CRH

Summary

CRH (corticotropin releasing hormone, HGNC:2355) is a protein-coding gene on chromosome 8q13.1, encoding Corticoliberin (P06850). Hormone regulating the release of corticotropin from pituitary gland.

This gene encodes a member of the corticotropin-releasing factor family. The encoded preproprotein is proteolytically processed to generate the mature neuropeptide hormone. In response to stress, this hormone is secreted by the paraventricular nucleus (PVN) of the hypothalamus, binds to corticotropin releasing hormone receptors and stimulates the release of adrenocorticotropic hormone from the pituitary gland. Marked reduction in this protein has been observed in association with Alzheimer’s disease. Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia and hepatitis. In addition to production in the hypothalamus, this protein is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta it is a marker that determines the length of gestation and the timing of parturition and delivery. A rapid increase in circulating levels of the hormone occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, this protein may act as a trigger for parturition.

Source: NCBI Gene 1392 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant nocturnal frontal lobe epilepsy (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 49 total
• Phenotypes (HPO): 21
• Druggable target: yes
• MANE Select transcript: NM_000756

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2355
Approved symbol	CRH
Name	corticotropin releasing hormone
Location	8q13.1
Locus type	gene with protein product
Status	Approved
Aliases	CRF, CRH1
Ensembl gene	ENSG00000147571
Ensembl biotype	protein_coding
OMIM	122560
Entrez	1392

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000276571, ENST00000948625

RefSeq mRNA: 1 — MANE Select: NM_000756 NM_000756

CCDS: CCDS6188

Canonical transcript exons

ENST00000276571 — 2 exons

Exon	Start	End
ENSE00000980688	66176376	66177491
ENSE00001222119	66178293	66178464

Expression profiles

Bgee: expression breadth broad, 97 present calls, max score 97.05.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.9309 / max 1063.4174, expressed in 134 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93393	1.5248	125
93396	0.2562	52
205212	0.0890	20
93394	0.0583	17
93390	0.0026	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	97.05	gold quality
placenta	UBERON:0001987	86.31	gold quality
buccal mucosa cell	CL:0002336	85.71	gold quality
Brodmann (1909) area 46	UBERON:0006483	84.85	gold quality
prefrontal cortex	UBERON:0000451	81.91	gold quality
Brodmann (1909) area 10	UBERON:0013541	79.13	gold quality
frontal pole	UBERON:0002795	78.80	gold quality
cingulate cortex	UBERON:0003027	78.24	gold quality
anterior cingulate cortex	UBERON:0009835	78.06	gold quality
orbitofrontal cortex	UBERON:0004167	78.02	gold quality
tendon of biceps brachii	UBERON:0008188	77.17	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	77.04	gold quality
frontal cortex	UBERON:0001870	76.46	gold quality
neocortex	UBERON:0001950	75.85	gold quality
hypothalamus	UBERON:0001898	75.61	gold quality
endothelial cell	CL:0000115	75.59	gold quality
dorsal plus ventral thalamus	UBERON:0001897	74.06	gold quality
right frontal lobe	UBERON:0002810	73.53	gold quality
cerebral cortex	UBERON:0000956	73.45	gold quality
Brodmann (1909) area 9	UBERON:0013540	72.34	gold quality
islet of Langerhans	UBERON:0000006	71.99	gold quality
superior frontal gyrus	UBERON:0002661	71.72	gold quality
medulla oblongata	UBERON:0001896	71.57	gold quality
middle frontal gyrus	UBERON:0002702	71.07	gold quality
ganglionic eminence	UBERON:0004023	70.54	gold quality
telencephalon	UBERON:0001893	70.39	gold quality
amygdala	UBERON:0001876	70.35	gold quality
paraflocculus	UBERON:0005351	70.16	gold quality
parietal lobe	UBERON:0001872	69.25	gold quality
postcentral gyrus	UBERON:0002581	69.16	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-81608	yes	115.25
E-HCAD-31	yes	28.04
E-MTAB-5061	yes	26.31
E-GEOD-83139	yes	8.64
E-ENAD-27	yes	7.99
E-ANND-3	yes	5.19

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
KRT1	Activation
KRT14	Repression

