TAC3

Summary

TAC3 (tachykinin precursor 3, HGNC:11521) is a protein-coding gene on chromosome 12q13.3, encoding Tachykinin-3 (Q9UHF0). Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles.

This gene encodes a member of the tachykinin family of secreted neuropeptides. The encoded preproprotein is proteolytically processed to generate the mature peptide, which is primarily expressed in the central and peripheral nervous systems and functions as a neurotransmitter. This peptide is the ligand for the neurokinin-3 receptor. This protein is also expressed in the outer syncytiotrophoblast of the placenta and may be associated with pregnancy-induced hypertension and pre-eclampsia. Mutations in this gene are associated with normosmic hypogonadotropic hypogonadism. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed.

Source: NCBI Gene 6866 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 10 with or without anosmia (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 42 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes
• MANE Select transcript: NM_013251

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11521
Approved symbol	TAC3
Name	tachykinin precursor 3
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	ZNEUROK1, NKB, NK3, LncZBTB39-1:2, LncZBTB39
Ensembl gene	ENSG00000166863
Ensembl biotype	protein_coding
OMIM	162330
Entrez	6866

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 nonsense_mediated_decay, 5 protein_coding, 1 retained_intron

ENST00000300108, ENST00000357616, ENST00000379411, ENST00000393867, ENST00000415231, ENST00000423597, ENST00000438756, ENST00000441881, ENST00000458521, ENST00000496757, ENST00000872423, ENST00000922108

RefSeq mRNA: 2 — MANE Select: NM_013251 NM_001178054, NM_013251

CCDS: CCDS53803, CCDS8928

Canonical transcript exons

ENST00000458521 — 7 exons

Exon	Start	End
ENSE00001107285	57012822	57012875
ENSE00001107300	57013359	57013388
ENSE00001705314	57010000	57010288
ENSE00001830516	57016387	57016529
ENSE00003524255	57012378	57012452
ENSE00003597966	57015684	57015802
ENSE00003649427	57013578	57013671

Expression profiles

Bgee: expression breadth ubiquitous, 162 present calls, max score 97.29.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6450 / max 984.5239, expressed in 312 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131613	2.2406	277
206747	0.3785	149
206748	0.0259	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	97.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.54	gold quality
placenta	UBERON:0001987	88.48	gold quality
anterior cingulate cortex	UBERON:0009835	87.72	gold quality
cingulate cortex	UBERON:0003027	87.69	gold quality
caudate nucleus	UBERON:0001873	87.35	gold quality
prefrontal cortex	UBERON:0000451	85.48	gold quality
nucleus accumbens	UBERON:0001882	84.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.64	gold quality
right frontal lobe	UBERON:0002810	83.43	gold quality
putamen	UBERON:0001874	83.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.80	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.89	gold quality
Brodmann (1909) area 9	UBERON:0013540	81.76	gold quality
frontal cortex	UBERON:0001870	81.35	gold quality
neocortex	UBERON:0001950	81.12	gold quality
spinal cord	UBERON:0002240	80.31	gold quality
tibialis anterior	UBERON:0001385	79.27	silver quality
endothelial cell	CL:0000115	79.15	silver quality
telencephalon	UBERON:0001893	79.15	gold quality
diaphragm	UBERON:0001103	79.02	gold quality
olfactory bulb	UBERON:0002264	78.93	gold quality
cerebral cortex	UBERON:0000956	78.47	gold quality
type B pancreatic cell	CL:0000169	78.18	gold quality
Brodmann (1909) area 46	UBERON:0006483	78.16	gold quality
hypothalamus	UBERON:0001898	78.07	gold quality
ileal mucosa	UBERON:0000331	77.33	silver quality
forebrain	UBERON:0001890	76.57	gold quality
mucosa of transverse colon	UBERON:0004991	75.47	gold quality
small intestine Peyer’s patch	UBERON:0003454	75.42	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-10485	yes	1499.16
E-ANND-3	no	1.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AR, ARNT, ESR1, ESR2, GATA1, REST, STAT5B

Literature-anchored findings (GeneRIF, showing 40)

