TRHR

Summary

TRHR (thyrotropin releasing hormone receptor, HGNC:12299) is a protein-coding gene on chromosome 8q23.1, encoding Thyrotropin-releasing hormone receptor (P34981). Receptor for thyrotropin-releasing hormone (TRH).

This gene encodes a G protein-coupled receptor for thyrotropin-releasing hormone (TRH). Upon binding to TRH, this receptor activates the inositol phospholipid-calcium-protein kinase C transduction pathway. Mutations in this gene have been associated with generalized thyrotropin-releasing hormone resistance.

Source: NCBI Gene 7201 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypothyroidism, congenital, nongoitrous, 7 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 66 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_003301

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12299
Approved symbol	TRHR
Name	thyrotropin releasing hormone receptor
Location	8q23.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000174417
Ensembl biotype	protein_coding
OMIM	188545
Entrez	7201

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000311762, ENST00000518632

RefSeq mRNA: 1 — MANE Select: NM_003301 NM_003301

CCDS: CCDS6311

Canonical transcript exons

ENST00000518632 — 3 exons

Exon	Start	End
ENSE00002095814	109087425	109088301
ENSE00002125874	109119048	109121565
ENSE00002134460	109086585	109086883

Expression profiles

Bgee: expression breadth broad, 22 present calls, max score 75.73.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.73	gold quality
calcaneal tendon	UBERON:0003701	58.04	gold quality
metanephric glomerulus	UBERON:0004736	55.97	gold quality
cortical plate	UBERON:0005343	55.85	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	53.88	gold quality
tendon	UBERON:0000043	51.25	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
stromal cell of endometrium	CL:0002255	47.66	gold quality
endometrium epithelium	UBERON:0004811	46.85	gold quality
pituitary gland	UBERON:0000007	46.59	gold quality
thymus	UBERON:0002370	46.28	gold quality
quadriceps femoris	UBERON:0001377	46.02	gold quality
vastus lateralis	UBERON:0001379	44.85	gold quality
buccal mucosa cell	CL:0002336	44.41	gold quality
layer of synovial tissue	UBERON:0007616	44.13	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
skeletal muscle tissue	UBERON:0001134	42.89	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
trachea	UBERON:0003126	42.28	gold quality
muscle tissue	UBERON:0002385	42.21	gold quality
hindlimb stylopod muscle	UBERON:0004252	41.73	gold quality
colonic epithelium	UBERON:0000397	41.57	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
adenohypophysis	UBERON:0002196	41.10	gold quality
oviduct epithelium	UBERON:0004804	41.10	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYB, POU1F1

miRNA regulators (miRDB)

9 targeting TRHR, 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-1250-3P	99.96	70.04	4038
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-6867-3P	98.12	66.07	1305
HSA-MIR-4287	97.55	67.24	1247
HSA-MIR-4685-3P	97.55	67.35	1255
HSA-MIR-3187-3P	97.38	65.80	904

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 11)

• TRH receptor in adenoma cells plays an important role in the paradoxical GH response to TRH administration in GH cell adenomas. (PMID:14599121)
• after agonist-driven receptor internalization, the plasma membrane is replenished with younger receptors, arising either from an intracellular pool or preferential recycling of younger receptors. (PMID:15117874)
• Controlled dimerization of the TRH receptor potentiates hormone-induced receptor trafficking. (PMID:16020481)
• TRHR gene is an important gene for LBM variation. (PMID:19268274)
• analysis of the effect of subcellular trafficking of the TRH receptor (PMID:19541745)
• A mutation in thyrotropin-releasing hormone receptor almost completely prevented receptor phosphorylation. (PMID:19906838)
• Data show that interactions of TRHR with GRKs and phosphatases are determined not simply by the amino acid sequences of the substrates, but by regions outside the cytoplasmic tails. (PMID:20345371)
• The precoupling of receptors with their cognate G-proteins can contribute to faster G-protein activation and subsequent signal transfer into the cell interior. (PMID:22240728)
• rs16892496 polymorphism in the TRHR gene may play a role in FFM variation. (PMID:23543262)
• a unique missense TRHR defect identified in a consanguineous family is associated with central hypothyroidism in homozygotes and hyperthyrotropinemia in heterozygotes, suggesting compensatory elevation of TSH with reduced biopotency; the I131T mutation decreases TRH binding and TRHR-Gq coupling and signaling (PMID:28419241)
• These results demonstrate for the first time that not only agonist binding but also abundance of some signaling proteins may strongly affect TRH receptor dynamics in the plasma membrane (PMID:29137494)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	trhrb	ENSDARG00000036159
danio_rerio	trhra	ENSDARG00000076546
mus_musculus	Trhr	ENSMUSG00000038760
rattus_norvegicus	Trhr	ENSRNOG00000005048

Paralogs (15): NTSR1 (ENSG00000101188), BRS3 (ENSG00000102239), MLNR (ENSG00000102539), GHSR (ENSG00000121853), GRPR (ENSG00000126010), NMUR2 (ENSG00000132911), NMBR (ENSG00000135577), EDNRB (ENSG00000136160), EDNRA (ENSG00000151617), NTSR2 (ENSG00000169006), GPR37L1 (ENSG00000170075), GPR37 (ENSG00000170775), NMUR1 (ENSG00000171596), GPR148 (ENSG00000173302), GPR39 (ENSG00000183840)

Protein

Protein identifiers

Thyrotropin-releasing hormone receptor — P34981 (reviewed: P34981)

Alternative names: Thyroliberin receptor

All UniProt accessions (1): P34981

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for thyrotropin-releasing hormone (TRH). Upon ligand binding, this G-protein-coupled receptor triggers activation of the phosphatidylinositol (IP3)-calcium-protein kinase C (PKC) pathway.

Subcellular location. Cell membrane.

Disease relevance. Hypothyroidism, congenital, non-goitrous, 7 (CHNG7) [MIM:618573] A form of central hypothyroidism, a disorder characterized by sub-optimal thyroid hormone secretion, due to insufficient stimulation by thyrotropin of an otherwise normal thyroid gland. It may be caused by congenital or acquired disorders of the pituitary gland or hypothalamus. CHNG7 is a congenital, autosomal recessive form characterized by normal-to-low T4 and normal-to-high thyrotropin levels, and reduced or absent pituitary responsiveness to thyrotropin-releasing hormone. Patients may exhibit short stature, growth retardation, and delayed bone age, as well as lethargy or fatigue. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (1): NP_003292* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR002120	TRH_rcpt_1	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (43 total): helix 11, topological domain 8, transmembrane region 7, sequence variant 6, strand 5, glycosylation site 2, turn 2, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7XW9	ELECTRON MICROSCOPY	2.7
7WKD	ELECTRON MICROSCOPY	3.01
7X1U	ELECTRON MICROSCOPY	3.19
7X1T	ELECTRON MICROSCOPY	3.26

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P34981-F1	79.74	0.56

Antibody-complex structures (SAbDab): 4 — 7WKD, 7X1T, 7X1U, 7XW9

Functional residue map

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

Disulfide bonds (1): 98–179

Glycosylation sites (2): 3, 10

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: 114 (showing top): YAGI_AML_WITH_INV_16_TRANSLOCATION, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, AACTTT_UNKNOWN, GOBP_PHOSPHOLIPASE_C_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, MEF2_Q6_01, CTAWWWATA_RSRFC4_Q2, KAYO_AGING_MUSCLE_UP, MEF2_03, NIKOLSKY_BREAST_CANCER_8Q23_Q24_AMPLICON, REACTOME_CLASS_A_1_RHODOPSIN_LIKE_RECEPTORS, REACTOME_G_ALPHA_Q_SIGNALLING_EVENTS, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, YOSHIMURA_MAPK8_TARGETS_UP

GO Biological Process (3): G protein-coupled receptor signaling pathway (GO:0007186), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), signal transduction (GO:0007165)