Upstream regulators (CollecTRI, top): AP1, AR, CEBPG, CREB1, CREM, CUX1, DNMT1, ESR1, ESR2, FOS, IRF6, JUN, MECP2, NCOA1, NCOR1, NCOR2, NFKB2, NFKB, NR3C1, NR4A1, NR4A2, NR4A3, PGR, PITX1, POU3F2, POU6F1, RARA, RELB, REST, TBX19, TFAP2A, TFCP2, ZGLP1, ZHX2, ZNF362

miRNA regulators (miRDB)

43 targeting CRH, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-4272	98.76	68.74	1810
HSA-MIR-4742-3P	98.73	69.82	1803

Literature-anchored findings (GeneRIF, showing 40)

• Findings of slightly diminished cerebrospinal fluid CRH levels after feeding may be accounted for by the rises in glucocorticoids and their associated negative feedback effects on central nervous system CRH. (PMID:11406119)
• during pregnancy CRH primarily activates intracellular signals that contribute to the maintenance of myometrial quiescence. (PMID:11854458)
• NPY regulates the CRH system of the human hypothalamus and some of the effects of NPY on metabolic, autonomic, and endocrine functions may be mediated through CRH (PMID:11932939)
• The ability of CRH to induce POMC expression in cultured melanoma cells; in CRH positive melanomas, seven out of nine cases (78%) of primary melanoma, and 7 out of 12 cases (58%) of MetM showed colocalization of CRH and POMC peptides (PMID:11936276)
• AP-2alpha modulates human corticotropin-releasing hormone gene expression in the placenta by direct protein-protein interaction. (PMID:12062896)
• CRH modulates human cardiovascular and pupillary autonomic reflexes. (PMID:12114295)
• Intraventricular insulin potentiates the anorexic effect of corticotropin releasing hormone in rats (PMID:12429558)
• CRH exerts inhibitory effects on steroidogenesis in rat and human granulosa cells, acting through the CRH receptor. (PMID:12450317)
• Placenta takes part in stress syndrome by releasing CRF, which may help to influence uterine perfusion, maternal metabolism, fluid balance, and uterine contractility, protecting fetus from hostile environment.(review) (PMID:12583606)
• in chorion trophoblast cells, endogenously produced corticotropin-releasing hormone exerts a tonic stimulatory effect on 15-hydroxyprostaglandin dehydrogenase activity (PMID:12679466)
• Detected in placenta, myometrium, decidua, and fetal membranes. Widespread expression of CRH system in gestational tissue suggests paracrine role CRH in birth process (e.g. effects on macrophages and endothelial cells). (PMID:12784189)
• reduced levels of circulating corticotropin releasing factor were associated with increased uterine artery resistance (PMID:12853091)
• human cord blood-derived cultured mast cells (hCBMC) at 10 wk, but not at 2 wk, are immunocytochemically positive for CRH and urocortin (PMID:14576187)
• progesterone, corticotropin-releasing factor, and activin A have roles in paracrine regulation of endometrial function [review] (PMID:14667971)
• corticotropin-releasing hormone inhibits nuclear factor-kappaB binding and transcriptional activity. (PMID:14675201)
• An association between an allele of the CRH-linked locus and behavioral inhibtion. Among offspring of parents with panic disorder, this association was marked. (PMID:14675801)
• CRH administration induced sympathotonic effects which were antagonized by ANP (PMID:14698679)
• Expression of urocortin mRNA is significantly downregulated in the Edinger-Westphal nucleus of CRF-overexpressing transgenic mice compared with wild-type. (PMID:14706771)
• The high expression of CRH in placenta and in choriodecidua and myometrium suggested that CRH derived from placenta exerts direct or indirect actions on these tissues. (PMID:15072543)
• CRH plays pathogenic role in modulating inflammatory joint disease with CREB/ATF family of transcription factors as principal effector molecules of proinflammatory mediator action in rheumatoid arthritis. (PMID:15077295)