• study demonstrates a paracrine role for neurokinin B in the regulation of fetal placental vascular tone (PMID:12727971)
• Higher neurokinin B concentrations in normotensive pregnant women may be due to the advanced gestational age and/or the result of a negative interaction of other vasoactive substances. The role of neurokinin B in preeclampsia remains to be determined. (PMID:14634580)
• NKB plays a role in the maintenance of high placental blood flow in normal pregnancy (PMID:14700748)
• mode of vascular regulation in which GATA-1 controls NK-B synthesis in erythroid cells (PMID:15123623)
• three-dimensional structure (PMID:15317475)
• Results determined the placenta to be the main site of TAC3 expression with levels 2.6-fold higher than the brain and TAC3 expression was found to be significantly higher in pre-eclamptic placenta (1.7-fold, P < 0.05) than in normal controls. (PMID:16709596)
• Placental mRNA expression of NKB was significantly higher after term and preterm labor (P<0.001) than cesarean section, and highest after preterm labor (PMID:17561251)
• Altered circulating neurokinin B (NKB) levels in preeclampsia are not due to sequence variants in the encoding genes (PMID:17976896)
• study confirms previous reports of elevated neurokinin B levels in the plasma of preeclampsia women in the third trimester (PMID:18240076)
• A role for TAC3 neurons in the regulation of steroid negative feedback is suggested by studies of the postmenopausal human hypothalamus. (PMID:18614256)
• Neurokinin B is a critical central regulator of human gonadal function. (PMID:19079066)
• The significantly increased maternal plasma levels of NKB and ET-1 of patients with preeclampsia occur at early pregnancy, before the onset of clinical symptoms. (PMID:19087492)
• Data show that both the TAC3 endogenous gene and its promoter are regulated, directly or indirectly, by the NRSF transcription factors resulting in both the increased expression of the endogenous gene and increased reporter gene activity. (PMID:19539370)
• elevated in plasma of pre-eclamptic women (PMID:20017703)
• Physiological significance of neurokinin B in the placenta and during preeclampsia. (PMID:20074343)
• NKB involvement in puberty is reviewed from the perspective of the regulation of puberty. (PMID:20176081)
• Possibility of a specific neuroendocrine impairment in patients with alteration of neurokinin B signaling. (PMID:20194706)
• broad cohort of normosmic hypogonadotropic hypogonadism probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships (PMID:20332248)
• Data describe the distribution and sex dimorphism of kisspeptin-immunoreactive elements in hypothalami, reveal contacts between kisspeptin-immunoreactive fibers and GnRH cells, and colocalize kisspeptins and neurokinin B in the infundibular nucleus. (PMID:20529119)
• A possible association of a single nucleotide polymorphism in the tachykinin-3 gene and susceptibility to asthma are found. (PMID:20580442)
• Future studies will be needed to determine whether NKB signaling plays a permissive role in the onset of puberty–REVIEW (PMID:20800582)
• kisspeptin and neurokinin B are coexpressed in the arcuate nucleus in the mammalian hypothalamus, suggesting that these systems are closely related and potential partners of the regulation of the reproductive axis–REVIEW (PMID:20816945)
• The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. (PMID:22031817)
• Report neurokinin B immunoreactivity in the human brainstem. (PMID:22318412)
• NKB/NK(3)R and kisspeptin/KISS1R are present in female peripheral reproductive tissues with colocalization of both systems in some non-neuronal cell populations of the human female genital tract. (PMID:22424618)
• NKB neurons in the arcuate nucleus do not synthesize detectable amounts of kisspeptin and dynorphin in young male humans. These data call for a critical use of the KNDy neuron terminology when referring to the pulse generator of the hypothalamus (PMID:22903610)
• these immunohistochemical data suggest an aging-related moderate enhancement in central NKB signaling. (PMID:23011920)
• Sex differences in the neurokinin B system in the human infundibular nucleus. (PMID:23019350)
• Rare variants in the TAC3 and TACR3 genes were identified in patients with central pubertal disorders and loss-of-function variants of TACR3 were associated with the normosmic IHH phenotype. (PMID:23329188)
• Interactions between kisspeptins and neurokinin B. (PMID:23550013)
• Expression of the gene encoding NKB (TAC3) is up-regulated 20-fold in leiomyomas, compared with matched myometrium. (PMID:23656837)
• Copper can enter cultured astrocytoma cells and subsequently open plasma membrane calcium channels, but when bound to NKB, copper ion uptake is inhibited. (PMID:23875773)
• SP may influence the KP and NKB secretory output via additional autocrine/paracrine mechanisms or regulate GnRH neurosecretion directly. (PMID:23977290)
• mutations in TAC and TACR3 are not a common cause for ICPP. (PMID:24802197)
• Colocalization experiments provided evidence for the presence of cocaine- and amphetamine-regulated transcript (CART) in KP-immunoreactive (IR) and perikarya and in KP-IR and NKB-IR axon varicosities. (PMID:25084101)
• Amino acid substitution A63P in TAC3 gene was statistically associated with the puberty onset time in Chinese girls. (PMID:25153567)
• Plasma neurokinin B level is higher in patients with NDHT, indicating an unfavorable cardiovascular prognosis. (PMID:25647283)
• acts through NK3 receptors in granulosa cells to stimulate steroid production (PMID:27580802)
• Data suggest that basal serum neurokinin B level can be used as an adjunctive parameter to differentiate idiopathic central precocious puberty (ICPP) from premature thelarche (PT). (PMID:28008860)
• The administration of an NK3R antagonist indicates a role for Neurokinin B in the regulation of luteinising hormone (LH)/gonadotropin-releasing hormone (GnRH) in postmenopausal women, whereas the lack of response to kisspeptin may reflect the hypo-oestrogenic state. These data support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R antagonism as a potential therapeutic approach. (PMID:28380486)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tac3a	ENSDARG00000093089
mus_musculus	Tac2	ENSMUSG00000025400
rattus_norvegicus	Tac3	ENSRNOG00000004229

