CORT

Summary

CORT (cortistatin, HGNC:2257) is a protein-coding gene on chromosome 1p36.22, encoding Cortistatin (O00230). Precursor of neuropeptides that bind to all somatostatin receptor (SSTR) subtypes.

This gene encodes a neuropeptide that is structurally similar to somatostatin. It binds to all known somatostatin receptors, and shares many pharmacological and functional properties with somatostatin, including the depression of neuronal activity. However, it also has many properties distinct from somatostatin, such as induction of slow-wave sleep, apparently by antagonism of the excitatory effects of acetylcholine on the cortex, reduction of locomotor activity, and activation of cation selective currents not responsive to somatostatin. The preproprotein undergoes further processing into multiple mature products. Read-through transcripts exist between this gene and the upstream APITD1 (apoptosis-inducing, TAF9-like domain 1) gene, as represented in GeneID:100526739.

Source: NCBI Gene 1325 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 2 total
• MANE Select transcript: NM_001302

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2257
Approved symbol	CORT
Name	cortistatin
Location	1p36.22
Locus type	gene with protein product
Status	Approved
Aliases	MGC32686, SST2
Ensembl gene	ENSG00000241563
Ensembl biotype	protein_coding
OMIM	602784
Entrez	1325

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000377049

RefSeq mRNA: 1 — MANE Select: NM_001302 NM_001302

CCDS: CCDS117

Canonical transcript exons

ENST00000377049 — 2 exons

Exon	Start	End
ENSE00001472620	10450031	10450322
ENSE00001887610	10451377	10451998

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 93.93.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.7924 / max 147.3834, expressed in 134 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
585	0.5278	67
582	0.4883	97
586	0.4069	85
583	0.1676	80
589	0.0695	42
587	0.0684	30
588	0.0640	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
putamen	UBERON:0001874	93.93	gold quality
caudate nucleus	UBERON:0001873	92.98	gold quality
prefrontal cortex	UBERON:0000451	88.66	gold quality
nucleus accumbens	UBERON:0001882	87.56	gold quality
superior frontal gyrus	UBERON:0002661	86.25	gold quality
frontal cortex	UBERON:0001870	85.53	gold quality
anterior cingulate cortex	UBERON:0009835	84.87	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.81	gold quality
temporal lobe	UBERON:0001871	84.44	gold quality
amygdala	UBERON:0001876	84.33	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.93	gold quality
cerebral cortex	UBERON:0000956	82.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	82.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.27	gold quality
right frontal lobe	UBERON:0002810	81.04	gold quality
brain	UBERON:0000955	79.30	gold quality
primary visual cortex	UBERON:0002436	79.01	gold quality
Ammon’s horn	UBERON:0001954	78.26	gold quality
mucosa of transverse colon	UBERON:0004991	71.37	gold quality
hypothalamus	UBERON:0001898	70.26	gold quality
cortical plate	UBERON:0005343	68.66	gold quality
pituitary gland	UBERON:0000007	66.50	gold quality
cerebellar hemisphere	UBERON:0002245	66.22	gold quality
cerebellum	UBERON:0002037	66.17	gold quality
cerebellar cortex	UBERON:0002129	66.15	gold quality
adenohypophysis	UBERON:0002196	66.02	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.59	gold quality
stromal cell of endometrium	CL:0002255	64.74	gold quality
adult mammalian kidney	UBERON:0000082	64.68	gold quality
cortex of kidney	UBERON:0001225	64.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	858.85
E-ANND-3	no	0.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFATC1

miRNA regulators (miRDB)

33 targeting CORT, 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-12118	100.00	65.88	1270
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-1294	98.91	69.26	1030
HSA-MIR-9986	98.91	69.28	1024
HSA-MIR-4539	98.78	67.18	888
HSA-MIR-11399	98.71	65.69	869
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6837-3P	98.42	66.71	1149

Literature-anchored findings (GeneRIF, showing 20)