GO Molecular Function (3): thyrotropin-releasing hormone receptor activity (GO:0004997), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

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
G protein-coupled receptor activity	2
G protein-coupled receptor signaling pathway	2
signal transduction	1
phospholipase C activator activity	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1002 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRHR	TRH	P20396	996
TRHR	TSHB	P01222	894
TRHR	ARRB2	P32121	881
TRHR	ARRB1	P49407	837
TRHR	TSHR	P16473	732
TRHR	PRL	P01236	676
TRHR	IGSF1	Q8N6C5	651
TRHR	GNRHR	P30968	585
TRHR	THRA	P10827	568
TRHR	SAG	P10523	497
TRHR	GNAQ	P50148	482
TRHR	POU1F1	P28069	479
TRHR	ADCYAP1R1	P41586	459
TRHR	DRD4	P21917	454
TRHR	SLC5A5	Q92911	448

IntAct

54 interactions, top by confidence:

A	B	Type	Score
TRHR	ACP2	psi-mi:“MI:0915”(physical association)	0.560
SLC39A2	TRHR	psi-mi:“MI:0915”(physical association)	0.560
SLC39A9	TRHR	psi-mi:“MI:0915”(physical association)	0.560
COMT	TRHR	psi-mi:“MI:0915”(physical association)	0.560
TRHR	TMEM239	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	TRHR	psi-mi:“MI:0915”(physical association)	0.560
TRHR	SLC41A1	psi-mi:“MI:0915”(physical association)	0.560
TRHR	FAM241B	psi-mi:“MI:0915”(physical association)	0.560
TRHR	IER3IP1	psi-mi:“MI:0915”(physical association)	0.560
GJB2	TRHR	psi-mi:“MI:0915”(physical association)	0.560
TRHR	TMEFF2	psi-mi:“MI:0915”(physical association)	0.560
TRHR	NIPAL4	psi-mi:“MI:0915”(physical association)	0.560
TRHR	YIPF6	psi-mi:“MI:0915”(physical association)	0.560
TRHR	UBE2J1	psi-mi:“MI:0915”(physical association)	0.560
TRHR	EFNA5	psi-mi:“MI:0915”(physical association)	0.560
TRHR	C1QL4	psi-mi:“MI:0915”(physical association)	0.560
TRHR	SLC39A2	psi-mi:“MI:0915”(physical association)	0.560
PEDS1-UBE2V1	TRHR	psi-mi:“MI:0915”(physical association)	0.560
TRHR	SLC39A9	psi-mi:“MI:0915”(physical association)	0.560
	TRHR	psi-mi:“MI:0915”(physical association)	0.560
TRHR	CBX6	psi-mi:“MI:0914”(association)	0.350
IER3IP1	TRHR	psi-mi:“MI:0915”(physical association)	0.000
GJB2	TRHR	psi-mi:“MI:0915”(physical association)	0.000
TMEFF2	TRHR	psi-mi:“MI:0915”(physical association)	0.000
NIPAL4	TRHR	psi-mi:“MI:0915”(physical association)	0.000
YIPF6	TRHR	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): ACP2 (Affinity Capture-MS), ACP2 (Affinity Capture-MS), TRHR (Two-hybrid), TRHR (Two-hybrid), TRHR (Two-hybrid), TRHR (Two-hybrid), TRHR (Two-hybrid), TRHR (Two-hybrid), TRHR (Two-hybrid), TRHR (Two-hybrid), TRHR (Two-hybrid), TRHR (Two-hybrid), TRHR (Two-hybrid), YIPF6 (Two-hybrid), EFNA5 (Two-hybrid)

ESM2 similar proteins: A0A2L0VBG2, A1ZAX0, B2ZHY2, O43194, O43614, O46635, O46639, O54798, O62809, O93603, O97967, P08909, P14842, P18599, P20789, P21761, P28223, P28335, P30975, P32247, P32940, P34968, P34981, P35363, P35371, P41984, P47751, P50128, P50129, P56490, P56719, P58308, Q01717, Q28596, Q4V622, Q5IS53, Q5IS66, Q5IS98, Q5R4Q6, Q5U431