• CRH promoter region between -248 and -213 bp was essential for the effect of both E2 and ICI 182780. This region contains a consensus cAMP regulatory element that is a requirement for E2- and ICI 182780-mediated activity. (PMID:15126558)
• CRH inhibited the transition of keratinocytes from G0/1 to S phase of the cell cycle, which was accompanied by an increased expression of cdk inhibitor p16 (Ink4a) protein (PMID:15468147)
• calcium/calmodulin-dependent protein kinase IV signaling pathway may play an important role in the excitation-mediated regulation of CRH synthesis (PMID:15591024)
• CRH regulates IL-18 production through the MAPK signaling pathway in human keratinocytes. (PMID:15816833)
• Ileal-specific CRF promotes inflammation and modulates bowel motility. (PMID:15883387)
• CRH genetic alterations could explain several autosomal dominant nocturnal frontal lobe epilepsy clinical features (PMID:16222669)
• CRH and related peptides can couple CRH-R1 to any of diverse signal transduction pathways; they also regulate cell viability and proliferation in cell type and growth condition-dependent manners. (PMID:16245303)
• during pregnancy, early detection of stress signals by the placenta stimulate the subsequent release of CRH and may result in increased risk for preterm delivery (PMID:16309788)
• Colocalization of CRH and nuclear/cytoplasmic androgen receptor (AR) was found in neurons of the human hypothalamic paraventricular nucleus (PVN). In the presence of testosterone, recombinant human AR bound to CRH-androgen-responsive elements. (PMID:16446741)
• CRH promoter reactivity varies between the compound promoter alleles. (PMID:16523405)
• Nonalcoholic subjects with a family history of alcoholism exhibit lower plasma ACTH and beta-endorphin as well as lower ACTH, cortisol, and beta-endorphin responses to psychological stress and CRH stimulation. (PMID:16639867)
• CRH peptides can differentially influence hair follicle melanocyte behavior not only via CRH-R1 signaling but also by complex cross-talk between CRH-R1 and CRH-R2. (PMID:16675846)
• detection of substantial expression of the CRH and its receptor proteins, as well as receptor mRNA in the cervix suggests that the cervix may be a target for CRH action (PMID:16734917)
• Ultraviolet B radiation induces CRH production in human melanocytes through stimulation of the protein kinase A pathway (PMID:16740657)
• findings suggest that the increased levels of tumor necrosis factor-alpha and corticotropin-releasing hormone found in pregnant women presenting with preterm labor may be involved in the pathophysiological mechanism of the latter (PMID:16984517)
• CRH mediates inflammation induced by lipopolysaccharide in human adult epidermal keratinocytes (PMID:17068474)
• The elevated level of placental CRH may be a trigger of the transcription of its own receptor CRH-R1 during caesarian operations. (PMID:17294739)
• CRH, PLAC1, and selectin-P are distributed differently in preeclampsia cases compared to controls and correlate with signs of preeclampsia. (PMID:17554801)
• findings suggest that CRH augments LPS induced cytokine secretion in human trophoblast cells. Modulation of LPS induced immune responses by CRH may be mediated through regulation of TLR-4 and selective activation of the p38/MAPK signalling pathway. (PMID:17568667)
• Corticotropin-releasing hormone produced by ovarian cancer might favour survival and progression of the tumour by promoting its immune privilege. (PMID:17667919)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	crhb	ENSDARG00000027657
danio_rerio	crha	ENSDARG00000093401
mus_musculus	Crh	ENSMUSG00000049796
rattus_norvegicus	Crh	ENSRNOG00000012703