Protein

Protein identifiers

Tachykinin-3 — Q9UHF0 (reviewed: Q9UHF0)

Alternative names: ZNEUROK1

All UniProt accessions (1): Q9UHF0

UniProt curated annotations — full annotation on UniProt →

Function. Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles. Is a ligand for TACR3, and triggers G protein-coupled receptor signaling via activation of G(q) and phosphatidylinositol hydrolysis by phospholipase C. Binding to TACR3 also triggers signaling via activation of adenylate cyclase activity which results in increased intracellular levels of cyclic AMP (cAMP). Is a critical central regulator of gonadal function.

Subcellular location. Secreted.

Disease relevance. Hypogonadotropic hypogonadism 10 with or without anosmia (HH10) [MIM:614839] A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the tachykinin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UHF0-1	1, Beta tachykinin 3	yes
Q9UHF0-2	2, Alpha tachykinin 3
Q9UHF0-3	3, Gamma tachykinin 3

RefSeq proteins (2): NP_001171525, NP_037383* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003635	Neurokinin-B/TAC3	Family
IPR013055	Tachy_Neuro_lke_CS	Conserved_site

Pfam: PF03823

UniProt features (13 total): propeptide 2, sequence variant 2, splice variant 2, signal peptide 1, sequence conflict 1, helix 1, peptide 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8JBG	ELECTRON MICROSCOPY	2.8
1P9F	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHF0-F1	65.34	0.09

Antibody-complex structures (SAbDab): 1 — 8JBG

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): 90

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-380095	Tachykinin receptors bind tachykinins
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 192 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_CIRCULATORY_SYSTEM_PROCESS, SP3_Q3, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, BRN2_01, OCT1_03, GOBP_CILIUM_MOVEMENT, GOBP_REGULATION_OF_MICROTUBULE_BASED_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_REGULATION_OF_REPRODUCTIVE_PROCESS

GO Biological Process (4): tachykinin receptor signaling pathway (GO:0007217), neuropeptide signaling pathway (GO:0007218), female pregnancy (GO:0007565), positive regulation of blood pressure (GO:0045777)

GO Molecular Function (2): signaling receptor binding (GO:0005102), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide ligand-binding receptors	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
multi-organism reproductive process	1
multi-multicellular organism process	1
regulation of blood pressure	1
protein binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

