GNRH2

Summary

GNRH2 (gonadotropin releasing hormone 2, HGNC:4420) is a protein-coding gene on chromosome 20p13, encoding Progonadoliberin-2 (O43555). Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.

This gene is a member of the gonadotropin-releasing hormone (GnRH) gene family. Proteins encoded by members of this gene family are proteolytically cleaved to form neuropeptides which, in part, regulate reproductive functions by stimulating the production and release of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The human GNRH2 gene is predicted to encode a preproprotein from which a mature neuropeptide of 10 amino acids is cleaved. However, while the human genome retains the sequence for a functional GNRH2 decapeptide, translation of the human GNRH2 gene has not yet been demonstrated and the GNRH2 gene of chimpanzees, gorilla, and Sumatran orangutan have a premature stop at codon eight of the decapeptide sequence which suggests GNRH2 was a pseudogene in the hominid lineage. The GNRH2 gene is also believed to be a pseudogene in many other mammalian species such as mouse and cow. The receptor for this gene (GNRHR2) is predicted to be a pseudogene in human as well as many other mammalian species. The closely related GNRH1 and GNRHR1 genes are functional in human and other mammals and are generally functional in vertebrates.

Source: NCBI Gene 2797 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 21 total
• MANE Select transcript: NM_178331

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4420
Approved symbol	GNRH2
Name	gonadotropin releasing hormone 2
Location	20p13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000125787
Ensembl biotype	protein_coding
OMIM	602352
Entrez	2797

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000245983, ENST00000359100, ENST00000380346, ENST00000380347, ENST00000862748, ENST00000862749

RefSeq mRNA: 4 — MANE Select: NM_178331 NM_001310220, NM_001501, NM_178331, NM_178332

CCDS: CCDS13040, CCDS13041, CCDS13042

Canonical transcript exons

ENST00000359100 — 4 exons

Exon	Start	End
ENSE00000858708	3044408	3044568
ENSE00001108283	3043622	3043665
ENSE00001368984	3044700	3044836
ENSE00001484625	3045686	3045747

Expression profiles

Bgee: expression breadth ubiquitous, 157 present calls, max score 87.11.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.5740 / max 877.9778, expressed in 120 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183195	3.5740	120

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	87.11	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.35	silver quality
type B pancreatic cell	CL:0000169	77.51	gold quality
olfactory bulb	UBERON:0002264	77.34	gold quality
right lobe of liver	UBERON:0001114	73.66	gold quality
cerebellar hemisphere	UBERON:0002245	72.62	gold quality
cerebellar cortex	UBERON:0002129	72.42	gold quality
right hemisphere of cerebellum	UBERON:0014890	72.16	gold quality
cerebellum	UBERON:0002037	70.76	gold quality
granulocyte	CL:0000094	69.95	gold quality
triceps brachii	UBERON:0001509	69.73	gold quality
gluteal muscle	UBERON:0002000	69.05	gold quality
left ovary	UBERON:0002119	68.90	gold quality
epithelial cell of pancreas	CL:0000083	67.92	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	67.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	67.62	gold quality
vastus lateralis	UBERON:0001379	67.27	gold quality
quadriceps femoris	UBERON:0001377	67.15	gold quality
right ovary	UBERON:0002118	66.28	gold quality
deltoid	UBERON:0001476	65.19	gold quality
mucosa of stomach	UBERON:0001199	64.59	gold quality
right coronary artery	UBERON:0001625	64.17	gold quality
right testis	UBERON:0004534	64.15	gold quality
pituitary gland	UBERON:0000007	64.00	gold quality
stromal cell of endometrium	CL:0002255	63.96	gold quality
biceps brachii	UBERON:0001507	63.73	gold quality
ovary	UBERON:0000992	63.58	gold quality
gingival epithelium	UBERON:0001949	63.43	gold quality
adenohypophysis	UBERON:0002196	63.41	gold quality
endocervix	UBERON:0000458	63.25	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	8378.86
E-ANND-3	no	0.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CEBPB, CREB1, NFKB, RARA, RELA, RXRA

Literature-anchored findings (GeneRIF, showing 25)

• GnRH-II and GnRH-I interact directly with T cells and trigger gene transcription, adhesion, chemotaxis and homing to specific organs, which may be of clinical relevance. (PMID:12447356)
• a novel mechanism in stimulating basal human GnRH-II gene transcription mediated by cooperative actions of multiple regulatory elements within the untranslated first exon of the gene. (PMID:12663744)
• regulation of GnRH-I and GnRH-II gene expression in the ovary (PMID:12770744)
• gonadotropin releasing hormone-II is more effective than gonadotropin releasing hormone-I in stimulating leptin secretion (PMID:12969578)
• GnRH-II has been identified, together with a ‘putative’ type II GnRH receptor, both in the central nervous system and in peripheral structures, such as tissues of the reproductive tract (both normal and tumoral). (PMID:14726258)
• GnRH I and GnRH II have both common and discrete cellular distributions in the placenta and decidua and suggest that these two hormones are capable of eliciting their biological actions in an autocrine and/or paracrine manner (PMID:15001648)
• Progesterone receptor isoform p4 is a potent regulator of GnRHRI at the transcriptional level as well as GnRH I mRNA. (PMID:15562029)
• GnRH-II did not affect proliferation of normal B-cells alone, and did not alter the proliferative response to IL-2. (PMID:15578334)
• we observed that LHRH-(1-5), the specific processed peptide of LHRH-I, upregulates LHRH-II mRNA expression in Ishikawa cells, an endometrial cell line but does not exert any influence on LHRH-I mRNA levels (PMID:17202595)
• Expression of GnRH2 protein and receptor (GnRHR2) is confirmed in both leiomyoma and patient-matched myometrium. (PMID:17296196)
• these data demonstrate the differential roles of NF-kappaB p65 and RARalpha/RXRalpha, interacting with the same sequence in the promoter of the human GnRH II gene to influence gene expression in a cell-specific manner. (PMID:17451432)
• GnRH II is widely expressed in prostate cancer and is an AR-regulated gene. (PMID:17914092)
• analysis of how GNRH I and GNRH II inhibit cell growth (PMID:18467526)
• GnRH-I and -II induce apoptosis in human granulosa cells through GnRH-I receptors, which mediate the proteolytic caspase cascade involving caspase-8 (the initiator) and caspase-3 and -7 (the effectors). (PMID:18477660)
• p-CREB, C/EBPbeta, and CBP are recruited to the CRE of the GnRH-II promoter in a temporarily defined manner to enhance its transcription in JEG-3 and OVCAR-3 cells in response to cAMP (PMID:18599546)
• These results provide evidence that EGF is an upstream regulator of the autocrine actions of GnRH-II on the invasive properties of ovarian cancer cells. (PMID:19608641)
• These preliminary data suggest that local GnRH-II may participate in the regulation of ovarian tumor growth in post-menopausal women. (PMID:20018426)
• results suggest GnRH-II-induced laminin receptor precursor expression increases 67-kDa nonintegrin laminin receptor, which appears to interact with laminin in the extracellular matrix to promote MMP-2 expression and enhance ovarian cancer cell invasion (PMID:21193558)
• concluded that GnRHII stimulates PI3K/Akt pathway, and the phosphorylation of glycogen synthase kinase3beta, thereby enhancing the beta-catenin-dependent up-regulation of MT1-MMP production which contributes to ovarian cancer metastasis (PMID:21239435)
• GnRHII expression correlated significantly with poor prognosis in breast cancer patients. (PMID:23287110)
• rs6051545 (GNRH2) genetic variation may result in inadequate suppression of serum testosterone during androgen deprivation therapy. This may lead to detrimental effects of androgen deprivation therapy on prognosis in men with metastatic prostate cancer. (PMID:28941922)
• The effects of common variants in MDM2 and GNRH2 genes on the risk and survival of osteosarcoma in Han populations from Northwest China. (PMID:32994424)
• Copper(II) Binding by the Earliest Vertebrate Gonadotropin-Releasing Hormone, the Type II Isoform, Suggests an Ancient Role for the Metal. (PMID:33114333)
• EGF-Enhanced GnRH-II Regulation in Decidual Stromal Cell Motility through Twist and N-Cadherin Signaling. (PMID:37894950)
• Role of gonadotropin-releasing hormone 2 and its receptor in human reproductive cancers. (PMID:38260130)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnrh2	ENSDARG00000044754
danio_rerio	gnrh3	ENSDARG00000056214

Paralogs (1): GNRH1 (ENSG00000147437)

Protein

Protein identifiers

Progonadoliberin-2 — O43555 (reviewed: O43555)

Alternative names: Progonadoliberin II

All UniProt accessions (1): O43555

UniProt curated annotations — full annotation on UniProt →

Function. Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.

Subcellular location. Secreted.

Tissue specificity. Midbrain; expressed at significantly higher levels outside the brain (up to 30-fold), particularly in the kidney, bone marrow and prostate.

Similarity. Belongs to the GnRH family.

Isoforms (3)

UniProt ID	Names	Canonical?
O43555-1	1	yes
O43555-2	2
O43555-3	3

RefSeq proteins (4): NP_001297149, NP_001492, NP_847901, NP_847902 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002012	GnRH	Conserved_site
IPR019792	Gonadoliberin	Family

Pfam: PF00446

UniProt features (9 total): peptide 2, splice variant 2, signal peptide 1, chain 1, region of interest 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43555-F1	65.09	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.

Post-translational modifications (1): 33

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-375281	Hormone ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 56 (showing top): REACTOME_HORMONE_LIGAND_BINDING_RECEPTORS, GOMF_SIGNALING_RECEPTOR_BINDING, SHEN_SMARCA2_TARGETS_DN, GOMF_HORMONE_RECEPTOR_BINDING, GOMF_PEPTIDE_HORMONE_RECEPTOR_BINDING, GOMF_HORMONE_ACTIVITY, REACTOME_CLASS_A_1_RHODOPSIN_LIKE_RECEPTORS, REACTOME_G_ALPHA_Q_SIGNALLING_EVENTS, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, KEGG_GNRH_SIGNALING_PATHWAY, SU_PANCREAS, RAPA_EARLY_UP.V1_DN, RELA_DN.V1_DN, BRCA1_DN.V1_DN, IL2_UP.V1_UP

GO Biological Process (2): signal transduction (GO:0007165), multicellular organism development (GO:0007275)

GO Molecular Function (3): hormone activity (GO:0005179), gonadotropin hormone-releasing hormone activity (GO:0005183), gonadotropin-releasing hormone receptor binding (GO:0031530)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

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
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
multicellular organismal process	1
anatomical structure development	1
receptor ligand activity	1
hormone activity	1
peptide hormone receptor binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNRH2	GNRH1	P01148	981
GNRH2	GNRHR	P30968	971
GNRH2	KISS1	Q15726	838
GNRH2	KISS1R	Q969F8	821
GNRH2	TRPC7	Q9HCX4	764
GNRH2	ADAT2	Q7Z6V5	712
GNRH2	FSHB	P01225	700
GNRH2	RPSA	P08865	693
GNRH2	TAC3	Q9UHF0	687
GNRH2	TACR3	P29371	685
GNRH2	PROK2	Q9HC23	625
GNRH2	CHD7	Q9P2D1	568
GNRH2	NPY	P01303	557
GNRH2	CXCL12	P48061	548
GNRH2	GPR150	Q8NGU9	548

IntAct

0 interactions, top by confidence:

BioGRID (1): APP (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: O42241, O42471, O43555, O73811, O97655, O97686, P30973, P37044, P43306, P45652, P45653, P45656, P51921, P51923, P51924, P51925, P55246, P69107, P69108, P69109, Q8UW81, Q8UW82, Q90Y63, Q91330, Q92097, Q95336, Q9DD49, Q9DG36, Q9DGC9, Q9IA08, Q9IA09, P33439, P51917, P51922, Q92106, Q9IAU2, P37042, Q95335, O09163, O54713

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

539 predictions. Top by Δscore:

Variant	Effect	Δscore
20:3043664:TGG:T	donor_loss	0.9400
20:3043667:T:G	donor_loss	0.9400
20:3043668:G:GT	donor_loss	0.9400
20:3043666:G:GG	donor_gain	0.9300
20:3043669:AG:A	donor_loss	0.9300
20:3044407:G:C	acceptor_gain	0.9200
20:3044407:GAGCA:G	acceptor_gain	0.9200
20:3044406:A:AG	acceptor_gain	0.9100
20:3044407:G:GG	acceptor_gain	0.9100
20:3045684:A:AG	acceptor_gain	0.9000
20:3045685:G:GG	acceptor_gain	0.9000
20:3043670:G:C	donor_loss	0.8600
20:3044478:G:C	acceptor_gain	0.8600
20:3044699:GCA:G	acceptor_gain	0.8500
20:3045169:G:GC	acceptor_gain	0.8500
20:3044754:T:TA	acceptor_gain	0.8300
20:3044407:GA:G	acceptor_gain	0.7900
20:3044836:GGTG:G	donor_loss	0.7900
20:3044837:GTG:G	donor_loss	0.7900
20:3044838:TGA:T	donor_loss	0.7900
20:3044839:G:GC	donor_loss	0.7900
20:3044840:AG:A	donor_loss	0.7900
20:3045685:GACC:G	acceptor_gain	0.7900
20:3044841:G:C	donor_loss	0.7800
20:3045683:CA:C	acceptor_loss	0.7500
20:3044676:A:AC	acceptor_gain	0.7400
20:3044164:T:TA	donor_gain	0.7300
20:3044165:A:AA	donor_gain	0.7300
20:3044290:GGCA:G	donor_gain	0.7300
20:3044476:CAG:C	acceptor_gain	0.7300

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000105295 (20:3041772 A>T), RS1000129573 (20:3046214 A>G,T), RS1000680940 (20:3041747 C>T), RS1001120595 (20:3042029 C>G,T), RS1002301307 (20:3042576 C>T), RS1002446793 (20:3043261 G>A,C), RS1002490776 (20:3042853 G>A,T), RS1002977246 (20:3045541 G>A,T), RS1003006702 (20:3045780 C>A,G,T), RS1004502117 (20:3046153 A>C,G), RS1004564797 (20:3044292 C>T), RS1005342389 (20:3042526 A>G), RS1006470888 (20:3041856 G>A), RS1006487686 (20:3045737 G>A,C), RS1006594897 (20:3042050 A>G)

Disease associations

OMIM: gene MIM:602352 | 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
GCST006585_865	Blood protein levels	5.000000e-06

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
aristolochic acid I	increases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases expression, increases abundance	1
Catechin	affects cotreatment, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases abundance, increases expression	1

Clinical trials (associated diseases)

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