Paralogs (1): UCN (ENSG00000163794)

Protein

Protein identifiers

Corticoliberin — P06850 (reviewed: P06850)

Alternative names: Corticotropin-releasing factor, Corticotropin-releasing hormone

All UniProt accessions (2): P06850, A0A0S2Z478

UniProt curated annotations — full annotation on UniProt →

Function. Hormone regulating the release of corticotropin from pituitary gland. Induces NLRP6 in intestinal epithelial cells, hence may influence gut microbiota profile.

Subunit / interactions. Interacts (via C-terminus) with CRFR1 (via N-terminal extracellular domain).

Subcellular location. Secreted.

Tissue specificity. Produced by the hypothalamus and placenta.

Similarity. Belongs to the sauvagine/corticotropin-releasing factor/urotensin I family.

RefSeq proteins (1): NP_000747* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000187	CRF	Domain
IPR003620	Urocortin_CRF	Family
IPR018446	Corticotropin-releasing_fac_CS	Conserved_site

Pfam: PF00473

UniProt features (19 total): mutagenesis site 6, region of interest 3, compositionally biased region 3, helix 2, signal peptide 1, propeptide 1, sequence variant 1, peptide 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3EHU	X-RAY DIFFRACTION	1.96
6P9X	ELECTRON MICROSCOPY	2.91
3EHT	X-RAY DIFFRACTION	3.4
1GO9	SOLUTION NMR
1GOE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P06850-F1	62.82	0.15

Antibody-complex structures (SAbDab): 1 — 6P9X

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): 194

Mutagenesis-validated functional residues (6):

Position	Phenotype
183	strongly reduced affinity for crfr1.
187	no effect on affinity for crfr1.
188	strongly reduced affinity for crfr1.
190	strongly reduced affinity for crfr1.
191	strongly reduced affinity for crfr1.
192	no effect on affinity for crfr1.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-418555	G alpha (s) signalling events
R-HSA-9022702	MECP2 regulates transcription of neuronal ligands

MSigDB gene sets: 453 (showing top): GOBP_CIRCADIAN_RHYTHM, ATF_B, AHRARNT_01, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_MEMORY, GOBP_DIGESTION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOBP_ACID_SECRETION, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, HNF3ALPHA_Q6, GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS

GO Biological Process (51): synaptic transmission, dopaminergic (GO:0001963), negative regulation of systemic arterial blood pressure (GO:0003085), glucocorticoid biosynthetic process (GO:0006704), inflammatory response (GO:0006954), signal transduction (GO:0007165), chemical synaptic transmission (GO:0007268), female pregnancy (GO:0007565), parturition (GO:0007567), learning or memory (GO:0007611), positive regulation of cell population proliferation (GO:0008284), associative learning (GO:0008306), hormone-mediated apoptotic signaling pathway (GO:0008628), response to xenobiotic stimulus (GO:0009410), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), negative regulation of norepinephrine secretion (GO:0010700), positive regulation of circadian sleep/wake cycle, wakefulness (GO:0010841), regulation of serotonin secretion (GO:0014062), diterpenoid metabolic process (GO:0016101), hypothalamus development (GO:0021854), lung development (GO:0030324), adrenal gland development (GO:0030325), negative regulation of epinephrine secretion (GO:0032811), negative regulation of luteinizing hormone secretion (GO:0033685), locomotory exploration behavior (GO:0035641), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), response to immobilization stress (GO:0035902), negative regulation of circadian sleep/wake cycle, REM sleep (GO:0042322), response to estrogen (GO:0043627), response to ethanol (GO:0045471), response to ether (GO:0045472), response to pain (GO:0048265), monoatomic ion homeostasis (GO:0050801), neuron apoptotic process (GO:0051402), response to corticosterone (GO:0051412), positive regulation of corticotropin secretion (GO:0051461), positive regulation of cortisol secretion (GO:0051464), long-term synaptic potentiation (GO:0060291), positive regulation of digestive system process (GO:0060456), negative regulation of glucagon secretion (GO:0070093)

GO Molecular Function (7): signaling receptor binding (GO:0005102), hormone activity (GO:0005179), neuropeptide hormone activity (GO:0005184), corticotropin-releasing hormone activity (GO:0017045), corticotropin-releasing hormone receptor 1 binding (GO:0051430), corticotropin-releasing hormone receptor 2 binding (GO:0051431), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), varicosity (GO:0043196), perikaryon (GO:0043204), synapse (GO:0045202), neuronal dense core vesicle lumen (GO:0099013), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
GPCR ligand binding	1
GPCR downstream signalling	1
Transcriptional Regulation by MECP2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
multi-organism reproductive process	2
multi-multicellular organism process	2
gene expression	2
regulation of gene expression	2
hormone activity	2
corticotropin-releasing hormone receptor binding	2
chemical synaptic transmission	1
regulation of systemic arterial blood pressure	1
negative regulation of blood pressure	1
glucocorticoid metabolic process	1
steroid hormone biosynthetic process	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
anterograde trans-synaptic signaling	1
behavior	1
cognition	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
learning	1
hormone-mediated signaling pathway	1
apoptotic signaling pathway	1
response to chemical	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
regulation of norepinephrine secretion	1
negative regulation of catecholamine secretion	1
norepinephrine secretion	1
regulation of circadian sleep/wake cycle, wakefulness	1
circadian sleep/wake cycle, wakefulness	1
positive regulation of circadian rhythm	1
positive regulation of behavior	1
serotonin secretion	1
regulation of monoatomic ion transport	1
regulation of secretion by cell	1