• Identifies post-translational cleavage products of the homologous rat protein. (PMID:10461921)
• Endocrine activities of cortistatin-14 and its interaction with GHRH and ghrelin in humans. (PMID:12161511)
• first extensive study demonstrating that lymphoid tissues and immune cells express different levels of CST mRNA and that its expression can be regulated; hypothesize a role as an endogenous ligand of at least the sst2 receptor in the immune system (PMID:12519865)
• study demonstrates for the first time a selective and inducible expression of the recently discovered cortistatin, as well as somatostatin receptor 2, in human monocyte-derived cells (PMID:12684217)
• cortistatin-14 shown to be a high affinity ligand for G protein coupled receptor MrgX2 which is expressed in dorsal root ganglion (PMID:12915402)
• Cortistatin plays a role in the auto/paracrine regulation of the endocrine pancreas (PMID:14669820)
• Intravitreous somatostatin-like immunoreactivity deficit occurs in ptients with proliferative diabetic retinopathy. (PMID:16043736)
• Human immune cells produce CST, whereas macrophage lineage and activated endothelium express sst2, and human lymphocytes express sst3. The human thymus expresses sst1, 2, 3, MrgX2 and almost all immune cells express GHS-R. [review] (PMID:18450367)
• A lower expression of CST exists in diabetic retinas and it is associated with retinal neurodegeneration. (PMID:18709137)
• The cortistatin expression in the temporal lobe of Alzheimer’s disease patients is decressed. (PMID:20164562)
• Cortistatin emerges as a natural endogenous regulator of smooth muscle cells under pathological conditions and an attractive candidate for the pharmacological management of vascular diseases that course with neointimal lesion formation. (PMID:23595952)
• There is a relationship between plamsa CST and BCKDK in sepsis patients. (PMID:27773658)
• Patients with newly diagnosed type 2 diabetes mellitus had lower plasma levels of vortistatin (CST) than healthy controls, and plasma CST was associated with glucose metabolism and insulin resistance. (PMID:28526556)
• CST suppresses TNF-alphain-duction of cartilage degeneration through binding to TNFRs and main-tains homeostasis of chondrocytes in Osteoarthritis. (PMID:30826358)
• Decreased maternal serum cortistatin levels in pregnancies with gestational diabetes mellitus. (PMID:31154879)
• Cytoskeleton Protein Filamin A Is Required for Efficient Somatostatin Receptor Type 2 Internalization and Recycling through Rab5 and Rab4 Sorting Endosomes in Tumor Somatotroph Cells. (PMID:31574507)
• Comparison of predictive value of NT-proBNP, sST2 and MMPs in heart failure patients with different ejection fractions. (PMID:32354356)
• Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation. (PMID:32550919)
• Somatostatin, Cortistatin and Their Receptors Exert Antitumor Actions in Androgen-Independent Prostate Cancer Cells: Critical Role of Endogenous Cortistatin. (PMID:36361790)
• Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity. (PMID:37794493)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	cenps	ENSDARG00000070485
mus_musculus	Cort	ENSMUSG00000028971

Paralogs (1): CENPS (ENSG00000175279)

Protein

Protein identifiers

Cortistatin — O00230 (reviewed: O00230)

All UniProt accessions (1): O00230

UniProt curated annotations — full annotation on UniProt →

Function. Precursor of neuropeptides that bind to all somatostatin receptor (SSTR) subtypes. Inhibits cAMP production induced by forskolin through SSTRs. Neuropeptide with neuronal depressant and sleep-modulating properties. Acts as a ligand for MRGPRX2 receptor in mast cells.

Subcellular location. Secreted Secreted.

Tissue specificity. Expressed in a subset of GABAergic cells in the cortex and hippocampus.

Similarity. Belongs to the somatostatin family.

