UTS2

Summary

UTS2 (urotensin 2, HGNC:12636) is a protein-coding gene on chromosome 1p36.23, encoding Urotensin-2 (O95399). Highly potent vasoconstrictor.

This gene encodes a mature peptide that is an active cyclic heptapeptide absolutely conserved from lamprey to human. The active peptide acts as a vasoconstrictor and is expressed only in brain tissue. Despite the gene family name similarity, this gene is not homologous to urocortin, a member of the sauvagine/corticotropin-releasing factor/urotensin I family. Most of the proprotein is cleaved to make the mature peptide. Transcript variants encoding different preproprotein isoforms have been described for this gene.

Source: NCBI Gene 10911 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 41 total
• MANE Select transcript: NM_006786

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12636
Approved symbol	UTS2
Name	urotensin 2
Location	1p36.23
Locus type	gene with protein product
Status	Approved
Aliases	UII, U-II, UCN2, PRO1068
Ensembl gene	ENSG00000049247
Ensembl biotype	protein_coding
OMIM	604097
Entrez	10911

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000054668, ENST00000361696, ENST00000377516

RefSeq mRNA: 2 — MANE Select: NM_006786 NM_006786, NM_021995

CCDS: CCDS90, CCDS91

Canonical transcript exons

ENST00000361696 — 4 exons

Exon	Start	End
ENSE00000737420	7849640	7849683
ENSE00000900905	7850812	7850922
ENSE00001248273	7847612	7847882
ENSE00001880719	7852901	7853065

Expression profiles

Bgee: expression breadth ubiquitous, 157 present calls, max score 87.67.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9276 / max 647.4292, expressed in 306 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10078	1.3707	85
10080	1.3311	219
10079	0.1968	83
10077	0.0289	9

Top tissues by expression

282 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	87.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.75	silver quality
adrenal tissue	UBERON:0018303	77.93	gold quality
right adrenal gland cortex	UBERON:0035827	74.02	gold quality
buccal mucosa cell	CL:0002336	69.53	silver quality
right adrenal gland	UBERON:0001233	67.05	gold quality
granulocyte	CL:0000094	62.97	gold quality
adrenal cortex	UBERON:0001235	62.69	gold quality
lymph node	UBERON:0000029	61.40	gold quality
left adrenal gland cortex	UBERON:0035825	61.05	gold quality
adrenal gland	UBERON:0002369	60.77	gold quality
left adrenal gland	UBERON:0001234	59.83	gold quality
rectum	UBERON:0001052	59.70	gold quality
leukocyte	CL:0000738	59.63	gold quality
colonic epithelium	UBERON:0000397	58.87	gold quality
mononuclear cell	CL:0000842	58.75	gold quality
mucosa of transverse colon	UBERON:0004991	58.69	gold quality
monocyte	CL:0000576	58.32	gold quality
epithelium of nasopharynx	UBERON:0001951	57.61	silver quality
blood	UBERON:0000178	56.60	gold quality
spinal cord	UBERON:0002240	56.59	gold quality
decidua	UBERON:0002450	56.55	gold quality
spleen	UBERON:0002106	56.15	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	55.44	gold quality
smooth muscle tissue	UBERON:0001135	55.10	gold quality
hypothalamus	UBERON:0001898	54.58	gold quality
bone marrow cell	CL:0002092	54.48	gold quality
pancreatic ductal cell	CL:0002079	53.50	silver quality
lower esophagus mucosa	UBERON:0035834	52.62	gold quality
hair follicle	UBERON:0002073	52.43	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.07

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A

miRNA regulators (miRDB)

21 targeting UTS2, 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-548AW	99.99	72.57	3559
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-609	99.82	64.26	505
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-4662B	98.33	66.37	1163
HSA-MIR-4647	98.30	66.41	1139
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-1279	97.83	67.50	1898
HSA-MIR-376C-3P	97.63	68.88	1263
HSA-MIR-6831-3P	97.49	69.29	505
HSA-MIR-877-5P	94.62	66.30	710

Literature-anchored findings (GeneRIF, showing 40)

• Urocortin II exhibits motor suppressive and delayed anxiolytic-like effects, suggesting a time-dependent role in the regulation of stress-related behavior. (PMID:12088848)
• Structure-function analysis and its use in the construction of a ligand-receptor working model (PMID:12203418)
• Regulative effect of human urotensin-II on cardiovascular system (PMID:12297490)
• Circulating urotensin-II appears not to play a major role in human congestive heart failure (CHF). (PMID:12468107)
• Urotensin II gene may contribute to the genetic susceptibility to type 2 diabetes in Chinese population. (PMID:12509909)
• Elevated in the aortic root of congestive heart failure. Cleared at least in part from the microcirculation. (PMID:12791592)
• S89N polymorphism in the UTS2 gene is associated with the development of Type 2 diabetes, via insulin sensitivity, in Japanese subjects. (PMID:12830381)
• In addition to direct effects on the myocardium, U-II may contribute to the increased peripheral vascular tone that is characteristic of human CHF. (PMID:15007012)
• urotensin II may have an aetiological role in hypertension and its complications. (PMID:15201550)
• possible role for U-II in the pathophysiology of atherosclerosis. (PMID:15306183)
• Immunohistochemical labelling of the cervical segment of the human spinal cord revealed that the UII-immunoreactive material was confined to a subset of ventral horn motoneurones. (PMID:15379892)
• hU-II may play a novel role in pulmonary hypertension by promoting remodeling processes via activation of NADPH oxidases (PMID:15618545)
• study strongly suggest an important role for human Urotensin-II in the pathophysiology of preeclampsia-eclampsia (PMID:15866083)
• The evidence in this review points to urotensin II as an ancient peptide hormone involved in body fluid regulation in higher vertebrates, including humans. (PMID:15891007)
• May play role in formation of macrophage-derived foam cells by upregulating ACAT-1 expression via UT receptor/G-protein/c-Src/PKC/MEK and ROCK pathways but not by SR-A, thus contributing to relatively rapid development of atherosclerosis in hypertension. (PMID:16172428)
• hU-II promotes cell proliferation and inhibits apoptosis in HUVECs, and MAPKp42/44 activation may play a signal transduction role in this process. (PMID:16343502)
• Urotensin blood levels are the third factor in rank, after age and diabetes, explaining the incidence of cardiovascular events in end-stage kidney failure. (PMID:16508659)
• this article aims to review recent advances in our understanding of the physiology and pathophysiology of U-II with particular references to its role in cardiovascular health and disease–{REVIEW} (PMID:16783414)
• UII may also play a role in renal disease, being elevated in the circulation or urine of patients with renal failure and in experimental models of cardiovascular disease such as the spontaneously hypertensive rat. (PMID:16807543)
• The expression of urotensin 2 is increased in airways of rat asthmatic models and of patients with asthma. (PMID:17045018)
• Data show that both urotensin II and urotensin II receptor are expressed in adrenal tumors and attached non-neoplastic adrenal tissues, and suggest possible roles of UII and UT-R in tumor growth and/or secretion. (PMID:17686550)
• Results describe the synthesis and biological evaluation of 24 analogues of the urotensin II (U-II) fragment U-II(4-11) substituted in position 4 with coded and non-coded aromatic amino acids. (PMID:17822806)
• High UTN may be cardioprotective in end-stage renal disease, and interference by UTN with sympathetic activity and NO synthesis may represent intermediate mechanism mediating favorable echocardiographic profile of patients with high UTN. (PMID:18086953)
• Urotensin-induced expression of TF and of VCAM-1/ICAM-1 was mediated through the Rho A-activation of the transcription factor, NF-kappaB (PMID:18284603)
• Results demonstrates a state-dependent effect of urotensin-II in cultured human aortic endothelial cells, which may explain the variable responses to U-II under different experimental conditions. (PMID:18314227)
• It is now evident that UT expression in fish osmoregulatory tissues, such as the gill and kidney, exhibits considerable plasticity in response to physiological challenge, providing an important component of the adaptive organismal responses. (PMID:18440535)
• UII may play a contributory role in the vasoconstrictor state of diabetes by exerting a relative constrictor action in diabetic patients, compared to its vasodilator action in normal subjects. (PMID:18505448)
• Urotensin II is a putative mediator of the effects of the adrenal medulla and pheochromocytoma on the adrenocortical zona glomerulosa. (PMID:19001524)
• ROS-mediated oxidation of SHP-2 is essential for the hUII-induced mitogenic pathway in NRK-52E cells. (PMID:19326266)
• The U-II, in addition to the well known role in the regulation of cardiovascular function, also exert a specific angiogenic activity. (PMID:19362580)
• Data show that plasma urotensin II is elevated in chronic rheumatic valve disease, associated with severe mitral and tricuspid valve regurgitation. (PMID:19398874)
• Increased UII immunoreactivity is observed in subjects with acute coronary syndrome. (PMID:19797715)
• elevated in plasma of pre-eclamptic women (PMID:20017703)
• Endothelin-1 and urotensin-II levels are increased in plasma of patients with coronary heart disease. (PMID:20339975)
• These findings suggest that the intrahepatic UII/UT system has an important pathophysiological role in cirrhosis and portal hypertension. (PMID:20428787)
• This study suggest that UTS2 single gene (S89N) polymorphism is not associated with pre-eclampsia. (PMID:20653105)
• circulating urotensin II may participate in the worsening course of some type 2 diabetes mellitus patients. (PMID:20695946)
• Urotensin-II may have a vital role in systemic sclerosis. (PMID:21274584)
• Increased UT-II, sTM, and vWF in ankylosing spondylitis patient sera regardless of treatment and disease activity suggest an increased tendency for atherosclerosis. (PMID:21556780)
• polymorphisms in UTS2 and PER3 may have roles in glucose homeostasis and diabetes (PMID:21559414)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	uts2b	ENSDARG00000017340
danio_rerio	uts2a	ENSDARG00000053854
mus_musculus	Uts2	ENSMUSG00000028963
rattus_norvegicus	Uts2	ENSRNOG00000018393

Protein

Protein identifiers

Urotensin-2 — O95399 (reviewed: O95399)

Alternative names: Urotensin II

All UniProt accessions (2): O95399, Q5H8X8

UniProt curated annotations — full annotation on UniProt →

Function. Highly potent vasoconstrictor.

Subcellular location. Secreted.

Tissue specificity. Brain specific.

Similarity. Belongs to the urotensin-2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95399-1	1	yes
O95399-2	2

RefSeq proteins (2): NP_006777, NP_068835 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001483	Urotensin_II	Conserved_site

Pfam: PF02083

UniProt features (7 total): sequence variant 2, signal peptide 1, propeptide 1, peptide 1, disulfide bond 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6HVB	SOLUTION NMR
6HVC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95399-F1	58.50	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 (1): 118–123

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 141 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_DIGESTION, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CELL_SIGNALING, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, AP1_Q4_01, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_MUSCLE_CONTRACTION, HUTTMANN_B_CLL_POOR_SURVIVAL_DN, TGCTGAY_UNKNOWN, BACH2_01

GO Biological Process (5): muscle contraction (GO:0006936), chemical synaptic transmission (GO:0007268), regulation of blood pressure (GO:0008217), blood vessel diameter maintenance (GO:0097746), signal transduction (GO:0007165)

GO Molecular Function (2): signaling receptor binding (GO:0005102), hormone activity (GO:0005179)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
blood circulation	2
muscle system process	1
anterograde trans-synaptic signaling	1
regulation of biological quality	1
vascular process in circulatory system	1
regulation of tube diameter	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein binding	1
receptor ligand activity	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

858 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UTS2	UTS2R	Q9UKP6	999
UTS2	UTS2B	Q765I0	833
UTS2	UCN	P55089	800
UTS2	SST	P01166	769
UTS2	EDN1	P05305	764
UTS2	SSTR4	P31391	726
UTS2	CRH	P06850	667
UTS2	AGT	P01019	541
UTS2	UCN3	Q969E3	528
UTS2	GNAQ	P50148	491
UTS2	SSTR2	P30874	475
UTS2	CORT	O00230	463
UTS2	CXCR3	P49682	461
UTS2	ADM	P35318	447
UTS2	SLC45A1	Q9Y2W3	415

IntAct

6 interactions, top by confidence:

A	B	Type	Score
KSR2	POLR3A	psi-mi:“MI:0914”(association)	0.530
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CFTR	UBA6	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (19): UTS2 (Affinity Capture-MS), UTS2 (Synthetic Lethality), UTS2 (Affinity Capture-MS), UTS2 (Affinity Capture-MS), UTS2 (Affinity Capture-MS), UTS2 (Affinity Capture-MS), UTS2 (Affinity Capture-MS), UTS2 (Affinity Capture-MS), UTS2 (Reconstituted Complex), UTS2 (Affinity Capture-MS), UTS2 (Affinity Capture-MS), UTS2 (Affinity Capture-MS), UTS2 (Affinity Capture-MS), UTS2 (Proximity Label-MS), UTS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0F7YZQ7, B3IUE0, C0HKT5, D3Z752, M0R8L2, O62647, O93448, O95399, P01143, P01146, P01257, P01261, P04560, P06580, P08435, P08858, P09681, P0DP55, P0DQY8, P0DQY9, P13241, P20068, P25308, P49188, P55090, P55099, P57774, P67934, Q0VBW8, Q0VC44, Q1HA20, Q4QXT8, Q5H8A1, Q5H8A2, Q5H8A3, Q62923, Q64387, Q6RUW3, Q75UG5, Q765I2

Diamond homologs: O95399, Q8HYC2, Q95J46, Q9QZQ3, Q9QZQ4, P33715, Q7ZZY8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

761 predictions. Top by Δscore:

Variant	Effect	Δscore
1:7850806:TTTTA:T	donor_loss	1.0000
1:7850807:TTTAC:T	donor_loss	1.0000
1:7850808:TTA:T	donor_loss	1.0000
1:7850809:TACCT:T	donor_loss	1.0000
1:7850810:A:AG	donor_loss	1.0000
1:7850811:C:G	donor_loss	1.0000
1:7850811:CCTG:C	donor_gain	1.0000
1:7850818:T:A	donor_gain	1.0000
1:7850919:GGTG:G	acceptor_gain	1.0000
1:7850920:GTG:G	acceptor_gain	1.0000
1:7850921:TG:T	acceptor_gain	1.0000
1:7850921:TGCTA:T	acceptor_loss	1.0000
1:7850922:GCTA:G	acceptor_loss	1.0000
1:7850923:C:CC	acceptor_gain	1.0000
1:7850923:CTAC:C	acceptor_loss	1.0000
1:7850924:T:C	acceptor_loss	1.0000
1:7850918:AGGTG:A	acceptor_gain	0.9900
1:7850926:C:CT	acceptor_gain	0.9900
1:7853305:A:AC	donor_gain	0.9900
1:7853306:C:CC	donor_gain	0.9900
1:7847883:C:CC	acceptor_gain	0.9800
1:7847903:A:T	acceptor_gain	0.9800
1:7847906:A:T	acceptor_gain	0.9800
1:7849737:T:C	acceptor_gain	0.9800
1:7849742:T:C	acceptor_gain	0.9800
1:7849742:T:TC	acceptor_gain	0.9800
1:7853306:CAG:C	donor_gain	0.9800
1:7847894:C:CT	acceptor_gain	0.9700
1:7847895:A:T	acceptor_gain	0.9600
1:7850814:G:A	donor_gain	0.9600

AlphaMissense

804 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:7847781:C:A	W120C	0.978
1:7847781:C:G	W120C	0.978
1:7847779:T:A	K121I	0.966
1:7847784:G:C	F119L	0.965
1:7847784:G:T	F119L	0.965
1:7847786:A:G	F119L	0.965
1:7847778:T:A	K121N	0.948
1:7847778:T:G	K121N	0.948
1:7847773:C:T	C123Y	0.939
1:7847779:T:G	K121T	0.936
1:7847770:A:T	V124D	0.935
1:7847772:A:C	C123W	0.934
1:7847789:A:G	C118R	0.934
1:7847787:G:C	C118W	0.930
1:7847785:A:C	F119C	0.929
1:7847776:T:C	Y122C	0.926
1:7847788:C:G	C118S	0.923
1:7847789:A:T	C118S	0.923
1:7847774:A:G	C123R	0.918
1:7847783:A:G	W120R	0.914
1:7847783:A:T	W120R	0.914
1:7847788:C:T	C118Y	0.908
1:7847777:A:G	Y122H	0.906
1:7847780:T:C	K121E	0.892
1:7847773:C:A	C123F	0.891
1:7847785:A:G	F119S	0.874
1:7847788:C:A	C118F	0.872
1:7852967:C:G	G13R	0.867
1:7852967:C:T	G13R	0.867
1:7847773:C:G	C123S	0.863

dbSNP variants (sampled 300 via entrez): RS1000009758 (1:7889996 G>T), RS1000107481 (1:7906582 C>A,G), RS1000108269 (1:7865948 A>T), RS1000108716 (1:7895944 A>C), RS1000200069 (1:7890971 C>A,G,T), RS1000252498 (1:7890604 A>G), RS1000262126 (1:7883626 A>C,G), RS1000349298 (1:7884257 C>A), RS1000378518 (1:7871546 T>C), RS1000488382 (1:7877164 A>T), RS1000529635 (1:7889820 A>G), RS1000532800 (1:7889374 T>C), RS1000543230 (1:7849234 G>A), RS1000578060 (1:7871783 C>T), RS1000594015 (1:7913167 G>A)

Disease associations

OMIM: gene MIM:604097 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000964_5	Ulcerative colitis	5.000000e-09
GCST004131_79	Inflammatory bowel disease	1.000000e-12
GCST004132_92	Crohn’s disease	3.000000e-06
GCST004133_62	Ulcerative colitis	4.000000e-09
GCST006988_206	Blond vs. brown/black hair color	1.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color

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	affects methylation	2
Cadmium Chloride	affects expression, decreases expression, increases abundance	2
bisphenol A	decreases methylation	1
butyraldehyde	increases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
nickel acetate	affects expression	1
(+)-JQ1 compound	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Amiodarone	increases expression	1
Cadmium	increases abundance, decreases expression	1
Hydrogen Peroxide	affects expression	1
Silicon Dioxide	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Aflatoxin B1	increases methylation	1
Endocannabinoids	affects binding, decreases reaction, increases activity	1

Clinical trials (associated diseases)

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