NHLH2

Summary

NHLH2 (nescient helix-loop-helix 2, HGNC:7818) is a protein-coding gene on chromosome 1p13.1, encoding Helix-loop-helix protein 2 (Q02577). Transcription factor which binds the E box motif 5’-CA[TC][AG]TG-3'.

Enables RNA polymerase II-specific DNA-binding transcription factor binding activity and sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within with a positive effect on apoptotic process; hypothalamus gonadotrophin-releasing hormone neuron development; and peripheral nervous system development. Predicted to act upstream of or within several processes, including cell migration in hindbrain; male gonad development; and male mating behavior. Predicted to be located in chromatin. Predicted to be part of transcription regulator complex. Implicated in hypogonadotropic hypogonadism.

Source: NCBI Gene 4808 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 27 without anosmia (Limited, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 16 total
• Phenotypes (HPO): 45
• MANE Select transcript: NM_005599

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7818
Approved symbol	NHLH2
Name	nescient helix-loop-helix 2
Location	1p13.1
Locus type	gene with protein product
Status	Approved
Aliases	NSCL2, bHLHa34
Ensembl gene	ENSG00000177551
Ensembl biotype	protein_coding
OMIM	162361
Entrez	4808

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000320238, ENST00000369506, ENST00000429731, ENST00000901303, ENST00000934375

RefSeq mRNA: 2 — MANE Select: NM_005599 NM_001111061, NM_005599

CCDS: CCDS885

Canonical transcript exons

ENST00000320238 — 3 exons

Exon	Start	End
ENSE00001260887	115836377	115838380
ENSE00001404142	115840948	115841126
ENSE00001405283	115840216	115840544

Expression profiles

Bgee: expression breadth ubiquitous, 116 present calls, max score 82.91.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6172 / max 181.2879, expressed in 153 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13995	0.5380	141
13992	0.0350	18
13994	0.0277	3
13993	0.0165	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	82.91	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	79.85	gold quality
superior vestibular nucleus	UBERON:0007227	79.39	gold quality
CA1 field of hippocampus	UBERON:0003881	78.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.51	gold quality
cortical plate	UBERON:0005343	76.13	gold quality
hypothalamus	UBERON:0001898	75.46	gold quality
cerebellar vermis	UBERON:0004720	74.79	gold quality
cerebellum	UBERON:0002037	74.64	gold quality
cerebellar cortex	UBERON:0002129	74.28	gold quality
cerebellar hemisphere	UBERON:0002245	74.24	gold quality
right hemisphere of cerebellum	UBERON:0014890	73.50	gold quality
Brodmann (1909) area 23	UBERON:0013554	73.13	gold quality
esophagus squamous epithelium	UBERON:0006920	72.85	gold quality
medulla oblongata	UBERON:0001896	72.66	gold quality
paraflocculus	UBERON:0005351	71.66	gold quality
tongue squamous epithelium	UBERON:0006919	71.13	silver quality
lateral nuclear group of thalamus	UBERON:0002736	71.12	gold quality
cranial nerve II	UBERON:0000941	70.18	gold quality
inferior olivary complex	UBERON:0002127	70.17	gold quality
pons	UBERON:0000988	69.89	silver quality
epithelium of esophagus	UBERON:0001976	69.43	gold quality
substantia nigra	UBERON:0002038	69.34	gold quality
upper leg skin	UBERON:0004262	69.15	gold quality
midbrain	UBERON:0001891	69.13	gold quality
squamous epithelium	UBERON:0006914	69.07	gold quality
primary visual cortex	UBERON:0002436	69.04	gold quality
ventral tegmental area	UBERON:0002691	68.82	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	67.94	gold quality
skin of hip	UBERON:0001554	67.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	16.52
E-ANND-3	yes	3.41

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
ASCL1	Activation
HES1	Repression
LEP
MAOA	Activation
MC4R
NDN	Activation

JASPAR motifs

Motif	Name	Family
MA1529.1	NHLH2	Tal-related
MA1529.2	NHLH2	Tal-related

JASPAR matrix evidence (PMIDs): PMID:23354101

Upstream regulators (CollecTRI, top): ATOH7, TP53

miRNA regulators (miRDB)

177 targeting NHLH2, 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-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-27A-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 9)

• The deregulated expression of neuronal-specific LMO3 and HEN2 contributes to the genesis and progression of human neuroblastoma in a lineage-specific manner. (PMID:15930276)
• proposes the novel hypothesis that transcriptional activity by Nhlh2 (NHLH2 in humans) controls either the ability or the motivation for exercise [review] (PMID:18815487)
• The present results suggest that a transcriptional complex of LMO3 and HEN2 may contribute to the genesis and malignant phenotype of neuroblastoma by inhibiting HES1 which suppresses the transactivation of Mash1. (PMID:21573214)
• Two single nucleotide polymorphisms in the human nescient helix-loop-helix 2 (NHLH2) gene reduce mRNA stability or reduce helical structure in the DNA binding domain of the protein. (PMID:23026212)
• Leptin signaling regulates hypothalamic expression of Nhlh2 through Stat3. (PMID:24486192)
• These data support part of our hypothesis that NHLH2 or MAO-A polymorphism is associated with sedentary behavior. (PMID:26196864)
• Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder. (PMID:32877896)
• Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans. (PMID:35066646)
• In Silico Examination of Single Nucleotide Missense Mutations in NHLH2, a Gene Linked to Infertility and Obesity. (PMID:36834605)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nhlh2	ENSMUSG00000048540
rattus_norvegicus	Nhlh2	ENSRNOG00000054375

Paralogs (4): LYL1 (ENSG00000104903), TAL1 (ENSG00000162367), NHLH1 (ENSG00000171786), TAL2 (ENSG00000186051)

Protein

Protein identifiers

Helix-loop-helix protein 2 — Q02577 (reviewed: Q02577)

Alternative names: Class A basic helix-loop-helix protein 34, Nescient helix loop helix 2

All UniProt accessions (2): A6PVY9, Q02577

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor which binds the E box motif 5’-CA[TC][AG]TG-3’. Involved in regulating energy expenditure, body mass, voluntary physical activity, mating behavior and reproductive longevity, acting through the hypothalamic-pituitary-gonadal axis. Acts as a transcriptional activator of target genes, including NDN, PCSK1, MC4R. Is also a transcriptional activator of KISS1. May act centrally to regulate function of both white and brown adipose tissue. Together with NHLH1, required to maintain migration and survival of cells in the anterior extramural migration stream (aes), which forms the precerebellar nuclei. Also, in concert with NHLH1, may determine fate of gonadotropin releasing hormone-1 (GnRH-1) neurons.

Subunit / interactions. Homodimer. Interacts and may form heterodimers with STAT3.

Subcellular location. Nucleus.

Disease relevance. Hypogonadotropic hypogonadism 27 without anosmia (HH27) [MIM:619755] A form of hypogonadotropic hypogonadism, a group of disorders 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. 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). HH27 is an autosomal recessive normosmic form characterized by lack of pubertal development associated with onset of obesity in early adolescence. The disease may be caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_001104531, NP_005590* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR040238	TAL-like	Family

Pfam: PF00010

UniProt features (8 total): sequence variant 3, compositionally biased region 2, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02577-F1	77.76	0.56

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 320 (showing top): GOBP_FOREBRAIN_NEURON_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_BEHAVIOR, NKX25_02, TGCACTT_MIR519C_MIR519B_MIR519A, GCANCTGNY_MYOD_Q6, TTTGTAG_MIR520D, TATTATA_MIR374, GOBP_NEUROGENESIS, TAL1ALPHAE47_01, CAGCTG_AP4_Q5, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_FOREBRAIN_GENERATION_OF_NEURONS, NKX61_01, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN

GO Biological Process (11): regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), central nervous system development (GO:0007417), peripheral nervous system development (GO:0007422), male gonad development (GO:0008584), cell migration in hindbrain (GO:0021535), hypothalamus gonadotrophin-releasing hormone neuron development (GO:0021888), ovulation cycle (GO:0042698), positive regulation of transcription by RNA polymerase II (GO:0045944), male mating behavior (GO:0060179), cell differentiation (GO:0030154)

GO Molecular Function (10): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), protein dimerization activity (GO:0046983), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
nervous system development	2
system development	2
regulation of transcription by RNA polymerase II	2
regulation of DNA-templated transcription	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
gonad development	1
development of primary male sexual characteristics	1
cell migration	1
hindbrain development	1
forebrain neuron development	1
hypothalamus gonadotrophin-releasing hormone neuron differentiation	1
rhythmic process	1
multicellular organismal reproductive process	1
positive regulation of DNA-templated transcription	1
mating behavior	1
cellular developmental process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription coregulator binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
protein binding	1
DNA-binding transcription factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
transcription cis-regulatory region binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
protein-containing complex	1

Protein interactions and networks

STRING

966 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHLH2	BEX2	Q9BXY8	834
NHLH2	BEX1	Q9HBH7	833
NHLH2	LDB2	O43679	766
NHLH2	LDB1	Q86U70	764
NHLH2	LMO2	P25791	745
NHLH2	MC4R	P32245	615
NHLH2	PCSK1	P29120	566
NHLH2	KDM5A	P29375	452
NHLH2	OTP	Q5XKR4	446
NHLH2	NDN	Q99608	444
NHLH2	POMC	P01189	420
NHLH2	NEUROD2	Q15784	417
NHLH2	SNRPN	P14648	402
NHLH2	Q05D86	Q05D86	402
NHLH2	DLK1	P15803	400

IntAct

23 interactions, top by confidence:

A	B	Type	Score
MYF5	NHLH2	psi-mi:“MI:0915”(physical association)	0.560
TCF4	NHLH2	psi-mi:“MI:0915”(physical association)	0.560
NHLH2	TAF1D	psi-mi:“MI:0915”(physical association)	0.560
NHLH2	TCF12	psi-mi:“MI:0915”(physical association)	0.560
NHLH2	KCNIP1	psi-mi:“MI:0915”(physical association)	0.560
NHLH2	AP3B1	psi-mi:“MI:0914”(association)	0.530
SIRT1	NHLH2	psi-mi:“MI:0915”(physical association)	0.400
NHLH2	SIRT1	psi-mi:“MI:0915”(physical association)	0.400
CCL1	NHLH2	psi-mi:“MI:0915”(physical association)	0.370
CFTR	NHLH2	psi-mi:“MI:0915”(physical association)	0.370
NHLH2	MYF5	psi-mi:“MI:0915”(physical association)	0.000
NHLH2	TCF12	psi-mi:“MI:0915”(physical association)	0.000
NHLH2	KCNIP1	psi-mi:“MI:0915”(physical association)	0.000
NHLH2	TCF4	psi-mi:“MI:0915”(physical association)	0.000
NHLH2	TAF1D	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): HES1 (Affinity Capture-Western), HES1 (Reconstituted Complex), NHLH2 (Reconstituted Complex), LMO3 (Phenotypic Suppression), NHLH2 (Phenotypic Suppression), NHLH2 (Two-hybrid), NHLH2 (Two-hybrid), NHLH2 (Two-hybrid), KCNIP1 (Two-hybrid), TCF4 (Two-hybrid), TRPM3 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), TCF12 (Affinity Capture-MS), GTF3C1 (Affinity Capture-MS), GTF3C2 (Affinity Capture-MS)

ESM2 similar proteins: A8E5T6, O13125, O13126, O35437, O43680, O57598, O60682, O73615, O88940, P12979, P13903, P15173, P15375, P19335, P23409, P34060, P41133, P41138, P49812, P59101, P70562, P70661, P79782, P97831, Q01795, Q02535, Q02576, Q02577, Q16559, Q20561, Q32PV5, Q3YFL6, Q5E981, Q5E9S3, Q62282, Q6GNB7, Q6VNZ9, Q712G9, Q7YS80, Q8AW52

Diamond homologs: A8E5T6, B6VQA1, O13125, O13126, O16867, O35437, O42202, O42606, O43680, O57598, O60682, O73615, O73823, O88940, O93507, O96004, O96642, P13903, P17542, P22091, P24899, P26687, P46581, P48985, P48987, P57100, P57101, P57102, P59101, P61295, P61296, P70661, P79765, P79782, P97831, P97832, Q02575, Q02576, Q02577, Q0VCE2

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
NHLH2	“up-regulates quantity by expression”	ASCL1	“transcriptional regulation”
LMO3	“up-regulates activity”	NHLH2	binding
NHLH2	“down-regulates quantity by repression”	HES1	“transcriptional regulation”
NHLH2	“up-regulates quantity by expression”	MAOA	“transcriptional regulation”
SIRT1	“up-regulates activity”	NHLH2	deacetylation
HNRNPU	“up-regulates quantity by stabilization”	NHLH2	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

314 predictions. Top by Δscore:

Variant	Effect	Δscore
1:115840543:CT:C	acceptor_gain	0.9900
1:115840545:C:CC	acceptor_gain	0.9800
1:115840210:TCTTA:T	donor_loss	0.9700
1:115840211:CTTA:C	donor_loss	0.9700
1:115840212:TTA:T	donor_loss	0.9700
1:115840213:TACCT:T	donor_loss	0.9700
1:115840292:G:T	acceptor_gain	0.9700
1:115840543:CTCTA:C	acceptor_loss	0.9600
1:115840546:T:A	acceptor_loss	0.9600
1:115839457:A:C	donor_gain	0.9500
1:115840214:A:AC	donor_gain	0.9500
1:115840215:C:CC	donor_gain	0.9500
1:115840291:C:CT	acceptor_gain	0.9500
1:115840942:CTTTA:C	donor_loss	0.9500
1:115840943:TTTA:T	donor_loss	0.9500
1:115840944:TTAC:T	donor_loss	0.9500
1:115840945:TACC:T	donor_loss	0.9500
1:115840948:C:G	donor_loss	0.9500
1:115839564:T:TA	donor_gain	0.9400
1:115838394:G:T	acceptor_gain	0.9300
1:115839751:C:CC	acceptor_gain	0.9300
1:115838381:C:CC	acceptor_gain	0.9200
1:115839746:TGCTT:T	acceptor_gain	0.9100
1:115839748:CTT:C	acceptor_gain	0.9100
1:115840215:CCTTG:C	donor_gain	0.9100
1:115840448:T:TA	donor_gain	0.9100
1:115840540:GGTCT:G	acceptor_gain	0.9100
1:115838393:C:CT	acceptor_gain	0.9000
1:115840291:C:T	acceptor_gain	0.9000
1:115840319:A:AC	donor_gain	0.8900

AlphaMissense

864 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:115837975:A:G	L133P	1.000
1:115837987:A:G	L129P	1.000
1:115837987:A:T	L129H	1.000
1:115837996:A:T	I126N	1.000
1:115838008:G:T	A122D	1.000
1:115838009:C:G	A122P	1.000
1:115838011:A:G	L121P	1.000
1:115838017:A:G	L119P	1.000
1:115838017:A:T	L119Q	1.000
1:115838028:C:A	K115N	1.000
1:115838028:C:G	K115N	1.000
1:115838029:T:A	K115M	1.000
1:115838030:T:C	K115E	1.000
1:115838059:G:C	P105R	1.000
1:115838059:G:T	P105H	1.000
1:115838060:G:A	P105S	1.000
1:115838060:G:T	P105T	1.000
1:115838071:C:G	R101P	1.000
1:115838074:A:G	L100P	1.000
1:115838074:A:T	L100H	1.000
1:115838082:G:C	F97L	1.000
1:115838082:G:T	F97L	1.000
1:115838083:A:G	F97S	1.000
1:115838084:A:G	F97L	1.000
1:115838094:G:C	F93L	1.000
1:115838094:G:T	F93L	1.000
1:115838096:A:G	F93L	1.000
1:115838099:C:G	A92P	1.000
1:115838108:G:A	R89C	1.000
1:115838108:G:C	R89G	1.000

dbSNP variants (sampled 300 via entrez): RS1000208582 (1:115841178 AT>A,ATT), RS1000289206 (1:115835611 T>C), RS1000326314 (1:115839313 T>G), RS1000380081 (1:115842164 A>C), RS1000535764 (1:115835800 G>GT), RS1000886481 (1:115837079 T>C,G), RS1000926420 (1:115836820 T>C), RS1001020467 (1:115842544 G>C), RS1001132470 (1:115840603 C>G), RS1001864170 (1:115835118 G>A), RS1002124959 (1:115836027 C>T), RS1002131686 (1:115842158 A>C,G), RS1002162743 (1:115842457 C>A), RS1002231598 (1:115841886 A>G), RS1002335114 (1:115841031 T>C)

Disease associations

OMIM: gene MIM:162361 | disease phenotypes: MIM:147950, MIM:619755

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 27 without anosmia	Limited	Unknown

Mondo (2): hypogonadotropic hypogonadism (MONDO:0018555), hypogonadotropic hypogonadism 27 without anosmia (MONDO:0030684)

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

HPO phenotypes

45 total (30 of 45 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:0000802	Impotence
HP:0000823	Delayed puberty
HP:0000869	Secondary amenorrhea
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001513	Obesity
HP:0001608	Abnormality of the voice
HP:0002231	Sparse body hair
HP:0002750	Delayed skeletal maturation
HP:0002761	Generalized joint hypermobility
HP:0003187	Breast hypoplasia
HP:0003621	Juvenile onset

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004714_2	Heart rate variability traits (SDNN)	6.000000e-07
GCST009391_1442	Metabolite levels	3.000000e-06
GCST009391_1452	Metabolite levels	5.000000e-06
GCST009391_1467	Metabolite levels	9.000000e-06
GCST009391_1844	Metabolite levels	3.000000e-06
GCST009391_1855	Metabolite levels	3.000000e-06
GCST009391_934	Metabolite levels	7.000000e-06
GCST011010_54	Electrocardiographic traits (multivariate)	8.000000e-07

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0008003	heart rate variability measurement
EFO:0010409	triacylglycerol 50:2 measurement
EFO:0010405	triacylglycerol 48:2 measurement
EFO:0010406	triacylglycerol 48:3 measurement
EFO:0010413	triacylglycerol 52:1 measurement
EFO:0010410	triacylglycerol 50:3 measurement
EFO:0010401	triacylglycerol 46:1 measurement
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression, affects cotreatment	4
Valproic Acid	decreases expression, affects expression	3
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Lipopolysaccharides	increases expression, affects response to substance	1
Nickel	decreases expression	1
Silicon Dioxide	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	decreases methylation	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

79 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