Protein interactions and networks

STRING

2172 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRH	CRHR1	P34998	999
CRH	CRHR2	Q13324	999
CRH	CRHBP	P24387	997
CRH	UCN	P55089	990
CRH	POMC	P01189	987
CRH	UCN3	Q969E3	963
CRH	NPY	P01303	946
CRH	UCN2	Q96RP3	940
CRH	OXT	P01178	918
CRH	GHRH	P01286	909
CRH	TRH	P20396	885
CRH	NR3C1	P04150	873
CRH	HCRT	O43612	867
CRH	LEP	P41159	866
CRH	VIP	P01282	861

IntAct

44 interactions, top by confidence:

A	B	Type	Score
CRHR1	CRH	psi-mi:“MI:0407”(direct interaction)	0.680
CRH	CRHR1	psi-mi:“MI:0407”(direct interaction)	0.680
CRH	KRT31	psi-mi:“MI:0915”(physical association)	0.560
KRT31	CRH	psi-mi:“MI:0915”(physical association)	0.560
CRH	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	CRH	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-3	CRH	psi-mi:“MI:0915”(physical association)	0.560
CRH	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
CRH	MDFI	psi-mi:“MI:0915”(physical association)	0.560
CRH	NOTCH2NLC	psi-mi:“MI:0915”(physical association)	0.560
CRH	KRTAP9-3	psi-mi:“MI:0915”(physical association)	0.560
CRH	KRTAP1-5	psi-mi:“MI:0915”(physical association)	0.560
CRH	CSNK1D	psi-mi:“MI:0915”(physical association)	0.560
CRH	UBR1	psi-mi:“MI:0915”(physical association)	0.560
CRH	CRHR2	psi-mi:“MI:0915”(physical association)	0.540
CRH	UCN	psi-mi:“MI:0915”(physical association)	0.540
CRHR2	CRH	psi-mi:“MI:0407”(direct interaction)	0.540
CRH	CRHR2	psi-mi:“MI:0407”(direct interaction)	0.540
CRH	CRH	psi-mi:“MI:0407”(direct interaction)	0.440
CRH	RRAS	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
CRH	CST4	psi-mi:“MI:0914”(association)	0.350
CRH	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.000
CRH	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): KRT31 (Two-hybrid), UBR1 (Affinity Capture-MS), RRAS (Affinity Capture-MS), CRH (Protein-peptide), CRH (Two-hybrid), KRTAP10-8 (Two-hybrid), CYSRT1 (Two-hybrid), KRTAP9-3 (Two-hybrid), KRTAP1-5 (Two-hybrid), KRTAP1-3 (Two-hybrid), KRTAP5-9 (Two-hybrid), NOTCH2NL (Two-hybrid), NBPF19 (Two-hybrid), CRHR2 (Reconstituted Complex), CRHR1 (Reconstituted Complex)

ESM2 similar proteins: O02686, O43555, O97655, O97686, P01142, P01143, P01297, P01351, P01352, P01353, P01354, P06296, P06850, P07492, P08949, P08989, P09683, P11384, P13083, P24393, P47851, P55089, P61312, P63152, P63153, P63298, P68248, P81264, P81277, P81278, P83859, P83860, P83862, Q08535, Q15726, Q2T9U8, Q6Y4S4, Q7TNK8, Q7TSB7, Q7Z4H4

Diamond homologs: O93448, P01142, P01143, P01144, P01145, P01146, P06296, P06850, P13241, P21624, P25308, P49188, P49926, P55089, P55090, P81615, Q8CIT0, Q95MI6, Q9PTQ4, Q9PTS1

