GHRHR

Summary

GHRHR (growth hormone releasing hormone receptor, HGNC:4266) is a protein-coding gene on chromosome 7p14.3, encoding Growth hormone-releasing hormone receptor (Q02643). Receptor for GRF, coupled to G proteins which activate adenylyl cyclase.

This gene encodes a receptor for growth hormone-releasing hormone. Binding of this hormone to the receptor leads to synthesis and release of growth hormone. Mutations in this gene have been associated with isolated growth hormone deficiency (IGHD), also known as Dwarfism of Sindh, a disorder characterized by short stature.

Source: NCBI Gene 2692 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isolated growth hormone deficiency type IB (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 344 total — 25 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 7
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000823

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4266
Approved symbol	GHRHR
Name	growth hormone releasing hormone receptor
Location	7p14.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000106128
Ensembl biotype	protein_coding
OMIM	139191
Entrez	2692

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 4 protein_coding_CDS_not_defined, 3 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000326139, ENST00000337750, ENST00000396227, ENST00000409316, ENST00000409904, ENST00000461390, ENST00000461424, ENST00000463164, ENST00000466427, ENST00000473133, ENST00000489974

RefSeq mRNA: 1 — MANE Select: NM_000823 NM_000823

CCDS: CCDS5432

Canonical transcript exons

ENST00000326139 — 13 exons

Exon	Start	End
ENSE00001616053	30969063	30969170
ENSE00001677188	30968834	30968936
ENSE00001951419	30963953	30964125
ENSE00003467910	30975777	30975868
ENSE00003525016	30974429	30974489
ENSE00003534860	30971963	30972095
ENSE00003598265	30969867	30969964
ENSE00003641615	30974971	30975040
ENSE00003642770	30979119	30979528
ENSE00003665181	30977281	30977322
ENSE00003684263	30971119	30971216
ENSE00003688094	30976429	30976558
ENSE00003694024	30973985	30974138

Expression profiles

Bgee: expression breadth ubiquitous, 154 present calls, max score 98.60.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3273 / max 773.4305, expressed in 186 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
78030	0.3978	182
78021	0.2593	5
78022	0.2438	3
78019	0.1365	3
78028	0.1256	6
78020	0.0690	3
78023	0.0307	3
78029	0.0307	5
78027	0.0252	4
78026	0.0087	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pituitary gland	UBERON:0000007	98.60	gold quality
adenohypophysis	UBERON:0002196	97.60	gold quality
oocyte	CL:0000023	73.55	silver quality
secondary oocyte	CL:0000655	70.77	gold quality
hypothalamus	UBERON:0001898	69.04	gold quality
cingulate cortex	UBERON:0003027	67.81	gold quality
anterior cingulate cortex	UBERON:0009835	67.80	gold quality
amygdala	UBERON:0001876	67.06	gold quality
pancreatic ductal cell	CL:0002079	66.98	silver quality
descending thoracic aorta	UBERON:0002345	65.96	gold quality
nucleus accumbens	UBERON:0001882	64.05	gold quality
right frontal lobe	UBERON:0002810	63.47	gold quality
caudate nucleus	UBERON:0001873	63.23	gold quality
thoracic aorta	UBERON:0001515	63.02	gold quality
ascending aorta	UBERON:0001496	62.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	61.34	gold quality
forebrain	UBERON:0001890	60.96	gold quality
gluteal muscle	UBERON:0002000	60.51	gold quality
triceps brachii	UBERON:0001509	60.43	gold quality
substantia nigra	UBERON:0002038	60.43	gold quality
cerebellar hemisphere	UBERON:0002245	60.24	gold quality
cerebellar cortex	UBERON:0002129	60.15	gold quality
putamen	UBERON:0001874	60.10	gold quality
brain	UBERON:0000955	60.07	gold quality
right hemisphere of cerebellum	UBERON:0014890	60.06	gold quality
gall bladder	UBERON:0002110	59.39	gold quality
cerebellum	UBERON:0002037	58.78	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	58.75	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	58.54	gold quality
midbrain	UBERON:0001891	58.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, APEX1, AR, BCL6, BMAL1, CEBPB, CXXC1, EGR1, ELF1, EPAS1, ESR1, EZH2, FOXP3, HAND1, HIF3A, HOXA10, ID1, IRF1, JUN, JUNB, KDM5B, KMT2B, MYC, NR2C1, NRG1, PAX3, POU1F1, PRDM1, PROX1, RARA, SNAI1, SPI1, SRY, TCF3, TFAM, TFCP2, THRB, TP53, WT1

miRNA regulators (miRDB)