814 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TAC3	TACR3	P29371	999
TAC3	TAC1	P20366	998
TAC3	TACR2	P21452	998
TAC3	TACR1	P25103	996
TAC3	KISS1R	Q969F8	967
TAC3	KISS1	Q15726	955
TAC3	GNRH1	P01148	909
TAC3	TAC4	Q86UU9	908
TAC3	GNRHR	P30968	890
TAC3	PDYN	P01213	880
TAC3	NSMF	Q6X4W1	853
TAC3	PROK2	Q9HC23	816
TAC3	CHKB	Q9Y259	782
TAC3	CHD7	Q9P2D1	779
TAC3	PROKR2	Q8NFJ6	720

IntAct

20 interactions, top by confidence:

A	B	Type	Score
	TAC3	psi-mi:“MI:0915”(physical association)	0.560
PRB1	TAC3	psi-mi:“MI:0915”(physical association)	0.560
TAC3	JPH3	psi-mi:“MI:0915”(physical association)	0.560
THNSL1	TAC3	psi-mi:“MI:0915”(physical association)	0.400
TAC3	H2AC11	psi-mi:“MI:0915”(physical association)	0.400
TAC3	ITIH2	psi-mi:“MI:0914”(association)	0.350
AKAP7	PRKACG	psi-mi:“MI:0914”(association)	0.350
	TAC3	psi-mi:“MI:0915”(physical association)	0.000
PRB1	TAC3	psi-mi:“MI:0915”(physical association)	0.000
TAC3	FEZ1	psi-mi:“MI:0915”(physical association)	0.000
VOPP1	TAC3	psi-mi:“MI:0915”(physical association)	0.000
TAC3	ELP1	psi-mi:“MI:0915”(physical association)	0.000
TAC3	PTN	psi-mi:“MI:0915”(physical association)	0.000
TAC3	UBR1	psi-mi:“MI:0915”(physical association)	0.000
TAC3	CCDC90B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): CCDC90B (Two-hybrid), FEZ1 (Two-hybrid), GPRASP1 (Two-hybrid), IKBKAP (Two-hybrid), PTN (Two-hybrid), UBR1 (Two-hybrid), PRH1 (Two-hybrid), PRB1 (Two-hybrid), TAC3 (Reconstituted Complex), TAC3 (Affinity Capture-MS), EMC4 (Affinity Capture-MS), TAC3 (Affinity Capture-MS), ITIH2 (Affinity Capture-MS), HIST1H2AG (Affinity Capture-MS), TAC3 (Affinity Capture-MS)

ESM2 similar proteins: A0A077DF94, D2Z1D6, D6WT67, E2A3M7, E2E4E4, E2E4L2, E7EZ53, F1QQI2, I7C2V3, O42471, O96690, P07808, P08947, P08948, P0DQF0, P0DQY8, P15743, P16043, P16240, P28672, P28673, P33439, P33689, P43443, P51919, P57774, P70074, P81401, P84213, P85527, Q0VBW8, Q0VC44, Q1HA14, Q1HA20, Q29B55, Q4QXT8, Q4V645, Q5H8A1, Q5H8A3, Q91330

Diamond homologs: P08435, P08858, P55099, P67934, Q9UHF0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	22
Likely benign	7
Benign	7

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
14027	NM_013251.4(TAC3):c.269T>C (p.Met90Thr)	Pathogenic
66083	NM_013251.4(TAC3):c.61del (p.Ala21fs)	Pathogenic
180155	NM_013251.4(TAC3):c.238C>A (p.Arg80Ser)	Likely pathogenic
2029736	NM_013251.4(TAC3):c.238+1G>C	Likely pathogenic

SpliceAI

1145 predictions. Top by Δscore:

Variant	Effect	Δscore
12:57012372:CCTTA:C	donor_loss	1.0000
12:57012373:CTTAC:C	donor_loss	1.0000
12:57012374:TTACC:T	donor_loss	1.0000
12:57012375:TACC:T	donor_loss	1.0000
12:57012376:A:AC	donor_gain	1.0000
12:57012376:A:C	donor_loss	1.0000
12:57012376:AC:A	donor_gain	1.0000
12:57012377:C:CA	donor_loss	1.0000
12:57012377:C:CC	donor_gain	1.0000
12:57012377:CC:C	donor_gain	1.0000
12:57012449:GAGT:G	acceptor_gain	1.0000
12:57012450:AGT:A	acceptor_gain	1.0000
12:57012451:GT:G	acceptor_gain	1.0000
12:57012452:TC:T	acceptor_loss	1.0000
12:57012453:C:CC	acceptor_gain	1.0000
12:57012458:G:GC	acceptor_gain	1.0000
12:57013354:CTT:C	donor_loss	1.0000
12:57013355:TTA:T	donor_loss	1.0000
12:57013356:TAC:T	donor_loss	1.0000
12:57013357:A:AC	donor_gain	1.0000
12:57013358:C:CA	donor_gain	1.0000
12:57013358:CG:C	donor_gain	1.0000
12:57013574:CTACC:C	donor_loss	1.0000
12:57013575:TA:T	donor_loss	1.0000
12:57013577:C:CA	donor_loss	1.0000
12:57013667:TCCCT:T	acceptor_gain	1.0000
12:57013668:CCCT:C	acceptor_gain	1.0000
12:57013668:CCCTC:C	acceptor_gain	1.0000
12:57013669:CCTC:C	acceptor_gain	1.0000
12:57013670:CT:C	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000237206 (12:57017681 G>A,C), RS1000261020 (12:57010194 A>C), RS1000314517 (12:57014345 C>T), RS1000416130 (12:57017390 T>C), RS1000518927 (12:57011546 G>C), RS1000653494 (12:57016057 A>G), RS1000995740 (12:57011970 A>G), RS1001590040 (12:57017041 C>A,G,T), RS1001979443 (12:57018305 T>C), RS1002043810 (12:57016734 C>T), RS1002164051 (12:57016483 GT>G), RS1002313354 (12:57011075 G>A,T), RS1002328688 (12:57018495 A>G), RS1002525838 (12:57015002 T>A), RS1003007875 (12:57015360 C>T)

Disease associations

OMIM: gene MIM:162330 | disease phenotypes: MIM:146110, MIM:147950, MIM:614839

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 10 with or without anosmia	Strong	Autosomal recessive
hypogonadotropic hypogonadism	Supportive	Autosomal dominant

Mondo (4): infertility disorder (MONDO:0005047), hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794), hypogonadotropic hypogonadism (MONDO:0018555), hypogonadotropic hypogonadism 10 with or without anosmia (MONDO:0013912)

Orphanet (1): Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000118	Phenotypic abnormality
HP:0000134	Female hypogonadism
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000316	Hypertelorism
HP:0000458	Anosmia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000802	Impotence
HP:0000823	Delayed puberty
HP:0000869	Secondary amenorrhea
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001256	Mild intellectual disability
HP:0001608	Abnormality of the voice
HP:0002215	Sparse axillary hair
HP:0002225	Sparse pubic hair
HP:0002231	Sparse body hair
HP:0002750	Delayed skeletal maturation

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002539_15	Schizophrenia	2.000000e-12
GCST005312_1	Menopause (age at onset)	2.000000e-19
GCST006804_178	Red cell distribution width	5.000000e-08
GCST007563_7	Allergic disease (asthma, hay fever or eczema)	1.000000e-09
GCST007564_27	Asthma or allergic disease (pleiotropy)	8.000000e-13
GCST008916_110	Asthma	1.000000e-27
GCST008916_18	Asthma	8.000000e-18
GCST008916_2	Asthma	2.000000e-08
GCST009798_10	Asthma	3.000000e-29

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0009188	Red cell distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007246	Infertility	C12.100.750
C562785	Idiopathic Hypogonadotropic Hypogonadism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3707470 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

