HS6ST1

Summary

HS6ST1 (heparan sulfate 6-O-sulfotransferase 1, HGNC:5201) is a protein-coding gene on chromosome 2q14.3, encoding Heparan-sulfate 6-O-sulfotransferase 1 (O60243). 6-O-sulfation enzyme which catalyzes the transfer of sulfate from 3’-phosphoadenosine 5’-phosphosulfate (PAPS) to position 6 of the N-sulfoglucosamine residue (GlcNS) of heparan sulfate. It is a selective cancer dependency (DepMap: 43.9% of cell lines).

The protein encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biological activities. This enzyme is a type II integral membrane protein and is responsible for 6-O-sulfation of heparan sulfate. This enzyme does not share significant sequence similarity with other known sulfotransferases. A pseudogene located on chromosome 1 has been found for this gene.

Source: NCBI Gene 9394 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 181 total
• Phenotypes (HPO): 80
• Cancer dependency (DepMap): dependent in 43.9% of screened cell lines
• MANE Select transcript: NM_004807

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5201
Approved symbol	HS6ST1
Name	heparan sulfate 6-O-sulfotransferase 1
Location	2q14.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000136720
Ensembl biotype	protein_coding
OMIM	604846
Entrez	9394

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000259241, ENST00000463963, ENST00000469019, ENST00000494089

RefSeq mRNA: 1 — MANE Select: NM_004807 NM_004807

CCDS: CCDS42748

Canonical transcript exons

ENST00000259241 — 2 exons

Exon	Start	End
ENSE00000925882	128318037	128318868
ENSE00001366222	128265480	128268870

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 96.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.5944 / max 382.1660, expressed in 1758 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
30593	14.5241	1756
30594	0.0703	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	96.59	gold quality
pancreatic ductal cell	CL:0002079	96.55	gold quality
ganglionic eminence	UBERON:0004023	96.24	gold quality
renal medulla	UBERON:0000362	96.12	gold quality
cortical plate	UBERON:0005343	95.84	gold quality
upper arm skin	UBERON:0004263	94.70	gold quality
ventricular zone	UBERON:0003053	94.41	gold quality
right frontal lobe	UBERON:0002810	94.31	gold quality
postcentral gyrus	UBERON:0002581	94.29	gold quality
left adrenal gland cortex	UBERON:0035825	94.29	gold quality
left adrenal gland	UBERON:0001234	94.18	gold quality
adrenal cortex	UBERON:0001235	94.08	gold quality
parietal lobe	UBERON:0001872	94.08	gold quality
right adrenal gland	UBERON:0001233	94.00	gold quality
middle temporal gyrus	UBERON:0002771	93.77	gold quality
epithelial cell of pancreas	CL:0000083	93.75	gold quality
right adrenal gland cortex	UBERON:0035827	93.62	gold quality
superior frontal gyrus	UBERON:0002661	93.55	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.37	gold quality
frontal cortex	UBERON:0001870	93.19	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.10	gold quality
neocortex	UBERON:0001950	92.96	gold quality
prefrontal cortex	UBERON:0000451	92.58	gold quality
adrenal gland	UBERON:0002369	92.55	gold quality
anterior cingulate cortex	UBERON:0009835	92.28	gold quality
cerebral cortex	UBERON:0000956	92.21	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.05	gold quality
lateral globus pallidus	UBERON:0002476	91.67	gold quality
metanephros	UBERON:0000081	91.64	gold quality
occipital lobe	UBERON:0002021	91.56	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.49
E-MTAB-9801	yes	8.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

81 targeting HS6ST1, 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-5692A	100.00	74.40	6850
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4318	99.38	66.94	1505

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 43.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• we have characterized HS6ST-2 and HS6ST-1 human isologues, including their chromosomal localizations,HS6STs could also transfer sulphate to N -sulphoglucosamine residues located at the non-reducing terminal of HS with high affinity. (PMID:12492399)
• idiopathic hypogonadotrophic hypogonadism–associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development (PMID:21700882)
• Hs6st1 and Hs2st generate conditions conducive to corpus callosum development. (PMID:24501377)
• HS6ST-1 and HS6ST-2 have roles in regulating the angiogenic program in ovarian cancer cells affecting HB-EGF signaling and subsequent expression of angiogenic cytokines by cancer cells (PMID:24563483)
• RT-PCR analysis showed that the overall transcriptional activity of the main Heparan Sulfate biosynthesis-involved genes (EXT1, EXT2, NDST1, NDST2, GLCE, HS2ST1, HS3ST1, HS3ST2, HS6ST1, HS6ST2, SULF1, SULF2, HPSE) was decreased by 1.5-2-fold in Grade II-III glioma. (PMID:29104277)
• We have linked a deleterious mutation in HS6ST1 to familial self-limited delayed puberty and show that heterozygous Hs6st1 loss causes delayed puberty in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited delayed puberty and hypogonadotropic hypogonadism was limited to this one gene. (PMID:29931354)
• HS6ST1 overexpressed in cancer-associated fibroblast and inhibited cholangiocarcinoma progression. (PMID:36586771)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	hs6st1a	ENSDARG00000054754
danio_rerio	hs6st1b	ENSDARG00000071501
mus_musculus	Hs6st1	ENSMUSG00000045216
rattus_norvegicus	Hs6st1	ENSRNOG00000014516
drosophila_melanogaster	Hs6st	FBGN0038755
caenorhabditis_elegans		WBGENE00002031

