KISS1

Summary

KISS1 (KiSS-1 metastasis suppressor, HGNC:6341) is a protein-coding gene on chromosome 1q32.1, encoding Metastasis-suppressor KiSS-1 (Q15726). Kisspeptins are ligands for the G-protein coupled receptor KISS1R/GPR54.

This gene is a metastasis suppressor gene that suppresses metastases of melanomas and breast carcinomas without affecting tumorigenicity. The encoded protein may inhibit chemotaxis and invasion and thereby attenuate metastasis in malignant melanomas. Studies suggest a putative role in the regulation of events downstream of cell-matrix adhesion, perhaps involving cytoskeletal reorganization. A protein product of this gene, kisspeptin, stimulates gonadotropin-releasing hormone (GnRH)-induced gonadotropin secretion and regulates the pubertal activation of GnRH neurons. A polymorphism in the terminal exon of this mRNA results in two protein isoforms. An adenosine present at the polymorphic site represents the third position in a stop codon. When the adenosine is absent, a downstream stop codon is utilized and the encoded protein extends for an additional seven amino acid residues.

Source: NCBI Gene 3814 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 13 with or without anosmia (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 73 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 48
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_002256

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6341
Approved symbol	KISS1
Name	KiSS-1 metastasis suppressor
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170498
Ensembl biotype	protein_coding
OMIM	603286
Entrez	3814

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000367194, ENST00000882445

RefSeq mRNA: 1 — MANE Select: NM_002256 NM_002256

CCDS: CCDS41454

Canonical transcript exons

ENST00000367194 — 3 exons

Exon	Start	End
ENSE00001125940	204192774	204192914
ENSE00001443779	204190341	204190797
ENSE00001855471	204196376	204196491

Expression profiles

Bgee: expression breadth ubiquitous, 105 present calls, max score 97.14.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.1189 / max 1370.2303, expressed in 122 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16877	2.0736	113
16879	0.0256	12
16878	0.0197	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	97.14	gold quality
right lobe of liver	UBERON:0001114	68.66	gold quality
epithelium of bronchus	UBERON:0002031	66.33	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	64.35	gold quality
nucleus accumbens	UBERON:0001882	64.25	gold quality
right testis	UBERON:0004534	64.05	gold quality
left testis	UBERON:0004533	63.96	gold quality
testis	UBERON:0000473	62.69	gold quality
liver	UBERON:0002107	62.36	gold quality
pituitary gland	UBERON:0000007	62.05	gold quality
putamen	UBERON:0001874	61.31	gold quality
mucosa of transverse colon	UBERON:0004991	61.19	gold quality
vastus lateralis	UBERON:0001379	60.14	gold quality
quadriceps femoris	UBERON:0001377	60.02	gold quality
trachea	UBERON:0003126	59.07	gold quality
duodenum	UBERON:0002114	59.04	gold quality
dorsal plus ventral thalamus	UBERON:0001897	59.03	gold quality
dorsal root ganglion	UBERON:0000044	58.67	gold quality
thymus	UBERON:0002370	58.52	gold quality
adenohypophysis	UBERON:0002196	58.13	gold quality
layer of synovial tissue	UBERON:0007616	57.91	gold quality
cerebellar vermis	UBERON:0004720	57.59	gold quality
caudate nucleus	UBERON:0001873	57.36	gold quality
right hemisphere of cerebellum	UBERON:0014890	57.22	gold quality
cerebellum	UBERON:0002037	56.26	gold quality
cerebellar cortex	UBERON:0002129	56.08	gold quality
cerebellar hemisphere	UBERON:0002245	55.98	gold quality
metanephric glomerulus	UBERON:0004736	55.97	gold quality
endometrium epithelium	UBERON:0004811	54.35	gold quality
hypothalamus	UBERON:0001898	54.17	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-7407	yes	40835.07
E-ANND-5	yes	944.45
E-MTAB-8559	yes	905.08
E-ANND-3	no	1.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AR, ARNT, CASZ1, CUX1, ESR1, ESR2, IRF2BPL, MED23, NFKB1, NFKB, NFKBIA, NR5A2, RARB, RELA, SP1, SP3, STAT5B, TCF21, TCF3, TFAP2A, TFAP2B, TFF1, TP53, TTF1, USF1, YY1

miRNA regulators (miRDB)

2 targeting KISS1, 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-137-3P	99.87	74.74	2401
HSA-MIR-5572	98.55	65.84	970

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Gene has a tumor suppressor rele in bladder cancer: expression is associated with bladder cancer progression and clinical outcome (PMID:12547718)
• study provides evidence for metastin as a novel placenta-derived hormone in humans (PMID:12574233)
• The KISS1 metastasis suppressor gene inhibits metastasis in both in vivo melanoma and breast carcinoma models. (PMID:12650602)
• KiSS-1 is cleaved by matrix metalloproteinases (PMID:12879005)
• Overexpression of KiSS-1 gene was frequently observed and correlated with HCC progression; thus, the possibility that overexpressed KiSS-1 mediates growth signals into cancer cells in HCCs is suggested. (PMID:12898236)
• KiSS-1 and hOT7T175 gene expression have roles in preventing progression of lymph node metastasis in esophageal squamous cell carcinoma (PMID:14977840)
• KiSS-1 may play a crucial role in gastric cancer invasion and could be a useful target for therapeutic intervention. (PMID:15300798)
• Our investigations revealed significantly reduced mRNA expression of metastases suppressor gene KISS1 in breast cancer brain metastasis. (PMID:15592684)
• This review focuses on the role of the kisspeptin-GPR54 system in the activation of GnRH neurons at the time of pubertal awakening of the reproductive axis. (PMID:16034182)
• KISS1 is a metastasis suppressor [review] (PMID:16146758)
• AP-2alpha and Sp1 are strong transcriptional regulators of KiSS-1 (PMID:16260418)
• KiSS1 is a metastasis suppressor of ovarian cancer and may be a potential molecular target for the treatment (PMID:16283480)
• These results indicate that metastin is negatively associated with free androgen levels. (PMID:16650418)
• The peptide products of the KiSS-1 gene are the natural ligands of the G protein-coupled receptor, GPR54 and together have a role in reproduction. (PMID:16731583)
• transactivation in normal tissue is regulated by DRIP-130 (PMID:16964286)
• KISS1 is a vasoconstrictor in humans (PMID:17023533)
• Kisspeptin represents a novel tool for the manipulation of the hypothalamic-pituitary-gonadal axis in humans. (PMID:17323132)
• Kisspeptin function appears to be fundamental to the initiation of puberty. (PMID:17334929)
• kisspeptin neurons regulate estrogen negative feedback in the human (PMID:17488799)
• Expressions of Kiss-1 and KAI-1 mRNA in gastric cancer tissue were significantly lower than those in pericancerous tissue. (PMID:17520389)
• KiSS-1 and MMP-9 are closely related to the formation of portal vein tumor thrombus. KiSS-1 gene might suppress the formation of PVTT by suppressing MMP-9 synthesis. (PMID:17562263)
• Polymorphism scanning and typing of KISS1 in precocious puberty. (PMID:17609410)
• The expression of KiSS- 1 was negatively correlated with lymphatic metastasis and clinical stage, but not correlated with the cancer differentiation in gastric cardia carcinoma. (PMID:17659469)
• The metastasis suppressor gene KiSS1 is silenced in the vast majority of resected node-positive breast adenocarcinomas. (PMID:17695545)
• KiSS1 and its receptor tumoral mRNA levels could be new interesting markers of the tumoral resistance to anti-estrogen treatment. (PMID:17914099)
• The expression of both VEGF and metastin was related to colorectal carcinoma progression. (PMID:17959544)
• Kisspeptin and GPR54 immunoreactivity are significantly associated with favourable prognosis in both disease specific and overall survival. (PMID:18005407)
• We used suppression subtractive hybridization (SSH) to study molecular signature of melanoma progression, by showing characteristics of early neoplastic lesions including expression of KISS1, lack of alphavbeta3-integrin and low levels of RHOC. (PMID:18211678)
• Kisspeptin-10 injection results in peak-shaped responses for concentrations of LH and GH only in injected heifers. (PMID:18252956)
• Metastin is significantly lower in maternal plasma in the first trimester, in pregnancies with small for gestational age-neonates. (PMID:18317999)
• The propensity for systemic spread of unknown primary tumors may by due to mutations in genes other than KiSS1 or aberrant epigenetic regulation. (PMID:18351443)
• Metastin can inhibit mitrration and invasion of renal cell carcinoma cell lines. (PMID:18395325)
• Depolarizes gonadotropin-releasing hormone (GnRH)-secreting neurons through activating transient receptor potential type C-like (TRPC) channels and, to a lesser extent, inhibition of killer inhibitory receptor (Kir) channels. (PMID:18434521)
• Kiss-1 expression was downregulated in gastric cancer, compared with adjacent non-cancerous mucosa suggesting this process played a role in pathogenesis of gastric cancer (PMID:18437914)
• Herein we review the evidence which support the role of KiSS-1/GPR54 system in cancer biology. (PMID:18583061)
• Data suggest that KiSS-1 suppresses the motility and invasive ability of renal cell carcinoma cells which possess hOT7T175 with either a negative expression or very low expression level of KiSS-1 through, at least in part, the down-regulation of MMP-2. (PMID:18644390)
• The role of kisspeptins in regulating the hypothalamic-pituitary-gonodal axis is reviewed. [review] (PMID:19109311)
• Review discusses KP/GPR54 signalling as the principal trigger for activation of GnRH neurons and subsequent ovulation; modulation of this pathway could bring novel pharmacologic strategies for fertility treatment (and contraception) within reach [review] (PMID:19112386)
• conserved role of local KiSS-1 in the direct control of ovarian functions in mammals (PMID:19141682)
• Strong expression of metastin and GPR54 by pancreatic cancer is associated with longer survival (PMID:19154616)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	kiss1	ENSDARG00000075829
mus_musculus	Gm28040	ENSMUSG00000115958
mus_musculus	Kiss1	ENSMUSG00000116158
rattus_norvegicus	Kiss1	ENSRNOG00000047481

Protein

Protein identifiers

Metastasis-suppressor KiSS-1 — Q15726 (reviewed: Q15726)

Alternative names: Kisspeptin-1

All UniProt accessions (1): Q15726

UniProt curated annotations — full annotation on UniProt →

Function. Kisspeptins are ligands for the G-protein coupled receptor KISS1R/GPR54. The hypothalamic KISS1/KISS1R signaling system plays a central role in the regulation of the hypothalamic-pituitary-gonadal reproductive axis by modulating the secretion of gonadotropin-releasing hormone (GnRH) from GnRH neurons. In these neurons, kisspeptin binding to its receptor activates G(q)-dependent signaling, leading to phospholipase C (PLC) activation, and hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). The subsequent rise in intracellular calcium levels results in the inhibition of inward rectifier potassium channels and activation of TRPC-like cation channels, leading to GnRH neurons depolarization and stimulation. In addition to this pathway, kisspeptin also triggers G(q)-independent signaling via beta-arrestin, leading to MAPK cascade activation and ERK1/ERK2 phosphorylation. Kisspeptins are also involved in the regulation of other processes including cell growth, cell proliferation and cell migration. Binds the G-protein coupled receptor KISS1R/GPR54 and triggers G protein-coupled receptor signaling via activation of G(q) and phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by phospholipase C. Binding to the receptor also activates beta-arrestin-dependent signaling resulting in ERK1/2 phosphorylation. Activation of the receptor inhibits cell proliferation and cell migration, and is involved in the regulation of trophoblast invasion during early stages of pregnancy. Is also involved in the modulation of airway smooth muscle cells migration. In bone tissue, activation of KISS1R by kisspeptin-10 recruits phosphatase DUSP18 and SRC to the KISS1R C-terminus through a G(q)-dependent signaling pathway. This leads to DUSP18-mediated dephosphorylation of SRC, down-regulation of osteoclast differentiation and activity, and consequently suppression of bone resorption. Receptor binding triggers G-protein coupled receptor signaling via activation of G(q) and phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by phospholipase C.

Subcellular location. Secreted.

Tissue specificity. High expression in placenta. Expression levels increased in both early placentas and molar pregnancies and are reduced in choriocarcinoma cells. In first trimester trophoblasts is expressed at higher levels than at term of gestation, but only expressed in the villous trophoblast. Also expressed in testis, pancreas, liver, small intestine.

Post-translational modifications. Processed by MMP2 and MMP9.

Disease relevance. Hypogonadotropic hypogonadism 13 with or without anosmia (HH13) [MIM:614842] 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.

Miscellaneous. Was originally identified as a metastasis suppressor gene.

Similarity. Belongs to the KISS1 family.

RefSeq proteins (1): NP_002247* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR020207	Metastasis-suppressor_KiSS-1	Family

Pfam: PF15152

UniProt features (20 total): sequence variant 5, peptide 4, region of interest 3, compositionally biased region 2, modified residue 2, signal peptide 1, chain 1, site 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8XGS	ELECTRON MICROSCOPY	2.95
8ZJD	ELECTRON MICROSCOPY	3.06

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15726-F1	60.64	0.10

Antibody-complex structures (SAbDab): 2 — 8XGS, 8ZJD

Functional residue map

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

Catalytic / active sites (1): 118–119 (cleavage; by mmp2 and mmp9)

Post-translational modifications (2): 112, 121

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 196 (showing top): GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_TISSUE_REMODELING, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, MODULE_205, GOBP_REGULATION_OF_ENDOCRINE_PROCESS, GOBP_REGULATION_OF_BONE_REMODELING, GOBP_SECRETION, GOBP_POSITIVE_REGULATION_OF_HORMONE_SECRETION, GOBP_SIGNAL_RELEASE, GNF2_KISS1, GOBP_REGULATION_OF_SYSTEM_PROCESS, GNF2_CDKN1C

GO Biological Process (3): cytoskeleton organization (GO:0007010), G protein-coupled receptor signaling pathway (GO:0007186), positive regulation of luteinizing hormone secretion (GO:0033686)

GO Molecular Function (2): kisspeptin receptor binding (GO:0031773), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by GPCR	2
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
Signal Transduction	1
GPCR ligand binding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
organelle organization	1
G protein-coupled receptor activity	1
signal transduction	1
luteinizing hormone secretion	1
positive regulation of gonadotropin secretion	1
regulation of luteinizing hormone secretion	1
neuropeptide receptor binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2038 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KISS1	KISS1R	Q969F8	999
KISS1	GNRH1	P01148	967
KISS1	TACR3	P29371	958
KISS1	TAC3	Q9UHF0	955
KISS1	GNRHR	P30968	951
KISS1	LEP	P41159	936
KISS1	CARTPT	Q16568	864
KISS1	NPVF	Q9HCQ7	847
KISS1	PDYN	P01213	841
KISS1	GNRH2	O43555	838
KISS1	NPY	P01303	807
KISS1	FSHB	P01225	798
KISS1	PROK2	Q9HC23	776
KISS1	NPFF	O15130	768
KISS1	CHD7	Q9P2D1	732

IntAct

7 interactions, top by confidence:

A	B	Type	Score
UBQLN2	KISS1	psi-mi:“MI:0915”(physical association)	0.560
KISS1	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
KISS1	KLHL26	psi-mi:“MI:0914”(association)	0.350
KISS1	HSPA5	psi-mi:“MI:0914”(association)	0.350
KLHDC3	SMAP	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): KISS1 (Two-hybrid), UBQLN2 (Two-hybrid), KISS1 (Protein-peptide), KLHL15 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), VARS2 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), HSPA9 (Affinity Capture-MS), KLHL22 (Affinity Capture-MS), KLHL9 (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: O02686, O43555, O97655, O97686, P01142, P01143, P01297, P01351, P01352, P01353, P01354, P06296, P06850, P07492, P08949, P08989, P09683, P11384, P13083, P24393, P47851, P55089, P61312, P63152, P63153, P63298, P68248, P81264, P81277, P81278, P83859, P83860, P83862, Q08535, Q15726, Q2T9U8, Q6Y4S4, Q7TNK8, Q7TSB7, Q7Z4H4

Diamond homologs: Q15726, Q5PXH1, Q6Y4S4, Q7TSB7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
KISS1	up-regulates	KISS1R	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	37
Likely benign	13
Benign	19

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
30349	NM_002256.4(KISS1):c.339C>G (p.Asn113Lys)	Pathogenic
3381872	NM_002256.4(KISS1):c.345C>G (p.Asn115Lys)	Likely pathogenic

SpliceAI

346 predictions. Top by Δscore:

Variant	Effect	Δscore
1:204196372:CTA:C	donor_loss	1.0000
1:204196373:TAC:T	donor_loss	1.0000
1:204196374:ACCT:A	donor_loss	1.0000
1:204190798:C:CC	acceptor_gain	0.9900
1:204192769:CATA:C	donor_loss	0.9900
1:204192770:ATAC:A	donor_loss	0.9900
1:204192771:TA:T	donor_loss	0.9900
1:204192772:ACCTG:A	donor_loss	0.9900
1:204192773:C:CG	donor_loss	0.9900
1:204192915:C:CC	acceptor_gain	0.9900
1:204196375:CCTTG:C	donor_gain	0.9900
1:204196379:G:A	donor_gain	0.9900
1:204190796:GCC:G	acceptor_loss	0.9800
1:204190799:T:C	acceptor_loss	0.9800
1:204192913:GG:G	acceptor_gain	0.9800
1:204192913:GGCT:G	acceptor_gain	0.9800
1:204192914:GCTG:G	acceptor_gain	0.9800
1:204196374:A:AC	donor_gain	0.9800
1:204196375:C:CC	donor_gain	0.9800
1:204192768:ACAT:A	donor_loss	0.9700
1:204192912:AGGCT:A	acceptor_gain	0.9700
1:204192921:C:CT	acceptor_gain	0.9700
1:204196431:C:CT	donor_gain	0.9700
1:204190805:A:T	acceptor_gain	0.9600
1:204192909:TTGAG:T	acceptor_gain	0.9600
1:204192912:AGGC:A	acceptor_loss	0.9600
1:204192914:GCTGA:G	acceptor_loss	0.9600
1:204192915:CT:C	acceptor_gain	0.9600
1:204192915:CTGA:C	acceptor_loss	0.9600
1:204192916:T:G	acceptor_loss	0.9600

AlphaMissense

869 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:204190550:G:C	F117L	0.984
1:204190550:G:T	F117L	0.984
1:204190552:A:G	F117L	0.984
1:204190538:G:C	F121L	0.963
1:204190538:G:T	F121L	0.963
1:204190540:A:G	F121L	0.963
1:204190556:G:C	N115K	0.955
1:204190556:G:T	N115K	0.955
1:204190557:T:A	N115I	0.947
1:204190548:C:T	G118D	0.942
1:204190536:C:T	G122D	0.941
1:204190543:G:T	R120S	0.941
1:204190551:A:C	F117C	0.935
1:204190559:C:A	W114C	0.935
1:204190559:C:G	W114C	0.935
1:204190552:A:T	F117I	0.928
1:204190545:A:G	L119P	0.927
1:204190551:A:G	F117S	0.923
1:204190549:C:G	G118R	0.921
1:204190532:C:A	K123N	0.916
1:204190532:C:G	K123N	0.916
1:204190536:C:A	G122V	0.916
1:204190557:T:G	N115T	0.901
1:204190558:T:A	N115Y	0.893
1:204190548:C:A	G118V	0.888
1:204190558:T:C	N115D	0.887
1:204190558:T:G	N115H	0.882
1:204190552:A:C	F117V	0.877
1:204190554:G:A	S116F	0.870
1:204190555:A:G	S116P	0.870

dbSNP variants (sampled 300 via entrez): RS1000347627 (1:204189860 C>A), RS1000409804 (1:204195002 G>A), RS1000831775 (1:204194168 C>A,T), RS1000863823 (1:204194658 G>C), RS1000883887 (1:204193723 A>C), RS1001580147 (1:204195559 G>A), RS1002030814 (1:204195064 C>T), RS1002707583 (1:204190264 T>A,C), RS1002888715 (1:204190984 A>C,G), RS1003170164 (1:204190224 G>A), RS1003240500 (1:204189928 A>G), RS1003712976 (1:204191528 T>C), RS1003755926 (1:204196322 TC>T), RS1003766892 (1:204191317 C>G), RS1003872779 (1:204190836 G>A,T)

Disease associations

OMIM: gene MIM:603286 | disease phenotypes: MIM:614842

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 13 with or without anosmia	Moderate	Autosomal recessive
hypogonadotropic hypogonadism	Supportive	Autosomal dominant

Mondo (3): hypogonadotropic hypogonadism 13 with or without anosmia (MONDO:0013915), disorder of sexual differentiation (MONDO:0002145), hypogonadotropic hypogonadism (MONDO:0018555)

Orphanet (2): Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Difference of sex development (Orphanet:90771)

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: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
HP:0002761	Generalized joint hypermobility

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004678_1	Psychosis proneness (hypomanic personality scale)	3.000000e-07
GCST004679_1	Psychosis proneness (hypomanic personality scale and perceptual aberration scale)	2.000000e-06
GCST004681_1	Psychosis proneness (hypomanic personality scale and revised physical anhedonia scale)	2.000000e-06
GCST004682_1	Psychosis proneness (hypomanic personality scale and revised social anhedonia scale)	2.000000e-06
GCST008359_1	Response to cognitive-behavioural therapy in anxiety disorder	7.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008337	psychosis predisposition measurement
EFO:0007820	cognitive behavioural therapy

MeSH disease descriptors (1)

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

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
Diazinon	increases methylation, decreases methylation, increases abundance	2
aristolochic acid I	increases expression	1
bisphenol A	decreases methylation, increases abundance	1
mono-(2-ethylhexyl)phthalate	increases expression	1
potassium chromate(VI)	increases expression	1
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid	increases secretion, decreases methylation, increases abundance	1
bisphenol S	increases expression	1
2-isopropyl-6-methyl-4-pyrimidinol	decreases methylation, increases abundance	1
Sevoflurane	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	increases response to substance	1
Environmental Pollutants	decreases methylation, increases abundance, increases secretion	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	decreases expression, decreases phosphorylation, increases cleavage, increases expression, affects reaction	1
Insecticides	decreases methylation, increases abundance	1
Lipopolysaccharides	increases expression	1
Methionine	affects cotreatment, decreases expression	1
Methotrexate	decreases expression	1
Oxygen	increases expression	1
Phenols	decreases methylation, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Pyrethrins	increases secretion, decreases methylation, increases abundance	1
Testosterone	decreases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	increases methylation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_6814	C8161.9KFM	Cancer cell line	Female

Clinical trials (associated diseases)

91 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
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
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
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)
NCT01894308	PHASE2	NOT_YET_RECRUITING	A Dose Ranging Study to Examine TDS-Testosterone 5%
NCT02369796	PHASE2	TERMINATED	A Phase 2a Pharmacodynamic Study of TAK-448 in Participants With Hypogonadotropic Hypogonadism
NCT02443090	PHASE2	UNKNOWN	Safety and Efficacy Study of Oral Fispemifene for the Treatment of Sexual Dysfunction in Hypogonadal Men
NCT02651688	PHASE2	COMPLETED	A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene
NCT02730169	PHASE2	COMPLETED	Safety and Efficacy of BGS649 in Male Obese Subjects With Hypogonadotropic Hypogonadism
NCT02733133	PHASE2	NOT_YET_RECRUITING	Product Transference Study of Testagen™ TDS®-Testosterone
NCT02908074	PHASE2	COMPLETED	A 6 Month Safety Extension Study of MBGS205
NCT03245827	PHASE2	TERMINATED	Hypogonadotropic Hypogonadism in Obese Young Males
NCT04189133	PHASE2	UNKNOWN	Rec-LH PD and Safety Profile in Hypogonadotropic Hypogonadism Men