RefSeq proteins (1): NP_001293* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004250	Somatostatin	Family
IPR018142	Somatostatin/Cortistatin_C	Domain

Pfam: PF03002

UniProt features (7 total): peptide 3, signal peptide 1, propeptide 1, disulfide bond 1, strand 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7S8L	ELECTRON MICROSCOPY	2.45
7S8M	ELECTRON MICROSCOPY	2.54
8X8L	ELECTRON MICROSCOPY	2.7
7VV4	ELECTRON MICROSCOPY	2.97
7VDL	ELECTRON MICROSCOPY	3.22

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00230-F1	63.57	0.08

Antibody-complex structures (SAbDab): 4 — 7S8L, 7S8M, 7VDL, 8X8L

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): 93–104

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-418594	G alpha (i) signalling events

MSigDB gene sets: 89 (showing top): E2F_Q4, MODULE_274, E2F4DP1_01, SHEPARD_CRASH_AND_BURN_MUTANT_UP, MODULE_45, MODULE_16, GOBP_CELL_CELL_SIGNALING, MODULE_66, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, E2F1DP1_01, E2F1DP2_01, MODULE_289, DAZARD_RESPONSE_TO_UV_SCC_UP, GOBP_SYNAPTIC_SIGNALING

GO Biological Process (3): adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), chemical synaptic transmission (GO:0007268), regulation of cell migration (GO:0030334)

GO Molecular Function (5): G protein-coupled receptor binding (GO:0001664), neuropeptide hormone activity (GO:0005184), hormone activity (GO:0005179), protein binding (GO:0005515), receptor ligand activity (GO:0048018)

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
signaling receptor binding	2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
anterograde trans-synaptic signaling	1
cell migration	1
regulation of cell motility	1
hormone activity	1
neuropeptide activity	1
receptor ligand activity	1
binding	1
signal transduction	1
signaling receptor activator activity	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

922 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CORT	MRGPRX2	Q96LB1	968
CORT	SST	P01166	892
CORT	SSTR1	P30872	885
CORT	GHSR	Q92847	867
CORT	SSTR2	P30874	717
CORT	SSTR5	P34988	688
CORT	SMO	Q99835	670
CORT	SSTR4	P31391	659
CORT	VIP	P01282	659
CORT	SNED1	Q8TER0	579
CORT	GHRL	Q9UBU3	570
CORT	NPY	P01303	523
CORT	UTS2	O95399	463
CORT	SSTR3	P32745	449
CORT	GHRH	P01286	447

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CORT	MB	psi-mi:“MI:0914”(association)	0.560
CORT	MB	psi-mi:“MI:0915”(physical association)	0.560
CORT	HS3ST1	psi-mi:“MI:0914”(association)	0.350

BioGRID (19): AP1S2 (Affinity Capture-MS), MB (Affinity Capture-MS), MB (Affinity Capture-MS), SSTR1 (Protein-peptide), SSTR2 (Protein-peptide), SSTR3 (Protein-peptide), SSTR4 (Protein-peptide), SSTR5 (Protein-peptide), PCDH1 (Affinity Capture-MS), B4GALT5 (Affinity Capture-MS), HS3ST1 (Affinity Capture-MS), BMP4 (Affinity Capture-MS), NMU (Affinity Capture-MS), HSPA13 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS)

ESM2 similar proteins: A5LHG2, A8YPR6, B0VXV8, B8K1V9, D1MZV3, D5J9S0, D9IX97, D9IX98, F5CPE8, O00230, P01021, P01142, P01160, P01169, P06296, P07499, P0C7P5, P0C7P6, P0DMD5, P16859, P18104, P23582, P27596, P55206, P55207, P56283, P56469, P61312, P68515, P79799, P83228, P84715, Q09GK2, Q1HCM0, Q27J49, Q2PE51, Q2XXL8, Q61839, Q62949, Q6LEM5

Diamond homologs: O00230, P56469, P87385, Q62949, Q9YGH3, O46688, P01168, P01169, P01170, P01171, P09876, P19209, P21779, P21780, P26917, P33094, P49670, P60041, P60042, P61278, P61279, P61298, P61299, P69132, P69133, P69134, P81029, P87384, Q91194, Q9PRR0, Q9PRZ6, Q9W7E9, Q9W7F0, Q9YGH4, Q9YGH5

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CORT	up-regulates	MRGPRX2	binding
CORT	up-regulates	SSTR4	binding
CORT	up-regulates	GHSR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

294 predictions. Top by Δscore:

Variant	Effect	Δscore
1:10450321:AGG:A	donor_loss	0.9900
1:10450318:GCGAG:G	donor_gain	0.9800
1:10450324:T:A	donor_loss	0.9800
1:10451372:A:AG	acceptor_gain	0.9800
1:10451375:A:G	acceptor_gain	0.9800
1:10450320:GAG:G	donor_gain	0.9700
1:10450323:G:GC	donor_loss	0.9700
1:10450324:T:TC	donor_loss	0.9700
1:10450325:GAG:G	donor_loss	0.9700
1:10451373:A:G	acceptor_gain	0.9700
1:10450323:G:GG	donor_gain	0.9600
1:10451376:G:GG	acceptor_gain	0.9600
1:10450154:ATT:A	acceptor_loss	0.9500
1:10450159:TTTCA:T	acceptor_loss	0.9500
1:10450160:TTCAG:T	acceptor_loss	0.9500
1:10450162:CA:C	acceptor_loss	0.9500
1:10450163:A:T	acceptor_loss	0.9500
1:10450164:G:GA	acceptor_loss	0.9500
1:10450152:ACATT:A	acceptor_loss	0.9400
1:10450158:ATTTC:A	acceptor_loss	0.9400
1:10450163:AG:A	acceptor_gain	0.9400
1:10450164:GG:G	acceptor_gain	0.9400
1:10451361:T:TA	acceptor_gain	0.9400
1:10450155:T:G	acceptor_loss	0.9300
1:10451379:T:G	acceptor_gain	0.9300
1:10450156:T:A	acceptor_loss	0.9200
1:10450163:A:AG	acceptor_gain	0.9200
1:10450164:G:GG	acceptor_gain	0.9200
1:10450164:GGGCT:G	acceptor_gain	0.9200
1:10450321:AG:A	donor_gain	0.9200

AlphaMissense

669 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:10451578:T:C	F101L	0.987
1:10451580:C:A	F101L	0.987
1:10451580:C:G	F101L	0.987
1:10451571:G:C	W98C	0.982
1:10451571:G:T	W98C	0.982
1:10451563:T:C	F96L	0.970
1:10451565:C:A	F96L	0.970
1:10451565:C:G	F96L	0.970
1:10451566:T:C	F97L	0.969
1:10451568:C:A	F97L	0.969
1:10451568:C:G	F97L	0.969
1:10451574:G:C	K99N	0.961
1:10451574:G:T	K99N	0.961
1:10451573:A:C	K99T	0.959
1:10451579:T:G	F101C	0.959
1:10451573:A:T	K99M	0.956
1:10451588:G:A	C104Y	0.953
1:10451567:T:G	F97C	0.946
1:10451588:G:T	C104F	0.935
1:10451587:T:C	C104R	0.934
1:10451591:A:T	K105I	0.929
1:10451564:T:G	F96C	0.927
1:10451576:C:T	T100I	0.927
1:10451587:T:A	C104S	0.926
1:10451588:G:C	C104S	0.926
1:10451555:G:A	C93Y	0.921
1:10451589:C:G	C104W	0.919
1:10451556:C:G	C93W	0.917
1:10451592:A:C	K105N	0.911
1:10451592:A:T	K105N	0.911

dbSNP variants (sampled 300 via entrez): RS1001417607 (1:10448348 A>G), RS1001762701 (1:10448556 A>G), RS1002363836 (1:10449578 A>G), RS1003749246 (1:10448451 G>A,C,T), RS1004227637 (1:10449523 C>G), RS1004825849 (1:10450424 C>T), RS1004983020 (1:10450496 A>G), RS1005656550 (1:10448233 G>A), RS1008915627 (1:10452124 A>C,G), RS1009179110 (1:10451771 CTT>C), RS1009367377 (1:10448713 A>G), RS1010663381 (1:10451136 A>T), RS1012306194 (1:10450534 G>A), RS1013569213 (1:10449391 C>T), RS1013594382 (1:10452287 A>C,G)

Disease associations

OMIM: gene MIM:602784 | disease phenotypes: MIM:615513

GenCC curated gene-disease

Mondo (1): immunodeficiency 14 (MONDO:0014222)

Orphanet (2): Activated PI3K-delta syndrome (Orphanet:397596), Activated PI3K-delta syndrome 1 (Orphanet:693661)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006661_56	Male-pattern baldness	4.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	affects methylation	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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