.52	493
HSA-MIR-4758-5P	94.82	67.06	499

Literature-anchored findings (GeneRIF, showing 27)

• relaxin-3/INSL7 is a ligand for GPCR142 (PMID:14522967)
• GPCR135 is the receptor for relaxin-3 (PMID:14522968)
• RLN3 chimeric peptide is a potential tool to study in vivo function of GPCR135. (PMID:15465925)
• Intracerebroventricular injections of human relaxin-3 (H3) to satiated rats significantly increased food intake. (PMID:15845619)
• NMR spectroscopy and simulated annealing calculations were used to determine the three-dimensional structure of relaxin-3 and to identify key structural differences between the human relaxins. (PMID:15956686)
• functional response to H3 relaxin and other relaxin/insulin peptides of GPCR135 expressed in CHO-K1 cells was measured in the cytosensor microphysiometer and analyzed using inhibitors of signal transduction proteins (PMID:15956730)
• Results describe the solution structure of human relaxin-3. (PMID:16365033)
• analysis of truncated human relaxin-2 and -3 (H2 and H3) relaxin peptides and their binding and cAMP activities on RXFP1, RXFP2, and RXFP3 (PMID:18434306)
• Results decribe the structural and functional aspects of the interaction between relaxin-3 and its receptor, RXFP3. (PMID:19152634)
• Relaxin-3 and receptors in the human and rhesus brain and reproductive tissues. (PMID:19778557)
• H3 relaxin exerts antifibrotic actions via RXFP1 receptor (PMID:21229994)
• [review] Relaxin-3 (RXF3P) is expressed within GABA neurons of the brainstem including an area known as the nucleus incertus; ascending relaxin-3 projections innervate a broad range of RXFP3-rich forebrain areas. (PMID:21693186)
• metabolic syndrome is associated with increased serum relaxin-3 levels in women (PMID:23018057)
• Relaxin-2 or relaxin-3 levels are not related to component traits in patients with diabetes. (PMID:23994775)
• Glu141 and Asp145 of the RXFP3 interact with the highly conserved arginine residues of relaxin-3. (PMID:24615237)
• we demonstrated distinct patterns of signalling for H3 and H2 relaxin and R3(BDelta23-27)R/I5 at the RXFP3 receptor (PMID:24641548)
• Mutant relaxin-3 shows a significant decrease in receptor-activation potency towards RXFP4. (PMID:24802387)
• Review of research depicts the connection of relaxin-3 with phenomena such as feeding behavior, spatial memory, sleep/wake cycle or modulation of pituitary gland hormone secretion. (PMID:24988606)
• Serum concentrations of relaxin showed a positive association to duration of gestation among women with miscarriage but no association to duration of gestation among women with spontaneous onset of labour. (PMID:26272327)
• the relaxin-3 B-chain C-terminus changes from the original folding-back conformation to an extended conformation during binding with RXFP3, to allow its B27Trp and B26Arg residues to interact with the Trp138 and Glu141 residues of RXFP3, respectively. (PMID:27193232)
• the negatively charged transmembrane aspartate residue controls activation of the relaxin-3 receptor RXFP3 (PMID:27353281)
• In a population of acute HF patients, admission relaxin serum levels were associated with clinical and echocardiographic markers of pulmonary hypertension, RV dysfunction, and overload, suggesting a role for circulating relaxin as a biomarker in this setting. (PMID:27488261)
• Therefore, we conclude that stapling of the relaxin3 B chain does not compromise its ability to activate RXFP3 and is a promising method for developing stable peptide agonists and antagonists of RXFP3 to aid relaxin-3/RXFP3 research. (PMID:27498038)
• Relaxin-3 is a high-efficacy agonist at RXFP4 with a comparable signal transduction profile to INSL5. (PMID:27888281)
• Serum level of relaxin-3 hormone is an important mediator in the pathophysiological process of normal puberty being significantly decreased in males with delayed puberty. (PMID:28786126)
• The putative role of the relaxin-3/RXFP3 system in clinical depression and anxiety: A systematic literature review. (PMID:34537263)
• Investigating the role of the relaxin-3/RXFP3 system in neuropsychiatric disorders and metabolic phenotypes: A candidate gene approach. (PMID:37967073)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rln3a	ENSDARG00000070780
danio_rerio	rln3b	ENSDARG00000116898
mus_musculus	Rln3	ENSMUSG00000045232
rattus_norvegicus	Rln3	ENSRNOG00000005911

Paralogs (1): INSL5 (ENSG00000172410)

Protein

Protein identifiers

Relaxin-3 — Q8WXF3 (reviewed: Q8WXF3)

Alternative names: Insulin-like peptide INSL7, Prorelaxin H3

All UniProt accessions (2): K7ENX1, Q8WXF3

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in neuropeptide signaling processes. Ligand for LGR7, RXFP3 and RXFP4.

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

Subcellular location. Secreted.

Similarity. Belongs to the insulin family.

RefSeq proteins (2): NP_001298126, NP_543140* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016179	Insulin-like	Domain
IPR022352	Ins/IGF/rlx	Family
IPR022353	Insulin_CS	Conserved_site
IPR036438	Insulin-like_sf	Homologous_superfamily
IPR051777	Insulin-like_neuro_ligands	Family

Pfam: PF00049

UniProt features (11 total): helix 3, disulfide bond 3, peptide 2, signal peptide 1, propeptide 1, strand 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9KFI	ELECTRON MICROSCOPY	2.91
9KFK	ELECTRON MICROSCOPY	2.95
2FHW	SOLUTION NMR
2K1V	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WXF3-F1	62.72	0.08

Antibody-complex structures (SAbDab): 2 — 9KFI, 9KFK

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): 35–129, 47–142, 128–133

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events
R-HSA-418594	G alpha (i) signalling events
R-HSA-444821	Relaxin receptors

MSigDB gene sets: 31 (showing top): REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, GOMF_SIGNALING_RECEPTOR_BINDING, chr19p13, GOMF_HORMONE_ACTIVITY, REACTOME_CLASS_A_1_RHODOPSIN_LIKE_RECEPTORS, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, REACTOME_RELAXIN_RECEPTORS, GSE13522_WT_VS_IFNAR_KO_SKIN_DN, MIR1207_5P, MIR4763_3P, GSE11864_UNTREATED_VS_CSF1_IFNG_PAM3CYS_IN_MAC_DN, MIR6132, MIR6836_5P

GO Biological Process (1): 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-2 pathways:

Category	Pathways
GPCR downstream signalling	2
Peptide ligand-binding receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
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

618 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RLN3	RXFP3	Q9NSD7	999
RLN3	RXFP4	Q8TDU9	993
RLN3	RXFP1	Q9HBX9	993
RLN3	RLN2	P04090	940
RLN3	RLN1	P04808	939
RLN3	RXFP2	Q8WXD0	867
RLN3	INSL3	P51460	863
RLN3	INSL5	Q9Y5Q6	812
RLN3	INSL6	Q9Y581	771
RLN3	INSL4	Q14641	716
RLN3	INS	P01308	689
RLN3	NPS	P0C0P6	646
RLN3	NPY5R	Q15761	606
RLN3	GPR135	Q8IZ08	568
RLN3	CRHR1	P34998	567

IntAct

10 interactions, top by confidence:

A	B	Type	Score
RLN3	RXFP4	psi-mi:“MI:0915”(physical association)	0.400
RXFP4	RLN3	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (4): RLN3 (Reconstituted Complex), RLN3 (Reconstituted Complex), RLN3 (Protein-peptide), RLN3 (Protein-peptide)

ESM2 similar proteins: O00230, O00253, O14836, O46541, O62827, O77559, P01160, P01169, P07499, P0C8A3, P0C8S2, P0CG36, P0CG37, P13204, P16859, P18104, P23582, P24393, P35318, P47851, P49192, P51461, P53366, P55206, P55207, P56283, P56388, P56413, P56473, P81172, P81277, P84715, P97297, Q5CZK2, Q5NVR8, Q61839, Q62715, Q62716, Q6PAL1, Q7TNK8

Diamond homologs: P01349, P11184, P11185, P11952, P11953, Q5CZK2, Q8BFS3, Q8CHK2, Q8HY17, Q8WXF3, P51460, P81191, Q5CZK3, Q9WUK0, Q9WV41, Q5CZK5, Q6X7V3, Q9Y5Q6, Q9WUG6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