20 targeting GHRHR, 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-4500	99.99	72.72	2367
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-6861-3P	99.60	68.46	444
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-1199-5P	98.44	66.51	829
HSA-MIR-6751-3P	98.44	66.35	835
HSA-MIR-211-3P	98.14	66.77	1052
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-379-5P	97.52	67.81	485
HSA-MIR-3529-5P	97.12	67.06	440
HSA-MIR-6772-3P	97.04	65.89	784
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-5702	96.68	68.21	958
HSA-MIR-4268	94.45	64.09	819

Literature-anchored findings (GeneRIF, showing 40)

• To ascertain whether (splice variant) SV1 mediates mitogenic effects on nonpituitary tissues, we expressed SV1 in 3T3 mouse fibroblasts and studied the properties of the transfected cells (PMID:11773624)
• results demonstrate that mutations in the GHRHR are not limited to the coding sequence and that promoter mutations that impair Pit-1 binding can reduce expression of the GHRHR gene (PMID:11875102)
• human GHRHR isoforms are found in experimental prostate neoplasms in mice; this could explain the effects of GHRH antagonists on growth of prostate cancer (PMID:12126741)
• expression of mRNA and splice variants of this receptor in human malignant bone tumors (PMID:12220726)
• an examination of the possible clinical significance of a polymorphism in the gene of this receptor: involvement in acromegaly (PMID:12220735)
• presence of GHRH and its tumoral receptor splice variants in prostate cancers suggests the possible existence of an autocrine mitogenic loop (PMID:12364462)
• mutations in the GHRH receptor gene make abnormalities of this gene one of the most common causes of of isolated growth hormone deficiency–REVIEW (PMID:12424433)
• Compound heterozygotes for two previously undescribed mutations in the GHRHR that are predicted to cause complete lack of functional GHRHR protein: a nonsense mutation in codon 43 (Q43X), and a splice mutation at the beginning of intron 3 (IVS3+1G–>A). (PMID:12444890)
• GHRH receptor may be associated with carcinogenesis (PMID:12867592)
• autocrine stimulatory loop between GHRH and SV1 variant of GHRH receptor in primary cancers. (PMID:15362970)
• GHRH-R was demonstrated in prostate and breast carcinomas, opening a variety of possibilities for the use of GHRH antagonists in the treatment of prostatic and mammary tumors. (PMID:15944917)
• analysis of receptors for growth hormone-releasing hormone in human osteosarcomas and Ewing’s sarcomas (PMID:16820890)
• Heterozygosity for a null GHRHR mutation is not associated with reduction in adult stature or in serum IGF-I but is associated with changes in body composition and possibly an increase in insulin sensitivity (PMID:17356054)
• Size of individual abdominal organs is influenced in different ways by severe and congenital lack of GH due to a GHRH-R mutation. (PMID:18034778)
• the expression of GHRH and its tumoral receptor SV1 in primary human melanomas and dysplastic nevi by immunohistochemistry. None of the specimens tested expressed GHRH (PMID:18255167)
• targeting the GHRH receptor may be a therapeutic option in Triple-negative breast cancers (PMID:18629632)
• Genetic screening of GH1 and GHRHR mutations in a Dutch population with isolated GH deficiency (IGHD). (PMID:18785993)
• Gsp mutations up-regulate GHRHR mRNA expression in GH-secreting pituitary adenoma cells & desensitize the adenoma cells to GHRH in terms of their GHRHR mRNA expression. (PMID:19029774)
• GHRHR might be one of the most important genes so far identified affecting normal variation in human height. (PMID:19209235)
• The endometriotic stromal cells (ESCs) and transformed human ESCs, but not normal endometrial tissues, expressed GHRH-R mRNA. (PMID:19524226)
• Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees, representing 11.1% of our cohort with a higher prevalence of mutations in familial cases (38.6%) and in consanguineous pedigrees (75%) of congenital growth hormone deficiency. (PMID:19567534)
• Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians (PMID:19640273)
• These results provide strong evidence that the splicing mutation IVS8+1G>A of growth hormone-releasing hormone receptor is a cause of pituitary dwarfism in the Chinese family. (PMID:19733620)
• These results show, for the first time, the activation of the MAPKs cascade by the splic variant (SV1) receptor. (PMID:19897610)
• Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene. (PMID:19965916)
• This chapter reviews the biology of the GHRHR, the mutations that affect its gene and their effects in homozygous and heterozygous individuals. (PMID:20374725)
• The homozygous GHRHR mutation was rare, being detected in only one Japanese isolated GH deficiency family. (PMID:21044116)
• study describes a new frame shift mutation in the coding sequence of exon 4 (corresponding to the extracellular domain of the receptor)(c.391delG) in the GHRHR in a family with isolated GH deficiency (PMID:21816782)
• bone quality and metabolism and its correlation with insulin sensitivity in subjects heterozygous for a null mutation in GHRHR (PMID:21995288)
• GHRH-R and Hsp90 were found to be independent predictive factors of histopathological response to neoadjuvant RCT. (PMID:22160161)
• The study established the GHRHR gene sequence variation map in isolated severe growth hormone deficiency patients and normal adult height. (PMID:22489751)
• We report a novel splice-disrupting mutation in GHRHR in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor (PMID:23052699)
• Compound heterozygous mutations of the growth hormone-releasing hormone receptor gene is associated with isolated growth hormone deficiency (PMID:23602557)
• we present the results of screening for mutations in GH1 and GHRHR genes in a large cohort of Argentinian patients with IGHD. These suggest that the p.Arg183His mutation associated with the type II dominant form of IGHD might be relatively common. (PMID:23789946)
• Genu valgum was more prevalent in growth hormone deficiency GHRHR mutation patients than controls. (PMID:24057284)
• These preliminary results suggest a greater than average GHRH-R expression in invasive lobular carcinomas and invasive ductal carcinomas associated with casting-type calcifications on the mammogram. (PMID:24479854)
• Indel mutation in the growth hormone releasing hormone receptor gene is associated with isolated growth hormone deficiency. (PMID:25153028)
• Identification of new missense mutations and an insertion mutation for the GHRHR gene in patients with isolated growth hormone deficiency. (PMID:25541890)
• we found that pGHRH-R and its main splice variant are expressed in thyroid tissue and was upregulated in tumor cells compared to normal thyroid cells (PMID:25752763)
• A reduced stature in older subjects heterozygous for the c.57+1G>A GHRHR mutation, indicating different effects of heterozygosis through lifespan. (PMID:25761575)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ghrhrl	ENSDARG00000095788
mus_musculus	Ghrhr	ENSMUSG00000004654
rattus_norvegicus	Ghrhr	ENSRNOG00000011808

Paralogs (42): CALCR (ENSG00000004948), GIPR (ENSG00000010310), ADGRA2 (ENSG00000020181), CALCRL (ENSG00000064989), GLP2R (ENSG00000065325), ADGRF5 (ENSG00000069122), ADGRL1 (ENSG00000072071), ADCYAP1R1 (ENSG00000078549), SCTR (ENSG00000080293), VIPR2 (ENSG00000106018), CRHR2 (ENSG00000106113), ADGRD1 (ENSG00000111452), GLP1R (ENSG00000112164), ADGRG6 (ENSG00000112414), VIPR1 (ENSG00000114812), ADGRL2 (ENSG00000117114), CRHR1 (ENSG00000120088), ADGRB2 (ENSG00000121753), ADGRE5 (ENSG00000123146), ADGRE2 (ENSG00000127507), ADGRE3 (ENSG00000131355), ADGRB3 (ENSG00000135298), PTH2R (ENSG00000144407), ADGRG7 (ENSG00000144820), ADGRL3 (ENSG00000150471), ADGRA3 (ENSG00000152990), ADGRF1 (ENSG00000153292), ADGRF4 (ENSG00000153294), ADGRG4 (ENSG00000156920), ADGRG5 (ENSG00000159618), PTH1R (ENSG00000160801), ADGRL4 (ENSG00000162618), EVA1C (ENSG00000166979), ADGRF3 (ENSG00000173567), ADGRG2 (ENSG00000173698), ADGRE1 (ENSG00000174837), ADGRD2 (ENSG00000180264), ADGRB1 (ENSG00000181790), ADGRG3 (ENSG00000182885), ADGRA1 (ENSG00000197177)

Protein

Protein identifiers

Growth hormone-releasing hormone receptor — Q02643 (reviewed: Q02643)

Alternative names: Growth hormone-releasing factor receptor

All UniProt accessions (6): Q02643, A0A090N8Y6, Q9HB42, Q9HB43, Q9HB44, Q9HB45

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for GRF, coupled to G proteins which activate adenylyl cyclase. Stimulates somatotroph cell growth, growth hormone gene transcription and growth hormone secretion.

Subcellular location. Cell membrane.

Tissue specificity. Pituitary gland.

Disease relevance. Growth hormone deficiency, isolated, 4 (IGHD4) [MIM:618157] An autosomal recessive deficiency of growth hormone leading to early and severe growth failure and short stature. Patients have low but detectable levels of growth hormone, significantly retarded bone age, and a positive response and immunologic tolerance to growth hormone therapy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the G-protein coupled receptor 2 family.

RefSeq proteins (1): NP_000814* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000832	GPCR_2_secretin-like	Family
IPR001879	GPCR_2_extracellular_dom	Domain
IPR003288	GPCR_2_GHRH_rcpt	Family
IPR017981	GPCR_2-like_7TM	Domain
IPR017983	GPCR_2_secretin-like_CS	Conserved_site
IPR036445	GPCR_2_extracell_dom_sf	Homologous_superfamily
IPR050332	GPCR_2	Family

Pfam: PF00002, PF02793

UniProt features (57 total): helix 17, sequence variant 11, topological domain 8, transmembrane region 7, strand 7, disulfide bond 3, signal peptide 1, chain 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2XDG	X-RAY DIFFRACTION	1.95
7CZ5	ELECTRON MICROSCOPY	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02643-F1	75.89	0.26

Antibody-complex structures (SAbDab): 1 — 7CZ5

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 41–64, 55–96, 78–112

Glycosylation sites (1): 50

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events
R-HSA-420092	Glucagon-type ligand receptors

MSigDB gene sets: 218 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_GLUCAGON_TYPE_LIGAND_RECEPTORS, GOBP_BEHAVIOR, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_RESPONSE_TO_CORTICOSTEROID, MODULE_64, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_GROWTH, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE, GOBP_HORMONE_TRANSPORT

GO Biological Process (29): cell surface receptor signaling pathway (GO:0007166), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), lactation (GO:0007595), positive regulation of cell population proliferation (GO:0008284), determination of adult lifespan (GO:0008340), growth hormone secretion (GO:0030252), response to insulin (GO:0032868), cellular response to insulin stimulus (GO:0032869), regulation of intracellular steroid hormone receptor signaling pathway (GO:0033143), positive regulation of multicellular organism growth (GO:0040018), hormone metabolic process (GO:0042445), positive regulation of insulin-like growth factor receptor signaling pathway (GO:0043568), response to estrogen (GO:0043627), positive regulation of circadian sleep/wake cycle, non-REM sleep (GO:0046010), cell maturation (GO:0048469), regulation of protein metabolic process (GO:0051246), response to glucocorticoid (GO:0051384), establishment of localization in cell (GO:0051649), positive regulation of growth hormone secretion (GO:0060124), somatotropin secreting cell development (GO:0060133), cellular response to glucose stimulus (GO:0071333), cAMP/PKA signal transduction (GO:0141156), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), adenohypophysis development (GO:0021984), mammary gland development (GO:0030879), regulation of insulin-like growth factor receptor signaling pathway (GO:0043567), hormone secretion (GO:0046879), positive regulation of hormone secretion (GO:0046887)

GO Molecular Function (7): G protein-coupled receptor activity (GO:0004930), G protein-coupled peptide receptor activity (GO:0008528), growth hormone-releasing hormone receptor activity (GO:0016520), peptide hormone binding (GO:0017046), growth factor binding (GO:0019838), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (9): nuclear inner membrane (GO:0005637), nuclear outer membrane (GO:0005640), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), nuclear matrix (GO:0016363), secretory granule (GO:0030141), sarcolemma (GO:0042383)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
GPCR downstream signalling	1
Class B/2 (Secretin family receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell development	2
G protein-coupled receptor activity	2
nuclear membrane	2
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
multicellular organismal process	1
peptide hormone secretion	1
response to peptide hormone	1
response to insulin	1
cellular response to peptide hormone stimulus	1
nuclear receptor-mediated steroid hormone signaling pathway	1
regulation of intracellular signal transduction	1
multicellular organism growth	1
regulation of multicellular organism growth	1
positive regulation of developmental growth	1
positive regulation of multicellular organismal process	1
metabolic process	1
regulation of hormone levels	1
positive regulation of signal transduction	1
regulation of insulin-like growth factor receptor signaling pathway	1
insulin-like growth factor receptor signaling pathway	1
response to hormone	1
circadian sleep/wake cycle, non-REM sleep	1
regulation of circadian sleep/wake cycle, non-REM sleep	1
positive regulation of circadian sleep/wake cycle, sleep	1
cellular developmental process	1
anatomical structure maturation	1
protein metabolic process	1
regulation of macromolecule metabolic process	1
regulation of primary metabolic process	1
response to corticosteroid	1
establishment of localization	1

Protein interactions and networks

STRING

926 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GHRHR	GHRH	P01286	999
GHRHR	PROP1	O75360	916
GHRHR	GH1	P01241	909
GHRHR	GHSR	Q92847	888
GHRHR	POU1F1	P28069	869
GHRHR	GHR	P10912	843
GHRHR	PRL	P01236	833
GHRHR	IGF1	P01343	821
GHRHR	GHRL	Q9UBU3	798
GHRHR	A6NFB4	A6NFB4	785
GHRHR	CSH1	P01243	774
GHRHR	GNRHR	P30968	771
GHRHR	CSH1	P01243	758
GHRHR	SST	P01166	720
GHRHR	FSHB	P01225	700

IntAct

119 interactions, top by confidence:

A	B	Type	Score
GHRHR	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
TAMALIN	GHRHR	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	HTRA3	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	GHRHR	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	GIPC2	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	MPDZ	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	LIN7A	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	SNTG2	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.440
GHRHR	PTPN13	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (2): GHRHR (Affinity Capture-MS), GHRH (Reconstituted Complex)

ESM2 similar proteins: A0A2Z2U4G9, O35659, O46502, O95838, P23811, P25107, P25117, P25961, P30082, P30083, P30988, P32082, P32214, P32215, P32241, P32301, P34999, P35000, P41587, P41588, P41593, P43218, P43219, P43220, P47871, P47872, P48546, P49190, P50133, P51839, P70555, P79222, P97751, Q02643, Q02644, Q03431, Q0P543, Q1LZF7, Q28992, Q29627

Diamond homologs: A0A2Z2U4G9, A6QP74, O35659, O42602, O42603, O46502, O62772, O95838, P23811, P25107, P25117, P25961, P30082, P30083, P32082, P32215, P32241, P32301, P34998, P34999, P35000, P35347, P35353, P41586, P41587, P41588, P41593, P43218, P43219, P43220, P47866, P47871, P47872, P48546, P48960, P49190, P50133, P70205, P70555, P97751

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 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
Ras activation upon Ca2+ influx through NMDA receptor	5	59.5×	9e-07
Unblocking of NMDA receptors, glutamate binding and activation	5	56.6×	9e-07
Negative regulation of NMDA receptor-mediated neuronal transmission	5	56.6×	9e-07
Long-term potentiation	5	49.6×	1e-06
Assembly and cell surface presentation of NMDA receptors	9	47.6×	3e-11
Neurexins and neuroligins	9	36.9×	2e-10
Protein-protein interactions at synapses	5	27.7×	3e-05
RHOA GTPase cycle	5	7.8×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	88.8×	6e-17
receptor clustering	7	60.7×	4e-09
protein localization to synapse	5	53.2×	2e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	7	48.2×	2e-08
cell-cell adhesion	9	12.7×	2e-06
protein-containing complex assembly	8	12.7×	1e-05
regulation of small GTPase mediated signal transduction	5	10.0×	4e-03
protein localization to plasma membrane	5	7.5×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	11
Uncertain significance	123
Likely benign	119
Benign	39

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012249	NM_000823.4(GHRHR):c.1102C>T (p.Gln368Ter)	Pathogenic
1064692	NM_000823.4(GHRHR):c.967C>T (p.Gln323Ter)	Pathogenic
1322999	NM_000823.4(GHRHR):c.1069C>T (p.Arg357Cys)	Pathogenic
1449976	NM_000823.4(GHRHR):c.280C>T (p.Arg94Trp)	Pathogenic
1459534	NM_000823.4(GHRHR):c.22dup (p.Ala8fs)	Pathogenic
15989	NM_000823.4(GHRHR):c.214G>T (p.Glu72Ter)	Pathogenic
15990	NM_000823.4(GHRHR):c.57+1G>A	Pathogenic
15992	NM_000823.4(GHRHR):c.725T>G (p.Phe242Cys)	Pathogenic
15993	NM_000823.4(GHRHR):c.665C>A (p.Ala222Glu)	Pathogenic
15994	NM_000823.4(GHRHR):c.985A>G (p.Lys329Glu)	Pathogenic
15995	NC_000007.14:g.30963945A>C	Pathogenic
2418946	NC_000007.14:g.30969869dup	Pathogenic
265396	NM_000823.4(GHRHR):c.1089_1093del (p.Leu364fs)	Pathogenic
2719597	NM_000823.4(GHRHR):c.290del (p.Thr97fs)	Pathogenic
2811869	NM_000823.4(GHRHR):c.461_462del (p.Leu154fs)	Pathogenic
3026388	NM_000823.4(GHRHR):c.160+1G>T	Pathogenic
3616306	NM_000823.4(GHRHR):c.22del (p.Ala8fs)	Pathogenic
3697787	NM_000823.4(GHRHR):c.848G>A (p.Trp283Ter)	Pathogenic
3720730	NM_000823.4(GHRHR):c.1146G>A (p.Glu382=)	Pathogenic
4281667	NM_000823.4(GHRHR):c.367-1G>A	Pathogenic
4725915	NM_000823.4(GHRHR):c.675_676del (p.Tyr226fs)	Pathogenic
56966	NC_000007.14:g.30959635_30967328delinsAGAGATCCA	Pathogenic
597306	NM_000823.4(GHRHR):c.194G>A (p.Trp65Ter)	Pathogenic
626257	NC_000007.14:g.31008681G>T	Pathogenic
998031	NM_000823.4(GHRHR):c.731G>A (p.Trp244Ter)	Pathogenic
161435	NM_000823.4(GHRHR):c.418T>C (p.Ser140Pro)	Likely pathogenic
161437	NM_000823.4(GHRHR):c.495C>A (p.His165Gln)	Likely pathogenic
1693449	NM_000823.4(GHRHR):c.527C>T (p.Ala176Val)	Likely pathogenic
2440458	NM_000823.4(GHRHR):c.260C>A (p.Ser87Ter)	Likely pathogenic
3339202	NM_000823.4(GHRHR):c.847T>C (p.Trp283Arg)	Likely pathogenic

SpliceAI

2220 predictions. Top by Δscore:

Variant	Effect	Δscore
7:30972096:G:GG	donor_gain	1.0000
7:30974105:A:T	donor_gain	1.0000
7:30974490:G:GG	donor_gain	1.0000
7:30974585:G:GT	donor_gain	1.0000
7:30975116:G:GT	donor_gain	1.0000
7:30975117:A:T	donor_gain	1.0000
7:30975131:GC:G	donor_gain	1.0000
7:30964122:GACC:G	donor_gain	0.9900
7:30964126:G:GG	donor_gain	0.9900
7:30971115:CCAG:C	acceptor_loss	0.9900
7:30971116:CA:C	acceptor_loss	0.9900
7:30971118:G:GT	acceptor_loss	0.9900
7:30971212:CTCAG:C	donor_loss	0.9900
7:30971213:TCAG:T	donor_loss	0.9900
7:30971214:CAGGT:C	donor_loss	0.9900
7:30971215:AGGTT:A	donor_loss	0.9900
7:30971216:G:GA	donor_loss	0.9900
7:30971217:G:T	donor_loss	0.9900
7:30971218:T:G	donor_loss	0.9900
7:30972102:GCCA:G	donor_gain	0.9900
7:30974488:GC:G	donor_gain	0.9900
7:30974579:G:T	donor_gain	0.9900
7:30974595:G:T	donor_gain	0.9900
7:30975863:G:GG	donor_gain	0.9900
7:30976084:A:G	donor_gain	0.9900
7:30976428:GGC:G	acceptor_gain	0.9900
7:30976554:TCCAG:T	donor_loss	0.9900
7:30976555:CCAG:C	donor_loss	0.9900
7:30976556:CAGGT:C	donor_loss	0.9900
7:30976557:AGGT:A	donor_loss	0.9900

AlphaMissense

2753 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:30969097:G:C	W65C	0.996
7:30969097:G:T	W65C	0.996
7:30969901:G:C	W101C	0.996
7:30969901:G:T	W101C	0.996
7:30969079:G:C	W59C	0.993
7:30969079:G:T	W59C	0.993
7:30974977:G:C	W273C	0.992
7:30974977:G:T	W273C	0.992
7:30969879:G:C	R94P	0.991
7:30969899:T:A	W101R	0.989
7:30969899:T:C	W101R	0.989
7:30969884:T:A	C96S	0.988
7:30969885:G:C	C96S	0.988
7:30969932:T:A	C112S	0.987
7:30969933:G:C	C112S	0.987
7:30977281:G:C	G369R	0.987
7:30974036:T:C	F217L	0.985
7:30974038:C:A	F217L	0.985
7:30974038:C:G	F217L	0.985
7:30969932:T:C	C112R	0.984
7:30969095:T:A	W65R	0.982
7:30969095:T:C	W65R	0.982
7:30969134:T:A	C78S	0.982
7:30969135:G:C	C78S	0.982
7:30969886:T:G	C96W	0.982
7:30974042:T:A	W219R	0.982
7:30974042:T:C	W219R	0.982
7:30974135:T:A	W250R	0.981
7:30974135:T:C	W250R	0.981
7:30972003:T:C	F169L	0.980

dbSNP variants (sampled 300 via entrez): RS1000183830 (7:30972775 T>C), RS1000200624 (7:30966696 A>G), RS1000301392 (7:30978294 G>A,T), RS1000810563 (7:30978296 G>A,T), RS1000936639 (7:30967771 C>T), RS1000986556 (7:30963510 A>T), RS1001017625 (7:30963203 C>G), RS1001067010 (7:30967981 A>G), RS1001090446 (7:30968109 C>A,G,T), RS1001176311 (7:30979355 C>A,T), RS1001179931 (7:30971526 C>T), RS1001211138 (7:30971157 G>A), RS1001411091 (7:30976999 T>C), RS1001603909 (7:30962686 C>T), RS1001841226 (7:30976721 T>C)

Disease associations

OMIM: gene MIM:139191 | disease phenotypes: MIM:618157, MIM:612781

GenCC curated gene-disease

Disease	Classification	Inheritance
isolated growth hormone deficiency type IB	Definitive	Autosomal recessive
isolated growth hormone deficiency, type 4	Strong	Autosomal recessive

Mondo (3): isolated growth hormone deficiency, type 4 (MONDO:0032567), isolated growth hormone deficiency type IB (MONDO:0013006), disorder of sexual differentiation (MONDO:0002145)

Orphanet (4): Isolated growth hormone deficiency type IV (Orphanet:684247), Isolated growth hormone deficiency type IB (Orphanet:231671), Non-acquired isolated growth hormone deficiency (Orphanet:631), Difference of sex development (Orphanet:90771)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000824	Decreased response to growth hormone stimulation test
HP:0002750	Delayed skeletal maturation
HP:0003510	Severe short stature
HP:0010627	Anterior pituitary hypoplasia
HP:0030353	Decreased circulating serum insulin-like growth factor 1 concentration
HP:0031079	Impaired growth-hormone response to insulin stimulation test

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012048_9	Triglyceride levels	8.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
C567564	Isolated Growth Hormone Deficiency, Type IB (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2032 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,009 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3545252	DOCETAXEL	4	1,009

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Glucagon receptor family

Most potent curated ligand interactions (25 total), top 25:

Ligand	Action	Affinity	Parameter
JV-1-36	Antagonist	10.41	pKi
JV-1-37	Antagonist	10.4	pKi
JV-1-40	Antagonist	10.4	pKi
JV-1-41	Antagonist	10.4	pKi
JV-1-42	Antagonist	10.4	pKi
JV-1-43	Antagonist	10.4	pKi
MZ-4-169	Antagonist	10.4	pKi
MZ-4-243	Antagonist	10.4	pKi
JV-1-10	Antagonist	10.3	pKi
MZ-4-181	Antagonist	10.3	pKi
JV-1-62	Antagonist	10.2	pKi
JV-1-63	Antagonist	10.2	pKi
MZ-5-156	Antagonist	10.2	pKi
MZ-5-192	Antagonist	10.2	pIC50
MZ-5-78	Antagonist	10.2	pIC50
MZ-6-55	Antagonist	10.2	pKi
JV-1-38	Antagonist	10.1	pKi
JV-1-39	Antagonist	10.1	pKi
MZ-4-71	Antagonist	9.9	pKi
JMR-132	Agonist	9.85	pIC50
GHRH-(1-29)-NH2 (rat)	Full agonist	9.1	pIC50
[Ac-Tyr1, D-Arg2]GHRH-(1-29)-NH2 (human)	Antagonist	8.5	pKi
GHRH-(1-29)-NH2 (human)	Full agonist	8.2	pIC50
GHRH-(1-29)-OH (human)	Full agonist	8.0	pIC50
[125I]GHRH (human)	Full agonist	7.6	pKd

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
9.85	IC50	0.14	nM	DOCETAXEL

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
[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-acetyloxy-1,9,12-trihydroxy-15-[(2R,3S)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]oxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate;trihydrate	329118: Displacement of [125I]JV1-42 from GHRH receptor expressed in human MX1 cells	ic50	0.0001	uM

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
clothianidin	increases expression	1
MZ-J-7-118	affects binding, decreases activity	1
Cadmium	decreases expression, increases abundance	1
Estradiol	affects binding, increases expression	1
Folic Acid	decreases expression	1
Phosphorus	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Okadaic Acid	decreases expression	1
Raloxifene Hydrochloride	affects response to substance	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4883384	Binding	PRESTO-Tango GPCRome screening (GHRHR)	Data for DCP probe UCSF924

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_H369	293/GHRH/Galpha15	Transformed cell line	Female
CVCL_KV22	cAMP Hunter CHO-K1 GHRHR Gs	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT00485186	Not specified	WITHDRAWN	Gene Polymorphisms Influencing Steroid Synthesis and Action
NCT01875640	Not specified	COMPLETED	Decision Support for Parents Receiving Information About Child’s Rare Disease
NCT02784184	Not specified	UNKNOWN	COPENHAGEN Minipuberty Study
NCT03102554	Not specified	ENROLLING_BY_INVITATION	Genetics of Differences of Sex Development and Hypospadias
NCT03283852	Not specified	RECRUITING	Identifying New Genetic Causes to Development Disorders
NCT04195490	Not specified	UNKNOWN	Evaluation of Outcomes of Feminizing Genitoplasty in Children With Disorders of Sex Development
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04717349	Not specified	RECRUITING	Data Collection Study of Pediatric and Adolescent Gynecology Conditions
NCT05058781	Not specified	RECRUITING	Minipuberty in Infants Born With Potential Hypogonadism Hypogonadotrope
NCT06692049	Not specified	RECRUITING	Gonadal Tissue Cryopreservation for Fertility Preservation in Children with a Disorder of Sex Development
NCT06989593	Not specified	RECRUITING	Breaking Silence Through Story: A Narrative Medicine Intervention for Parents of Children With Urogenital Conditions