Diamond homologs: A5A4K9, A5A4L1, C3ZQF9, O08725, O17239, O43193, O55040, O88319, P19020, P20789, P20905, P30728, P30989, P34981, P58826, Q09388, Q28553, Q58CW4, Q5QD24, Q63384, Q8BZ39, Q8ITC7, Q8WPA2, Q90WY4, Q923Y8, Q92847, Q93126, Q95254, Q99P50, Q9ESQ4, Q9GZQ4, Q9HB89, Q9JJI5, Q9N2B1, Q9N2B2, Q9VML9, O08556, O08786, O18935, O19025

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TRH	“up-regulates activity”	TRHR	binding
TRHR	“up-regulates activity”	GNA11	binding
TRHR	“up-regulates activity”	GNAQ	binding
TRHR	“up-regulates activity”	GNA15	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	43
Likely benign	10
Benign	6

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
12682	NM_003301.7(TRHR):c.49C>T (p.Arg17Ter)	Pathogenic
686772	GRCh37/hg19 8q23.1(chr8:110059050-110132754)x1	Pathogenic
689396	NM_003301.7(TRHR):c.392T>C (p.Ile131Thr)	Pathogenic
12681	NM_003301.7(TRHR):c.343_352delinsA (p.Ser115_Ala118delinsThr)	Likely pathogenic
3595038	NM_003301.7(TRHR):c.597_598del (p.Phe199fs)	Likely pathogenic
4849395	NM_003301.7(TRHR):c.1016del (p.Gln339fs)	Likely pathogenic
689395	NM_003301.7(TRHR):c.242C>G (p.Pro81Arg)	Likely pathogenic

SpliceAI

515 predictions. Top by Δscore:

Variant	Effect	Δscore
8:109086881:AAGGT:A	donor_loss	1.0000
8:109086882:AGGTA:A	donor_loss	1.0000
8:109086883:GGTA:G	donor_loss	1.0000
8:109086878:GA:G	donor_gain	0.9900
8:109086884:G:GG	donor_gain	0.9900
8:109086885:T:G	donor_loss	0.9800
8:109117691:C:G	donor_gain	0.9800
8:109094912:A:AG	acceptor_gain	0.9700
8:109094913:G:GG	acceptor_gain	0.9700
8:109114531:A:AG	donor_gain	0.9400
8:109087423:AGGG:A	acceptor_gain	0.9200
8:109087424:GGGG:G	acceptor_gain	0.9200
8:109119037:T:G	acceptor_loss	0.9200
8:109119042:CCCTA:C	acceptor_loss	0.9200
8:109119043:CCTA:C	acceptor_loss	0.9200
8:109119044:CTAGG:C	acceptor_loss	0.9200
8:109119045:TAGG:T	acceptor_loss	0.9200
8:109119046:A:C	acceptor_loss	0.9200
8:109086708:T:A	donor_gain	0.9100
8:109087423:AG:A	acceptor_gain	0.9100
8:109087424:GG:G	acceptor_gain	0.9100
8:109094911:T:G	acceptor_gain	0.9100
8:109119195:A:AG	acceptor_gain	0.9100
8:109119196:G:GG	acceptor_gain	0.9100
8:109087423:AGGGG:A	acceptor_gain	0.9000
8:109087424:GGGGG:G	acceptor_gain	0.9000
8:109112623:A:AG	donor_gain	0.9000
8:109114527:A:G	donor_gain	0.9000
8:109087419:TCACA:T	acceptor_loss	0.8900
8:109087420:CACAG:C	acceptor_loss	0.8900

AlphaMissense

2627 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:109087627:G:C	G39R	1.000
8:109087636:G:C	G42R	1.000
8:109087641:C:A	N43K	1.000
8:109087641:C:G	N43K	1.000
8:109087703:T:C	L64P	1.000
8:109087708:A:C	S66R	1.000
8:109087710:C:A	S66R	1.000
8:109087710:C:G	S66R	1.000
8:109087712:T:C	L67P	1.000
8:109087723:G:C	D71H	1.000
8:109087724:A:C	D71A	1.000
8:109087724:A:G	D71G	1.000
8:109087724:A:T	D71V	1.000
8:109087880:G:T	R123M	1.000
8:109087960:T:A	W150R	1.000
8:109087960:T:C	W150R	1.000
8:109119081:T:C	F275L	1.000
8:109119083:T:A	F275L	1.000
8:109119083:T:G	F275L	1.000
8:109119208:C:A	P317Q	1.000
8:109119237:T:C	F327L	1.000
8:109119239:C:A	F327L	1.000
8:109119239:C:G	F327L	1.000
8:109087628:G:A	G39D	0.999
8:109087637:G:A	G42D	0.999
8:109087695:C:A	N61K	0.999
8:109087695:C:G	N61K	0.999
8:109087703:T:A	L64Q	0.999
8:109087712:T:A	L67Q	0.999
8:109087721:C:A	A70D	0.999

dbSNP variants (sampled 300 via entrez): RS1000066903 (8:109099430 C>G), RS1000200716 (8:109097319 C>G), RS1000218019 (8:109090386 G>A,T), RS1000297506 (8:109121998 G>A,C), RS1000319063 (8:109103658 G>A), RS1000504048 (8:109084695 C>T), RS1000510074 (8:109110326 A>G), RS1000528587 (8:109110620 T>A,C), RS1000595276 (8:109097596 T>C), RS1000732385 (8:109096935 C>G,T), RS1000806442 (8:109109540 A>G), RS1000915485 (8:109116704 A>C,G), RS1001055896 (8:109085997 G>T), RS1001094811 (8:109109199 A>C), RS1001169394 (8:109099882 G>A,C)

Disease associations

OMIM: gene MIM:188545 | disease phenotypes: MIM:618573

GenCC curated gene-disease

Disease	Classification	Inheritance
hypothyroidism, congenital, nongoitrous, 7	Strong	Autosomal recessive
resistance to thyrotropin-releasing hormone syndrome	Supportive	Autosomal recessive

Mondo (3): hypothyroidism, congenital, nongoitrous, 7 (MONDO:0032819), congenital hypothyroidism (MONDO:0018612), (MONDO:0020503)

Orphanet (3): Resistance to thyrotropin-releasing hormone syndrome (Orphanet:99832), Congenital hypothyroidism (Orphanet:442), Non-syndromic bicoronal craniosynostosis (Orphanet:35099)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000707	Abnormality of the nervous system
HP:0000716	Depression
HP:0000853	Goiter
HP:0000870	Increased circulating prolactin concentration
HP:0000958	Dry skin
HP:0001254	Lethargy
HP:0001510	Growth delay
HP:0001609	Hoarse voice
HP:0002750	Delayed skeletal maturation
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration
HP:0004322	Short stature
HP:0005990	Thyroid hypoplasia
HP:0006579	Prolonged neonatal jaundice
HP:0008202	Reduced circulating prolactin concentration
HP:0008245	Pituitary hypothyroidism
HP:0011437	Maternal autoimmune disease
HP:0012378	Fatigue
HP:0012758	Neurodevelopmental delay
HP:0025483	Abnormal circulating thyroglobulin concentration
HP:0025502	Overweight
HP:0030057	Autoimmune antibody positivity
HP:0031219	Reduced radioactive iodine uptake
HP:0031507	Decreased circulating T4 concentration
HP:0032210	Decreased circulating free T3
HP:0033082	Reduced TSH response to thyrotrophin-releasing hormone stimulation test

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000352_1	Body mass (lean)	4.000000e-10
GCST003518_76	Daytime sleep phenotypes	2.000000e-06
GCST003542_207	Night sleep phenotypes	5.000000e-06
GCST006629_66	Pulse pressure	3.000000e-13
GCST009379_116	Type 2 diabetes	3.000000e-08
GCST010245_85	LDL cholesterol levels	5.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004995	lean body mass
EFO:0007828	daytime rest measurement
EFO:0005763	pulse pressure measurement
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003409	Congenital Hypothyroidism	C05.116.099.343.347; C05.116.132.256; C16.320.240.625; C19.297.155; C19.874.482.281

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1810 (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: 13,012 (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
CHEMBL1472	PROTIRELIN	4	13,012

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Thyrotropin-releasing hormone receptors

Most potent curated ligand interactions (7 total), top 7:

Ligand	Action	Affinity	Parameter
MeTRH	Partial agonist	8.5	pKi
[3H]MeTRH	Partial agonist	8.5	pKd
TRH	Full agonist	7.4	pKi
taltirelin	Full agonist	6.5	pKi
midazolam	Antagonist	5.49	pKi
diazepam	Antagonist	5.15	pKi
chlordiazepoxide	Antagonist	4.7	pKi

ChEMBL bioactivities

12 potent at pChembl≥5 of 13 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.52	Ki	3	nM	CHEMBL224730
8.52	EC50	3	nM	PROTIRELIN
8.49	Ki	3.2	nM	CHEMBL223972
8.31	EC50	4.9	nM	CHEMBL223972
8.30	EC50	5	nM	CHEMBL224730
7.96	Ki	11	nM	CHEMBL390942
7.85	EC50	14	nM	CHEMBL390942
7.70	Ki	20	nM	PROTIRELIN
6.42	EC50	380	nM	CHEMBL224525
6.40	Ki	400	nM	CHEMBL224525
5.29	EC50	5100	nM	CHEMBL388528
5.12	Ki	7500	nM	CHEMBL388528

PubChem BioAssay actives

12 with measured affinity, of 50 total; 6 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
(2S)-1-[(2S)-2-amino-3-(3-methyl-1H-imidazol-3-ium-4-yl)propanoyl]-N-[(2S)-1-[(2S)-2-carbamoylpyrrolidin-1-yl]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide	283905: Displacement of [3H]N(1)-Me-His-TRH from TRHR1	ki	0.0030	uM
Protirelin	283907: Agonist activity at TRHR1 expressed in HEK293EM cells assessed as activation potency by measuring CREB-luciferase reporter activity	ec50	0.0030	uM
(2S)-N-[(2S)-1-[(2S)-2-carbamoylpyrrolidin-1-yl]-3-(1-methylimidazol-4-yl)-1-oxopropan-2-yl]-6-oxopiperidine-2-carboxamide	283905: Displacement of [3H]N(1)-Me-His-TRH from TRHR1	ki	0.0032	uM
(2S)-N-[(2S)-1-[(2S)-2-carbamoylpyrrolidin-1-yl]-3-(1-ethylimidazol-4-yl)-1-oxopropan-2-yl]-6-oxopiperidine-2-carboxamide	283905: Displacement of [3H]N(1)-Me-His-TRH from TRHR1	ki	0.0110	uM
(2S)-N-[(2S)-1-[(2S)-2-carbamoylpyrrolidin-1-yl]-1-oxo-3-(2-propyl-1H-imidazol-5-yl)propan-2-yl]-6-oxopiperidine-2-carboxamide	283907: Agonist activity at TRHR1 expressed in HEK293EM cells assessed as activation potency by measuring CREB-luciferase reporter activity	ec50	0.3800	uM
(2S)-N-[(2S)-1-[(2S)-2-carbamoylpyrrolidin-1-yl]-1-oxo-3-(1-prop-2-enylimidazol-4-yl)propan-2-yl]-6-oxopiperidine-2-carboxamide	283907: Agonist activity at TRHR1 expressed in HEK293EM cells assessed as activation potency by measuring CREB-luciferase reporter activity	ec50	5.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
pyrazolanthrone	decreases expression, decreases reaction	1
bisphenol S	increases methylation	1
Wortmannin	decreases reaction, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Diethylhexyl Phthalate	increases expression, decreases reaction	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

15 unique, capped per target: 12 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1737857	Functional	PUBCHEM_BIOASSAY: qHTS for Small Molecule Agonists and Allosteric Enhancers of Human TRH Receptor: Confirmation Screen for Enhancers. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID485365]	PubChem BioAssay data set
CHEMBL1809429	Binding	Inhibition of Thyrotropin releasing hormone receptor at 4 uM	Discovery of N-(1-ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98-2): an orally active corticotropin releasing factor-1 (CRF-1) receptor antagonist. — J Med Chem

Cellosaurus cell lines

4 cell lines: 2 spontaneously immortalized cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_H505	CHO-K1/TRH1	Spontaneously immortalized cell line	Female
CVCL_KZ22	PathHunter CHO-K1 TRHR beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_LB43	PathHunter U2OS TRHR Total GPCR Internalization	Cancer cell line	Female
CVCL_YK63	U2OS TRH1 HiTSeeker	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05228184	PHASE4	TERMINATED	Use of Tirosint®-SOL or Tablet Formulations of Levothyroxine in Pediatric Patients With Congenital Hypothyroidism (CH)
NCT05371262	PHASE4	COMPLETED	Influence of Initial Levothyroxine Dose on Neurodevelopmental and Growth Outcomes in Congenital Hypothyroidism
NCT00403390	Not specified	COMPLETED	Generic vs. Name-Brand Levothyroxine
NCT00493103	Not specified	COMPLETED	TG Gene Mutations and Congenital Hypothyroidism
NCT00497575	Not specified	COMPLETED	Diagnosis and Follow-up of Patients With Subclinical Hypothyroidism
NCT00505479	Not specified	UNKNOWN	Iodine Status in Pregnant Women and Their Newborns: is Congenital Hypothyroidism Related to Iodine Deficiency in Pregnancy?
NCT01223638	Not specified	WITHDRAWN	The Prevalence of Hearing Loss Among Children With Congenital Hypothyroidism
NCT01349634	Not specified	COMPLETED	The Effects of Iodized Salt on Cognitive Development in Ethiopia
NCT01488721	Not specified	COMPLETED	Clinical Evaluation of NeoPlex4 Assay and NeoPlex System
NCT01916018	Not specified	COMPLETED	Clinical and Genetic Analysis in Congenital Hypothyroidism Due to Thyroid Dysgenesis.
NCT02307175	Not specified	COMPLETED	A Study of 99m Tc Pertechnetate Produced in High Energy Cyclotron in Patients With Thyroid Scan Indication
NCT02374593	Not specified	COMPLETED	Targeted Levothyroxine Dosing in Infants With Congenital Hypothyroidism
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04712760	Not specified	UNKNOWN	Congenital Hypothyroidism in Children With Eutopic Gland or Thyroid Hemiagenesis: Predictive Factors for Transient vs Permanent Hypothyroidism.
NCT04734457	Not specified	UNKNOWN	Final Height in Patients With CH Diagnosed by the Screening
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06724224	Not specified	RECRUITING	Comparison of Levothyroxine Formulations in the Treatment of Congenital Hypothyroidism
NCT06728735	Not specified	RECRUITING	Role of Next Generation Sequencing in the Etiological Diagnosis of Permanent Congenital Hypothyroidism With in Situ Thyroid
NCT06864039	Not specified	ENROLLING_BY_INVITATION	Quality of Life and Long-term Outcome of Adequately Treated Congenital Hypothyroidism
NCT06864351	Not specified	RECRUITING	Prospective Evaluation of OptiThyDose
NCT07126353	Not specified	NOT_YET_RECRUITING	Metabolic Risk Assessment in Prepubertal Children With Congenital Hypothyroidism
NCT07280104	Not specified	RECRUITING	Infants With Primary Congenital Hypothyroidism and Development
NCT07425028	Not specified	NOT_YET_RECRUITING	Evaluation of an Intensified Systematic Screening for Congenital Hypothyroidism in Premature Newborns
NCT07579988	Not specified	NOT_YET_RECRUITING	Ultrasound Measurement of Thyroid Volume in Term Newborns