Paralogs (2): HS6ST2 (ENSG00000171004), HS6ST3 (ENSG00000185352)

Protein

Protein identifiers

Heparan-sulfate 6-O-sulfotransferase 1 — O60243 (reviewed: O60243)

All UniProt accessions (1): O60243

UniProt curated annotations — full annotation on UniProt →

Function. 6-O-sulfation enzyme which catalyzes the transfer of sulfate from 3’-phosphoadenosine 5’-phosphosulfate (PAPS) to position 6 of the N-sulfoglucosamine residue (GlcNS) of heparan sulfate. Critical for normal neuronal development where it may play a role in neuron branching. May also play a role in limb development. May prefer iduronic acid.

Subcellular location. Membrane.

Tissue specificity. Expressed in fetal brain.

Post-translational modifications. N-glycosylated.

Disease relevance. Hypogonadotropic hypogonadism 15 with or without anosmia (HH15) [MIM:614880] 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 distinct genetic loci, including the gene represented in this entry.

Similarity. Belongs to the sulfotransferase 6 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60243-1	1	yes
O60243-2	2

RefSeq proteins (1): NP_004798* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005331	Sulfotransferase	Family
IPR010635	Heparan_SO4-6-sulfoTrfase	Family
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF03567

Catalyzed reactions (Rhea), 1 shown:

• alpha-D-glucosaminyl-heparan sulfate + 3’-phosphoadenylyl sulfate = 6-sulfo-alpha-D-glucosaminyl-heparan sulfate + adenosine 3’,5’-bisphosphate + H(+) (RHEA:56604)

UniProt features (30 total): binding site 11, sequence variant 6, sequence conflict 3, topological domain 2, glycosylation site 2, splice variant 2, chain 1, transmembrane region 1, coiled-coil region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60243-F1	87.28	0.72

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): 150 (proton acceptor)

Ligand- & substrate-binding residues (11): 150; 185; 193; 197; 204; 317–319; 323–324; 93–101; 123–124; 140; 145

Glycosylation sites (2): 264, 320

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2022928	HS-GAG biosynthesis

MSigDB gene sets: 303 (showing top): GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, PEREZ_TP63_TARGETS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_NEUROGENESIS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PLACENTA_BLOOD_VESSEL_DEVELOPMENT, GOBP_EMBRYONIC_PLACENTA_DEVELOPMENT, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_LABYRINTHINE_LAYER_BLOOD_VESSEL_DEVELOPMENT, GOBP_HEPARAN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, MODULE_480, GOBP_BLOOD_VESSEL_MORPHOGENESIS

GO Biological Process (5): angiogenesis (GO:0001525), heparan sulfate proteoglycan biosynthetic process (GO:0015012), lung alveolus development (GO:0048286), neuron development (GO:0048666), labyrinthine layer blood vessel development (GO:0060716)

GO Molecular Function (4): sulfotransferase activity (GO:0008146), heparan sulfate 6-sulfotransferase activity (GO:0017095), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (4): Golgi membrane (GO:0000139), plasma membrane (GO:0005886), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Heparan sulfate/heparin (HS-GAG) metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
proteoglycan biosynthetic process	1
heparan sulfate proteoglycan metabolic process	1
protein O-linked glycosylation via xylose	1
lung development	1
anatomical structure development	1
neuron differentiation	1
cell development	1
embryonic organ development	1
placenta blood vessel development	1
labyrinthine layer development	1
transferase activity, transferring sulphur-containing groups	1
heparan sulfate sulfotransferase activity	1
binding	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
membrane	1
cell periphery	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

712 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HS6ST1	HS2ST1	Q7LGA3	996
HS6ST1	GLCE	O94923	861
HS6ST1	HS3ST1	O14792	755
HS6ST1	NDST1	P52848	750
HS6ST1	ANOS1	P23352	733
HS6ST1	NDST2	P52849	733
HS6ST1	PROKR2	Q8NFJ6	724
HS6ST1	NSMF	Q6X4W1	710
HS6ST1	IL17RD	Q8NFM7	700
HS6ST1	EXT1	Q16394	678
HS6ST1	KISS1R	Q969F8	676
HS6ST1	K7EP71	K7EP71	670
HS6ST1	TACR3	P29371	667
HS6ST1	SULF1	Q8IWU6	666
HS6ST1	SULF2	Q8IWU5	642

IntAct

49 interactions, top by confidence:

A	B	Type	Score
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
HS6ST1	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
HS6ST1	KRT31	psi-mi:“MI:0915”(physical association)	0.560
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
TAFA4	NRP1	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.530
CHRNA9	CHEK1	psi-mi:“MI:0914”(association)	0.530
INSL5	COCH	psi-mi:“MI:0914”(association)	0.530
HS6ST1	OPRM1	psi-mi:“MI:0915”(physical association)	0.370
CHRNA9	TMEM120B	psi-mi:“MI:0914”(association)	0.350
NRG1	HS6ST1	psi-mi:“MI:0914”(association)	0.350
INSL5	LAMA5	psi-mi:“MI:0914”(association)	0.350
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
CRLF2	METTL15	psi-mi:“MI:0914”(association)	0.350
TMEM106A	RTL8C	psi-mi:“MI:0914”(association)	0.350
NRSN1	FAM171A2	psi-mi:“MI:0914”(association)	0.350
TMEM59	GPR89A	psi-mi:“MI:0914”(association)	0.350
HFE	PODXL	psi-mi:“MI:0914”(association)	0.350

BioGRID (46): HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), HS6ST1 (Affinity Capture-RNA), HS6ST1 (Affinity Capture-RNA), HS6ST1 (Two-hybrid)

ESM2 similar proteins: A0A8C2LVE3, A0MGZ5, A0MGZ7, A4IID1, A5D7I4, A9X1C8, O08889, O12971, O60243, O93336, O97583, P0DJQ9, P52849, P52850, P61642, P69478, P97464, Q16394, Q56UJ5, Q5IGR7, Q5IGR8, Q5R621, Q5RBC3, Q5U4X8, Q6GQK9, Q6KFX9, Q6ZXD2, Q76KB1, Q76KB2, Q7LFX5, Q7LGA3, Q7T3S3, Q800H9, Q80UW0, Q86V40, Q8CHI9, Q8IZP7, Q8R3H7, Q91XQ5, Q91ZB4

Diamond homologs: A0MGZ5, A0MGZ7, O60243, Q56UJ5, Q76KB2, Q76LW2, Q800H9, Q80UW0, Q8IZP7, Q91ZB4, Q96MM7, Q9QYK4, Q9QYK5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	104
Likely benign	44
Benign	22

Top pathogenic / likely-pathogenic (0)

SpliceAI

726 predictions. Top by Δscore:

Variant	Effect	Δscore
2:128268867:CTTC:C	acceptor_gain	1.0000
2:128289833:A:C	acceptor_gain	1.0000
2:128268868:TTC:T	acceptor_gain	0.9900
2:128268869:TC:T	acceptor_gain	0.9900
2:128268869:TCCT:T	acceptor_loss	0.9900
2:128268870:CC:C	acceptor_gain	0.9900
2:128268870:CCTG:C	acceptor_loss	0.9900
2:128268871:C:CC	acceptor_gain	0.9900
2:128268871:C:CG	acceptor_loss	0.9900
2:128268872:T:G	acceptor_loss	0.9900
2:128289832:CA:C	acceptor_gain	0.9900
2:128289833:A:AC	acceptor_gain	0.9900
2:128318031:GCTCA:G	donor_loss	0.9800
2:128318032:CTCA:C	donor_loss	0.9800
2:128318033:TCAC:T	donor_loss	0.9800
2:128318034:CA:C	donor_loss	0.9800
2:128268874:C:CT	acceptor_gain	0.9700
2:128273651:T:TA	donor_gain	0.9700
2:128268875:A:T	acceptor_gain	0.9600
2:128275963:A:T	acceptor_gain	0.9600
2:128273610:C:A	donor_gain	0.9400
2:128268866:ACTTC:A	acceptor_gain	0.9300
2:128268867:CTTCC:C	acceptor_gain	0.9300
2:128268868:TTCCT:T	acceptor_gain	0.9300
2:128289825:A:T	acceptor_gain	0.9200
2:128268882:C:CT	acceptor_gain	0.9100
2:128289824:C:CT	acceptor_gain	0.9100
2:128289835:G:C	acceptor_gain	0.9100
2:128268162:C:CT	donor_gain	0.9000
2:128268163:T:TT	donor_gain	0.9000

AlphaMissense

2679 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:128268337:A:G	L354P	1.000
2:128268346:G:T	A351D	1.000
2:128268358:A:G	L347P	1.000
2:128268367:T:A	D344V	1.000
2:128268367:T:G	D344A	1.000
2:128268368:C:A	D344Y	1.000
2:128268368:C:G	D344H	1.000
2:128268375:G:C	N341K	1.000
2:128268375:G:T	N341K	1.000
2:128268450:G:C	F316L	1.000
2:128268450:G:T	F316L	1.000
2:128268451:A:C	F316C	1.000
2:128268451:A:G	F316S	1.000
2:128268452:A:G	F316L	1.000
2:128268462:G:C	F312L	1.000
2:128268462:G:T	F312L	1.000
2:128268463:A:C	F312C	1.000
2:128268463:A:G	F312S	1.000
2:128268464:A:C	F312V	1.000
2:128268464:A:G	F312L	1.000
2:128268469:A:G	L310P	1.000
2:128268475:A:G	F308S	1.000
2:128268486:G:C	F304L	1.000
2:128268486:G:T	F304L	1.000
2:128268487:A:C	F304C	1.000
2:128268487:A:G	F304S	1.000
2:128268488:A:G	F304L	1.000
2:128268488:A:T	F304I	1.000
2:128268490:A:G	L303P	1.000
2:128268495:C:A	Q301H	1.000

dbSNP variants (sampled 300 via entrez): RS1000022958 (2:128306489 G>A), RS1000071106 (2:128312536 G>A,T), RS1000107057 (2:128287155 G>A), RS1000144737 (2:128281288 C>T), RS1000199231 (2:128269191 C>G), RS1000205116 (2:128280680 T>C), RS1000302067 (2:128275021 GC>G), RS1000309956 (2:128311476 G>A,T), RS1000348012 (2:128265843 A>C,T), RS1000362282 (2:128306569 C>T), RS1000368915 (2:128271491 G>A), RS1000452855 (2:128281481 C>A,G), RS1000478952 (2:128285036 G>A), RS1000539593 (2:128306748 C>A), RS1000544733 (2:128285802 T>C)

Disease associations

OMIM: gene MIM:604846 | disease phenotypes: MIM:146110, MIM:614880

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism	Supportive	Autosomal dominant
Kallmann syndrome	Supportive	Autosomal dominant
hypogonadotropic hypogonadism 15 with or without anosmia	Limited	Autosomal dominant

Mondo (4): hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794), hypogonadotropic hypogonadism 15 with or without anosmia (MONDO:0013946), hypogonadotropic hypogonadism (MONDO:0018555), Kallmann syndrome (MONDO:0018800)

Orphanet (2): Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Kallmann syndrome (Orphanet:478)

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000013	Hypoplasia of the uterus
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000104	Renal agenesis
HP:0000118	Phenotypic abnormality
HP:0000134	Female hypogonadism
HP:0000144	Decreased fertility
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000316	Hypertelorism
HP:0000407	Sensorineural hearing impairment
HP:0000458	Anosmia
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000551	Color vision defect
HP:0000639	Nystagmus
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000802	Impotence
HP:0000823	Delayed puberty

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001838_11	Palmitic acid (16:0) levels	3.000000e-06
GCST003250_1	Urinary albumin-to-creatinine ratio in diabetes	6.000000e-07
GCST003875_32	Gut microbiota (bacterial taxa)	1.000000e-08
GCST003875_33	Gut microbiota (bacterial taxa)	4.000000e-09
GCST006585_1863	Blood protein levels	4.000000e-11
GCST006979_35	Heel bone mineral density	8.000000e-11
GCST012358_1	Acute lymphoblastic leukemia (adult vs childhood)	4.000000e-06
GCST90002388_293	Lymphocyte count	5.000000e-24
GCST90002389_125	Lymphocyte percentage of white cells	9.000000e-15

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007778	urinary albumin to creatinine ratio
EFO:0007874	gut microbiome measurement
EFO:0007883	taxonomic microbiome measurement
EFO:0009270	heel bone mineral density
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600
C562785	Idiopathic Hypogonadotropic Hypogonadism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Smoke	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
MT19c compound	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	decreases expression	1
Lead	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methapyrilene	increases methylation	1
Niclosamide	decreases expression	1
Progesterone	decreases expression	1
Puromycin Aminonucleoside	decreases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

84 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
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
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