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
CRH	up-regulates	CRHR1	binding
CRH	“up-regulates quantity by expression”	KRT1	“transcriptional regulation”
CRH	“down-regulates quantity by repression”	KRT14	“transcriptional regulation”
CRH	“up-regulates activity”	CRHR2	binding
ESR1	“up-regulates quantity by expression”	CRH	“transcriptional regulation”
ESR2	“up-regulates quantity by expression”	CRH	“transcriptional regulation”
AR	“down-regulates quantity by repression”	CRH	“transcriptional regulation”
MECP2	“down-regulates quantity by repression”	CRH	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Keratinization	6	25.7×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	8
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

285 predictions. Top by Δscore:

Variant	Effect	Δscore
8:66177500:C:CT	acceptor_gain	0.9900
8:66177501:A:T	acceptor_gain	0.9900
8:66177517:C:CT	acceptor_gain	0.9900
8:66177518:G:T	acceptor_gain	0.9900
8:66177488:CTCG:C	acceptor_gain	0.9800
8:66177492:C:CA	acceptor_loss	0.9800
8:66177492:C:CC	acceptor_gain	0.9800
8:66177493:T:G	acceptor_loss	0.9800
8:66177505:G:C	acceptor_gain	0.9800
8:66177510:C:CT	acceptor_gain	0.9800
8:66177511:G:T	acceptor_gain	0.9800
8:66177521:A:AC	acceptor_gain	0.9800
8:66177490:CG:C	acceptor_gain	0.9700
8:66177498:C:CT	acceptor_gain	0.9700
8:66177487:ACTCG:A	acceptor_gain	0.9600
8:66177488:CTCGC:C	acceptor_gain	0.9600
8:66177489:TCGCT:T	acceptor_gain	0.9600
8:66177496:G:T	acceptor_gain	0.9600
8:66177521:A:C	acceptor_gain	0.9600
8:66177489:TCG:T	acceptor_gain	0.9500
8:66177490:CGC:C	acceptor_gain	0.9500
8:66177451:C:CT	acceptor_gain	0.9200
8:66177451:C:T	acceptor_gain	0.9200
8:66177505:G:GC	acceptor_gain	0.9100
8:66178202:A:AC	donor_gain	0.9100
8:66178203:C:CC	donor_gain	0.9100
8:66178203:CA:C	donor_gain	0.9100
8:66177568:G:C	donor_gain	0.8900
8:66177591:T:TA	donor_gain	0.8600
8:66178196:A:T	donor_gain	0.8500

AlphaMissense

1242 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:66176983:G:C	F165L	0.999
8:66176983:G:T	F165L	0.999
8:66176984:A:C	F165C	0.999
8:66176985:A:G	F165L	0.999
8:66176990:A:G	L163P	0.999
8:66176975:A:G	L168P	0.998
8:66176975:A:T	L168H	0.998
8:66176978:A:G	L167P	0.998
8:66176984:A:G	F165S	0.998
8:66176894:C:T	G195E	0.996
8:66176918:T:A	N187I	0.996
8:66176982:G:C	H166D	0.996
8:66176987:G:A	T164I	0.996
8:66176990:A:T	L163H	0.996
8:66176993:T:A	D162V	0.996
8:66176993:T:C	D162G	0.996
8:66176914:C:A	R188S	0.995
8:66176914:C:G	R188S	0.995
8:66176985:A:T	F165I	0.995
8:66176993:T:G	D162A	0.995
8:66176894:C:A	G195V	0.994
8:66176915:C:A	R188M	0.994
8:66176917:G:C	N187K	0.994
8:66176917:G:T	N187K	0.994
8:66176972:C:G	R169P	0.994
8:66176996:A:T	L161Q	0.994
8:66176915:C:G	R188T	0.993
8:66176980:G:C	H166Q	0.993
8:66176980:G:T	H166Q	0.993
8:66176992:A:C	D162E	0.993

dbSNP variants (sampled 300 via entrez): RS1000540886 (8:66175965 A>G), RS1000597555 (8:66175895 A>C,G,T), RS1000650130 (8:66176170 T>G), RS1000816466 (8:66180441 CACA>C), RS1001591926 (8:66179730 T>A,C), RS1002337081 (8:66178919 T>C), RS1003345318 (8:66180359 A>G), RS1004411393 (8:66179740 A>G), RS1004437120 (8:66178172 A>G), RS1004824308 (8:66179314 C>T), RS1006952187 (8:66176428 T>C), RS1007429284 (8:66176283 G>A,T), RS1010249945 (8:66177662 A>C), RS1010341519 (8:66180310 T>A,C), RS1010717070 (8:66177954 G>A,T)

Disease associations

OMIM: gene MIM:122560 | disease phenotypes: MIM:600513

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nocturnal frontal lobe epilepsy	Supportive	Autosomal dominant
frontal lobe epilepsy	Limited	Autosomal dominant
epilepsy	Refuted Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
epilepsy	Refuted	AD

Mondo (4): familial sleep-related hypermotor epilepsy (MONDO:0000030), frontal lobe epilepsy (MONDO:0002612), epilepsy (MONDO:0005027), (MONDO:0020300)

Orphanet (1): Sleep-related hypermotor epilepsy (Orphanet:98784)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000020	Urinary incontinence
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000733	Motor stereotypy
HP:0000739	Anxiety
HP:0001256	Mild intellectual disability
HP:0001345	Psychotic mentation
HP:0002069	Bilateral tonic-clonic seizure
HP:0002268	Paroxysmal dystonia
HP:0002883	Hyperventilation
HP:0004305	Involuntary movements
HP:0007018	Attention deficit hyperactivity disorder
HP:0011174	Focal hyperkinetic seizure
HP:0011182	Interictal epileptiform activity
HP:0011193	EEG with focal spikes
HP:0025235	NREM parasomnia
HP:0025236	Sleep walking
HP:0031535	Increased theta frequency activity in EEG
HP:0031589	Suicidal ideation
HP:0031951	Nocturnal seizures
HP:0100543	Cognitive impairment

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001545_1	Coronary heart disease event reduction (statin therapy interaction)	5.000000e-07
GCST010988_299	Adult body size	3.000000e-10

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D017034	Epilepsy, Frontal Lobe	C10.228.140.490.360.270; C10.228.140.490.493.188
C579932	Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291554 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4737771	Efficacy	3	antidepressants	Major Depressive Disorder

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4737771	CRH	3	0.00	1	antidepressants

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.15	Ki	0.7	nM	CHEMBL5286255

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-(2-chloro-4,5-dimethoxyphenyl)-7-ethyl-8-heptan-4-yl-2-methylpyrazolo[1,5-a][1,3,5]triazine	1938558: Binding affinity to CRF (unknown origin) receptor assessed as inhibition constant	ki	0.0007	uM

CTD chemical–gene interactions

52 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	4
bisphenol A	increases methylation, increases expression, affects cotreatment	3
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	2
Diethylhexyl Phthalate	affects cotreatment, decreases expression, increases expression	2
Hydrocortisone	increases abundance	2
Progesterone	affects binding, increases activity, increases reaction, decreases reaction, increases abundance (+1 more)	2
Aflatoxin B1	decreases reaction, increases expression, decreases methylation	2
Asian ginseng	affects cotreatment, decreases expression	1
2,4-dichlorophenol	decreases secretion	1
methylmercuric chloride	decreases expression	1
mono-(2-ethylhexyl)phthalate	affects binding, increases reaction, affects reaction, increases expression	1
cobaltous chloride	increases secretion	1
perfluorooctanoic acid	increases expression	1
mesoporphyrin IX	decreases reaction, increases secretion	1
vanadyl sulfate	decreases expression	1
bisindolylmaleimide I	increases expression, decreases reaction	1
SR 48968	decreases activity, affects cotreatment	1
perfluorooctane sulfonic acid	increases expression, affects cotreatment	1
Go 6976	increases expression, decreases reaction, increases abundance	1
SR 140333	affects cotreatment, decreases activity	1
bisindolylmaleimide	increases expression, decreases reaction	1
SB 203580	decreases reaction, increases expression	1
pyrazolanthrone	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression, decreases reaction	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	decreases secretion	1
Pioglitazone	increases expression	1
Arsenic Trioxide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5242052	Binding	Binding affinity to CRF (unknown origin) receptor assessed as inhibition constant	Pyrazolotriazines: Biological activities, synthetic strategies and recent developments. — Eur J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy