TRH

Summary

TRH (thyrotropin releasing hormone, HGNC:12298) is a protein-coding gene on chromosome 3q22.1, encoding Pro-thyrotropin-releasing hormone (P20396). As a component of the hypothalamic-pituitary-thyroid axis, it controls the secretion of thyroid-stimulating hormone (TSH) and is involved in thyroid hormone synthesis regulation.

This gene encodes a member of the thyrotropin-releasing hormone family. Cleavage of the encoded proprotein releases mature thyrotropin-releasing hormone, which is a tripeptide hypothalamic regulatory hormone. The human proprotein contains six thyrotropin-releasing hormone tripeptides. Thyrotropin-releasing hormone is involved in the regulation and release of thyroid-stimulating hormone, as well as prolactin. Deficiency of this hormone has been associated with hypothalamic hypothyroidism.

Source: NCBI Gene 7200 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 48 total
• Phenotypes (HPO): 10
• MANE Select transcript: NM_007117

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12298
Approved symbol	TRH
Name	thyrotropin releasing hormone
Location	3q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170893
Ensembl biotype	protein_coding
OMIM	613879
Entrez	7200

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000302649, ENST00000507066

RefSeq mRNA: 1 — MANE Select: NM_007117 NM_007117

CCDS: CCDS3066

Canonical transcript exons

ENST00000302649 — 3 exons

Exon	Start	End
ENSE00001194446	129975809	129976027
ENSE00001264853	129974720	129974823
ENSE00002034338	129976699	129977935

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 84.29.

FANTOM5 (CAGE): breadth broad, TPM avg 4.0237 / max 695.8162, expressed in 298 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38572	3.1529	246
38570	0.3461	107
38571	0.3332	110
38569	0.1011	49
38568	0.0904	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
diaphragm	UBERON:0001103	84.29	gold quality
superficial temporal artery	UBERON:0001614	81.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.11	gold quality
type B pancreatic cell	CL:0000169	80.79	gold quality
tongue squamous epithelium	UBERON:0006919	78.79	gold quality
cervix squamous epithelium	UBERON:0006922	78.75	gold quality
olfactory bulb	UBERON:0002264	78.49	gold quality
hypothalamus	UBERON:0001898	78.21	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	77.34	gold quality
male germ cell	CL:0000015	77.16	gold quality
sperm	CL:0000019	76.90	gold quality
inferior olivary complex	UBERON:0002127	76.56	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	75.29	gold quality
cortical plate	UBERON:0005343	75.04	gold quality
vastus lateralis	UBERON:0001379	73.51	gold quality
CA1 field of hippocampus	UBERON:0003881	73.33	gold quality
frontal pole	UBERON:0002795	73.28	gold quality
paraflocculus	UBERON:0005351	73.01	gold quality
middle frontal gyrus	UBERON:0002702	72.69	gold quality
quadriceps femoris	UBERON:0001377	72.07	gold quality
hair follicle	UBERON:0002073	71.67	gold quality
decidua	UBERON:0002450	71.05	silver quality
cartilage tissue	UBERON:0002418	70.97	silver quality
epithelial cell of pancreas	CL:0000083	70.62	gold quality
thymus	UBERON:0002370	70.51	gold quality
cerebellar vermis	UBERON:0004720	70.32	gold quality
endocervix	UBERON:0000458	69.97	gold quality
Brodmann (1909) area 10	UBERON:0013541	69.96	gold quality
left ventricle myocardium	UBERON:0006566	69.80	gold quality
cardiac muscle of right atrium	UBERON:0003379	69.58	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	2540.40
E-GEOD-137537	yes	1254.30
E-MTAB-9154	yes	704.25
E-CURD-112	yes	158.10
E-MTAB-9067	yes	12.78
E-MTAB-10042	yes	8.71
E-ANND-3	no	1.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREB1, ESR1, GATA2, JUN, KLF4, NCOR1, NCOR2, NR3C1, NR4A1, POU1F1, PREB, RARA, RXRA, RXRB, SP1, STAT3, THRA, THRB

miRNA regulators (miRDB)

49 targeting TRH, 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-4283	100.00	66.42	2097
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-657	99.48	66.02	848
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628

Literature-anchored findings (GeneRIF, showing 16)

• TRH mRNA levels in “mute” thyrotropinomas: cause-effect or coincidence? (PMID:12067454)
• Cpe mutations in mouse may affect processing of prothyrotropin releasing hormone into thyrotropin releasing hormone. (PMID:12270926)
• results show that that leptin can regulate trh gene expression via activation of intracellular signal transducer and activator of transcription 3 (STAT3) proteins in TRH neurons in the hypothalamus (PMID:14764629)
• The presence of TRH in dysplastic nevi may be predictive for the development of melanoma. (PMID:15328193)
• Our results support the hypothesis that patients with pseudohypoparathyroidism Ia have impaired sensitivity to both TSH and TRH. (PMID:18805917)
• study shows: negative regulation of TRH gene by TH involves acetylation & methylation of specific residues of histone tails & changing amount of TR; impairment to histone modifications in TR mutant F455S was hyperacetylation of specific histone tails (PMID:19299458)
• Thus, human scalp hair follicles are both a source and a target of TRH, which operates as a potent hair-growth stimulator (PMID:19825978)
• Case Report: Isolated idiopathic central hypothyroidism in an adult, possibly caused by thyrotropin releasing hormone (TRH) deficiency. (PMID:20687402)
• This study introduces TRH as a novel, potent, selective, and evolutionarily highly conserved neuroendocrine factor controlling human pigmentation in situ. (PMID:21956127)
• TRH inhibits melanin-concentrating hormone (MCH) neurons by increasing synaptic inhibition from local GABA neurons. (PMID:22378876)
• TRH, LH-RH and substance P are not affected in Alzheimer disease and Down’s syndrome. (PMID:24010162)
• TRH rs13097335 may have a protective role toward the development of breast cancer. (PMID:25362934)
• Data indicate that decrease of cholesterol level impaired the functional coupling between the thyrotropin-releasing hormone receptor and the cognate G proteins. (PMID:25485475)
• cg01009664 of TRH as a potential biomarker for oral squamous cell carcinoma and oropharyngeal squamous cell carcinoma. (PMID:30081853)
• Is the link between elevated TSH and gestational diabetes mellitus dependant on diagnostic criteria and thyroid antibody status: a systematic review and meta-analysis. (PMID:33991314)
• Identification of the Thyrotropin-Releasing Hormone (TRH) as a Novel Biomarker in the Prognosis for Acute Myeloid Leukemia. (PMID:36291567)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	trh	ENSDARG00000006868
mus_musculus	Trh	ENSMUSG00000005892
rattus_norvegicus	Trh	ENSRNOG00000011824

Protein

Protein identifiers

Pro-thyrotropin-releasing hormone — P20396 (reviewed: P20396)

Alternative names: Prothyroliberin

All UniProt accessions (2): P20396, D6RFM1

UniProt curated annotations — full annotation on UniProt →

Function. As a component of the hypothalamic-pituitary-thyroid axis, it controls the secretion of thyroid-stimulating hormone (TSH) and is involved in thyroid hormone synthesis regulation. It also operates as modulator of hair growth. It promotes hair-shaft elongation, prolongs the hair cycle growth phase (anagen) and antagonizes its termination (catagen) by TGFB2. It stimulates proliferation and inhibits apoptosis of hair matrix keratinocytes.

Subcellular location. Secreted.

Tissue specificity. Hypothalamus. Expressed in the hair follicle epithelium (at protein level).

Similarity. Belongs to the TRH family.

RefSeq proteins (1): NP_009048* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008857	TRH	Family

Pfam: PF05438

UniProt features (21 total): modified residue 6, peptide 6, compositionally biased region 4, region of interest 2, signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20396-F1	60.00	0.08

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 (6): 86, 116, 137, 154, 188, 229

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

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

MSigDB gene sets: 124 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, MODULE_92, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, XU_GH1_AUTOCRINE_TARGETS_UP, GOCC_SECRETORY_GRANULE, GOBP_ADULT_BEHAVIOR, GOBP_ADULT_LOCOMOTORY_BEHAVIOR, GOBP_CELL_CELL_SIGNALING, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, MARTINEZ_RB1_TARGETS_DN, GOBP_RESPONSE_TO_HORMONE

GO Biological Process (10): histamine metabolic process (GO:0001692), signal transduction (GO:0007165), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), cell-cell signaling (GO:0007267), adult walking behavior (GO:0007628), hormone-mediated signaling pathway (GO:0009755), negative regulation of glutamate secretion (GO:0014050), positive regulation of gamma-aminobutyric acid secretion (GO:0014054), positive regulation of insulin secretion (GO:0032024), eating behavior (GO:0042755)

GO Molecular Function (3): thyrotropin-releasing hormone activity (GO:0008437), hormone activity (GO:0005179), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), secretory granule (GO:0030141)

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	2
signaling	2
biogenic amine metabolic process	1
imidazole-containing compound metabolic process	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
adult locomotory behavior	1
walking behavior	1
signal transduction	1
cellular response to hormone stimulus	1
glutamate secretion	1
regulation of glutamate secretion	1
negative regulation of organic acid transport	1
negative regulation of amino acid transport	1
negative regulation of secretion by cell	1
gamma-aminobutyric acid secretion	1
regulation of gamma-aminobutyric acid secretion	1
positive regulation of organic acid transport	1
positive regulation of secretion	1
positive regulation of amino acid transport	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
feeding behavior	1
hormone activity	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1
endomembrane system	1
secretory vesicle	1

Protein interactions and networks

STRING

1170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRH	TRHR	P34981	996
TRH	PRL	P01236	951
TRH	TRHDE	Q9UKU6	933
TRH	TSHB	P01222	920
TRH	PGPEP1	Q9NXJ5	919
TRH	POMC	P01189	915
TRH	GNRH1	P01148	893
TRH	CRH	P06850	885
TRH	GHRH	P01286	876
TRH	NTS	P30990	867
TRH	DIO2	Q92813	846
TRH	PREP	P48147	842
TRH	DIO3	P55073	830
TRH	SST	P01166	811
TRH	OXT	P01178	795

IntAct

7 interactions, top by confidence:

A	B	Type	Score
TRH	KCNIP4	psi-mi:“MI:0915”(physical association)	0.560
TRH	LCN2	psi-mi:“MI:0915”(physical association)	0.560
TRH	KCNIP4	psi-mi:“MI:0915”(physical association)	0.000
TRH	LCN2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): TRH (Two-hybrid), KCNIP4 (Two-hybrid)

ESM2 similar proteins: D3Z752, I3L3R5, M0R8L2, O35417, O62647, O93448, P01150, P01152, P01210, P01211, P01213, P01214, P01347, P01350, P01353, P01354, P05059, P06300, P08435, P08858, P09681, P0DP56, P10645, P16613, P20396, P23389, P26339, P45644, P47969, P48143, P55099, P67934, P83859, P83860, Q00643, Q28409, Q5EDF9, Q5KT10, Q5KT11, Q60478

Diamond homologs: P01150, P20396, Q62361

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TRH	“up-regulates activity”	TRHR	binding
GATA2	“up-regulates quantity by expression”	TRH	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	7
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

500 predictions. Top by Δscore:

Variant	Effect	Δscore
3:129976014:GG:G	donor_gain	1.0000
3:129976015:GG:G	donor_gain	1.0000
3:129976025:CCGGT:C	donor_loss	1.0000
3:129976027:GGT:G	donor_loss	1.0000
3:129976028:G:GA	donor_loss	1.0000
3:129976029:T:A	donor_loss	1.0000
3:129976030:G:GG	donor_loss	1.0000
3:129976697:A:AG	acceptor_gain	1.0000
3:129976697:AGC:A	acceptor_gain	1.0000
3:129976698:G:GG	acceptor_gain	1.0000
3:129976698:GC:G	acceptor_gain	1.0000
3:129976698:GCG:G	acceptor_gain	1.0000
3:129976698:GCGT:G	acceptor_gain	1.0000
3:129976698:GCGTC:G	acceptor_gain	1.0000
3:129974822:AGG:A	donor_loss	0.9900
3:129974824:GT:G	donor_loss	0.9900
3:129974825:T:A	donor_loss	0.9900
3:129975807:A:AG	acceptor_gain	0.9900
3:129975808:G:GG	acceptor_gain	0.9900
3:129975879:C:CA	acceptor_gain	0.9900
3:129976028:G:GG	donor_gain	0.9900
3:129975802:A:AG	acceptor_gain	0.9800
3:129975808:GAC:G	acceptor_gain	0.9800
3:129975829:T:A	acceptor_gain	0.9800
3:129976024:TCCG:T	donor_gain	0.9800
3:129976031:A:AC	donor_loss	0.9800
3:129976699:C:CA	acceptor_gain	0.9800
3:129975804:CCCA:C	acceptor_loss	0.9700
3:129975805:CCAGA:C	acceptor_loss	0.9700
3:129975806:CAG:C	acceptor_loss	0.9700

AlphaMissense

1547 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:129976832:C:A	H115Q	0.955
3:129976832:C:G	H115Q	0.955
3:129976733:A:C	K82N	0.949
3:129976733:A:T	K82N	0.949
3:129976742:T:A	H85Q	0.946
3:129976742:T:G	H85Q	0.946
3:129976823:A:C	K112N	0.937
3:129976823:A:T	K112N	0.937
3:129976895:T:A	H136Q	0.925
3:129976895:T:G	H136Q	0.925
3:129976740:C:G	H85D	0.921
3:129976946:C:A	H153Q	0.916
3:129976946:C:G	H153Q	0.916
3:129977048:T:A	H187Q	0.913
3:129977048:T:G	H187Q	0.913
3:129976830:C:G	H115D	0.908
3:129976734:C:A	R83S	0.904
3:129976886:G:C	K133N	0.894
3:129976886:G:T	K133N	0.894
3:129976831:A:G	H115R	0.886
3:129976829:G:C	Q114H	0.885
3:129976829:G:T	Q114H	0.885
3:129976739:G:C	Q84H	0.879
3:129976739:G:T	Q84H	0.879
3:129976732:A:T	K82I	0.875
3:129976751:A:C	K88N	0.874
3:129976751:A:T	K88N	0.874
3:129976893:C:G	H136D	0.862
3:129976741:A:G	H85R	0.859
3:129976944:C:G	H153D	0.850

dbSNP variants (sampled 300 via entrez): RS1000967871 (3:129976805 G>A,C), RS1001087343 (3:129977957 G>A,C), RS1001349538 (3:129973270 A>G), RS1001349805 (3:129975673 T>C,G), RS1001423425 (3:129976007 G>A,T), RS1001453723 (3:129976266 C>G), RS1002969932 (3:129977151 G>A), RS1003083241 (3:129974591 A>G), RS1003363131 (3:129976263 C>A), RS1003441774 (3:129974785 C>G,T), RS1005038278 (3:129974275 T>C), RS1005607031 (3:129975581 G>A), RS1005888885 (3:129977156 G>A,T), RS1007565227 (3:129978357 A>G), RS1007883459 (3:129973695 G>C)

Disease associations

OMIM: gene MIM:613879 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (1): Isolated thyrotropin-releasing hormone deficiency (Orphanet:238670)

HPO phenotypes

10 total (10 of 10 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000821	Hypothyroidism
HP:0000958	Dry skin
HP:0001249	Intellectual disability
HP:0001324	Muscle weakness
HP:0001609	Hoarse voice
HP:0002019	Constipation
HP:0002750	Delayed skeletal maturation
HP:0004322	Short stature
HP:0008237	Hypothalamic hypothyroidism

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST005956_82	Waist-to-hip ratio adjusted for BMI	2.000000e-07
GCST005958_5	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-10
GCST005962_16	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-11
GCST007600_50	Alzheimer’s disease	5.000000e-06
GCST90020025_472	Waist-to-hip ratio adjusted for BMI	2.000000e-14
GCST90020026_123	Hip index	4.000000e-14
GCST90020027_1845	Waist-hip index	4.000000e-08
GCST90020027_1846	Waist-hip index	2.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
terbufos	increases methylation	1
sodium arsenite	affects methylation	1
benzo(e)pyrene	increases methylation	1
2-palmitoylglycerol	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Ethanol	increases expression	1
Allergens	decreases expression	1
Amitriptyline	decreases expression, decreases reaction	1
Azacitidine	decreases expression	1
Benzo(a)pyrene	decreases methylation, affects methylation	1
Cadmium	increases abundance, decreases expression	1
Carbon Dioxide	increases response to substance	1
Doxorubicin	affects expression	1
Fonofos	increases methylation	1
Lead	affects expression	1
Methapyrilene	increases methylation	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Valproic Acid	decreases expression	1
Verapamil	decreases reaction, increases secretion, increases reaction	1
Octreotide	affects activity, decreases reaction	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Sodium Selenite	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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