340 predictions. Top by Δscore:

Variant	Effect	Δscore
19:14030707:CA:C	acceptor_loss	1.0000
19:14030708:A:AG	acceptor_gain	1.0000
19:14030708:AG:A	acceptor_gain	1.0000
19:14030709:G:GG	acceptor_gain	1.0000
19:14030709:GG:G	acceptor_gain	1.0000
19:14030709:GGA:G	acceptor_gain	1.0000
19:14030709:GGAGA:G	acceptor_gain	1.0000
19:14028388:GC:G	donor_gain	0.9900
19:14030355:GA:G	donor_gain	0.9900
19:14030357:G:GG	donor_gain	0.9900
19:14030705:T:TA	acceptor_gain	0.9900
19:14030700:T:G	acceptor_gain	0.9800
19:14028393:GG:G	donor_gain	0.9700
19:14028394:GG:G	donor_gain	0.9700
19:14028392:TGGG:T	donor_loss	0.9600
19:14028393:GGGT:G	donor_loss	0.9600
19:14028395:GTGA:G	donor_loss	0.9600
19:14028396:T:A	donor_loss	0.9600
19:14030707:CAGG:C	acceptor_gain	0.9600
19:14030707:CAGGA:C	acceptor_gain	0.9600
19:14030708:AGGA:A	acceptor_gain	0.9600
19:14030708:AGGAG:A	acceptor_gain	0.9600
19:14030709:GGAG:G	acceptor_gain	0.9600
19:14028395:G:GG	donor_gain	0.9500
19:14028397:GAG:G	donor_loss	0.9500
19:14030699:A:AG	acceptor_gain	0.9500
19:14028358:TGGAG:T	donor_gain	0.9400
19:14028389:C:G	donor_gain	0.9400
19:14030710:G:C	acceptor_gain	0.9400
19:14028359:GG:G	donor_gain	0.9100

AlphaMissense

902 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:14028360:G:C	W52C	0.994
19:14028360:G:T	W52C	0.994
19:14028320:T:G	F39C	0.993
19:14028320:T:C	F39S	0.992
19:14028319:T:C	F39L	0.986
19:14028321:C:A	F39L	0.986
19:14028321:C:G	F39L	0.986
19:14028332:T:A	V43D	0.986
19:14030932:T:G	I138S	0.985
19:14028344:G:A	C47Y	0.984
19:14030932:T:C	I138T	0.983
19:14030943:T:C	C142R	0.983
19:14028310:G:T	G36C	0.982
19:14028335:T:A	I44N	0.981
19:14028337:T:C	F45L	0.981
19:14028339:C:A	F45L	0.981
19:14028339:C:G	F45L	0.981
19:14028328:G:C	A42P	0.979
19:14030943:T:A	C142S	0.979
19:14030944:G:A	C142Y	0.979
19:14030944:G:C	C142S	0.979
19:14030945:C:G	C142W	0.978
19:14028311:G:T	G36V	0.977
19:14028343:T:A	C47S	0.976
19:14028344:G:C	C47S	0.976
19:14030916:T:A	C133S	0.974
19:14030917:G:C	C133S	0.974
19:14028323:T:A	I40N	0.973
19:14028343:T:C	C47R	0.973
19:14028344:G:T	C47F	0.973

dbSNP variants (sampled 300 via entrez): RS1000194760 (19:14030522 C>G,T), RS1000215944 (19:14027542 C>T), RS1001391551 (19:14027132 C>T), RS1001719499 (19:14031341 T>A), RS1002627174 (19:14026884 C>T), RS1002944069 (19:14026546 C>G), RS1003319069 (19:14031286 T>C), RS1003538792 (19:14027871 G>A), RS1004044670 (19:14029928 A>C), RS1004353033 (19:14031104 G>A,C), RS1005078964 (19:14031078 C>G,T), RS1005223260 (19:14028527 T>A,C), RS1006022797 (19:14029701 G>A), RS1006529497 (19:14026910 A>C), RS1006653335 (19:14031812 A>C,G)

Disease associations

OMIM: gene MIM:606855 | 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
GCST001762_253	Obesity-related traits	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003939	energy intake

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
bisphenol A	affects cotreatment, increases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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