6 measured of 6 human assays (6 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[(4R)-1-(1-acetylpiperidine-4-carbonyl)-3-(3,4-dichlorophenyl)piperidin-4-yl]-4-bromo-N-methylbenzamide	IC50	0.45 nM	US-8470816: Nitrogen-containing heterocyclic compound and use thereof
N-[(3R,4R)-1-(1-acetylpiperidine-4-carbonyl)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide	IC50	0.79 nM	US-8470816: Nitrogen-containing heterocyclic compound and use thereof
N-[(4R)-1-(1-acetylpiperidine-4-carbonyl)-3-(3,4-dichlorophenyl)piperidin-4-yl]-4-chloro-N-methylbenzamide	IC50	1.1 nM	US-8470816: Nitrogen-containing heterocyclic compound and use thereof
N-[(4R)-1-(1-acetylpiperidine-4-carbonyl)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methyl-4-phenylbenzamide	IC50	1.7 nM	US-8470816: Nitrogen-containing heterocyclic compound and use thereof
N-[(4R)-1-(1-acetylpiperidine-4-carbonyl)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N,4-dimethylbenzamide	IC50	2 nM	US-8470816: Nitrogen-containing heterocyclic compound and use thereof
N-[(4R)-1-(1-acetylpiperidine-4-carbonyl)-3-(3,4-dichlorophenyl)piperidin-4-yl]-4-methoxy-N-methylbenzamide	IC50	2.3 nM	US-8470816: Nitrogen-containing heterocyclic compound and use thereof

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.64	IC50	23	nM	CHEMBL3642160
7.62	IC50	24	nM	CHEMBL3642157
7.31	IC50	49	nM	CHEMBL3642159
6.89	IC50	130	nM	CHEMBL3642158
6.80	IC50	160	nM	CHEMBL3642161
6.48	IC50	330	nM	CHEMBL3642163

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment, increases expression, affects expression	5
methylmercuric chloride	decreases expression	2
Carbamazepine	affects expression, decreases reaction, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, increases expression	1
butyraldehyde	increases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
dorsomorphin	decreases expression, increases expression, affects cotreatment	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Amphotericin B	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression	1
Cisplatin	affects expression	1
Copper	affects binding, decreases uptake	1
Cytarabine	decreases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Triclosan	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3707767	Binding	Human NK1 Receptor Binding Assay: IM-9 cells (2×10^5 cells/mL) were cultured for 3 days after inoculation, and centrifuged at 500×g for 10 min to give cell pellets. The obtained pellets were washed with PBS (Phosphate-Buffered saline) (GIBC	Nitrogen-containing heterocyclic compound and use thereof

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT01388907	PHASE4	COMPLETED	Efficacity Assessment of PREVADH® in Adhesion Prevention in Gynaecologic Surgery
NCT01430650	PHASE4	COMPLETED	Endometrial Priming for Embryo Transfer
NCT02607319	PHASE4	COMPLETED	Low Molecular Weight Heparin to Improve Pregnancy Outcome in Patients With Recurrent Implantation Failure
NCT03169166	PHASE4	COMPLETED	The Use of GnRH Agonist Trigger for Final Follicle Maturation in Women Undergoing Assisted Reproductive Technologies
NCT03177122	PHASE4	UNKNOWN	Myo-Inositol- Based Co-treatment in Women With PCOS Undergoing Assisted Reproductive Technology
NCT03477929	PHASE4	UNKNOWN	Cetrorelix and Ganirelix Flexible Protocol for (IVF)
NCT03619707	PHASE4	COMPLETED	Oral Versus Vaginal Progesterone in the Luteal Support in Cryo-warmed Embryo Transfer Cycles
NCT03846544	PHASE4	COMPLETED	Double Pick up in Poor Prognosis Women
NCT05725512	PHASE4	RECRUITING	Prednisolone Administration in Patients With Unexplained REcurrent MIscarriages
NCT06195163	PHASE4	NOT_YET_RECRUITING	TRAP Study: Testosterone for Androgen Receptor Polymorphism
NCT06763926	PHASE4	NOT_YET_RECRUITING	Intranasal Nafarelin For Triggering Oocyte Maturation
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT00749853	PHASE3	SUSPENDED	Efficacy of Ovarian Stimulation Based on FSHR Genotype Status
NCT03238092	PHASE3	UNKNOWN	Comparison Between Testosterone and Estradiol Over the Homogenization of Follicular Cohort
NCT03803228	PHASE3	COMPLETED	Dual Ovarian Stimulation (DUOSTIM) for Poor Ovarian Responders
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone