NSMF

Summary

NSMF (NMDA receptor synaptonuclear signaling and neuronal migration factor, HGNC:29843) is a protein-coding gene on chromosome 9q34.3, encoding NMDA receptor synaptonuclear signaling and neuronal migration factor (Q6X4W1). Couples NMDA-sensitive glutamate receptor signaling to the nucleus and triggers long-lasting changes in the cytoarchitecture of dendrites and spine synapse processes.

The protein encoded by this gene is involved in guidance of olfactory axon projections and migration of luteinizing hormone-releasing hormone neurons. Defects in this gene are a cause of idiopathic hypogonadotropic hypogonadism (IHH). Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 26012 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 9 with or without anosmia (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 181 total — 1 likely-pathogenic
• Phenotypes (HPO): 51
• MANE Select transcript: NM_001130969

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29843
Approved symbol	NSMF
Name	NMDA receptor synaptonuclear signaling and neuronal migration factor
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000165802
Ensembl biotype	protein_coding
OMIM	608137
Entrez	26012

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 23 protein_coding, 3 retained_intron

ENST00000265663, ENST00000371468, ENST00000371472, ENST00000371473, ENST00000371474, ENST00000371475, ENST00000371482, ENST00000437259, ENST00000482448, ENST00000484316, ENST00000861166, ENST00000861167, ENST00000861168, ENST00000934992, ENST00000934993, ENST00000934994, ENST00000934995, ENST00000934996, ENST00000934998, ENST00000934999, ENST00000935000, ENST00000961353, ENST00000961354, ENST00000961355, ENST00000961356, ENST00000961357

RefSeq mRNA: 5 — MANE Select: NM_001130969 NM_001130969, NM_001130970, NM_001130971, NM_001178064, NM_015537

CCDS: CCDS48067, CCDS48068, CCDS48069, CCDS55357, CCDS7044

Canonical transcript exons

ENST00000371475 — 16 exons

Exon	Start	End
ENSE00001096666	137453056	137453180
ENSE00001320908	137449599	137449674
ENSE00001686032	137457407	137457901
ENSE00001721836	137456411	137456486
ENSE00001738815	137455239	137455307
ENSE00001783243	137458488	137458549
ENSE00002404248	137455629	137455634
ENSE00003486766	137452365	137452435
ENSE00003487537	137449923	137450025
ENSE00003489806	137453731	137453820
ENSE00003490403	137454391	137454443
ENSE00003533652	137452736	137452819
ENSE00003580386	137452553	137452586
ENSE00003612153	137450176	137450255
ENSE00003898776	137447570	137449491
ENSE00003900185	137459032	137459334

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 99.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.9856 / max 797.9299, expressed in 1795 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103378	32.0216	1791
103379	1.5420	873
103376	0.5630	295
205696	0.2995	127
103377	0.1819	69
103369	0.1274	55
103375	0.1231	38
103371	0.0557	13
103370	0.0465	6
103374	0.0141	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.09	gold quality
anterior cingulate cortex	UBERON:0009835	99.07	gold quality
cingulate cortex	UBERON:0003027	99.04	gold quality
right frontal lobe	UBERON:0002810	98.91	gold quality
amygdala	UBERON:0001876	98.89	gold quality
prefrontal cortex	UBERON:0000451	98.42	gold quality
CA1 field of hippocampus	UBERON:0003881	98.40	gold quality
ascending aorta	UBERON:0001496	98.12	gold quality
thoracic aorta	UBERON:0001515	98.11	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.04	gold quality
Ammon’s horn	UBERON:0001954	97.95	gold quality
caudate nucleus	UBERON:0001873	97.90	gold quality
descending thoracic aorta	UBERON:0002345	97.89	gold quality
nucleus accumbens	UBERON:0001882	97.79	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.52	gold quality
frontal cortex	UBERON:0001870	97.49	gold quality
frontal lobe	UBERON:0016525	97.49	gold quality
neocortex	UBERON:0001950	97.37	gold quality
adenohypophysis	UBERON:0002196	97.24	gold quality
ganglionic eminence	UBERON:0004023	97.11	gold quality
cerebral cortex	UBERON:0000956	97.09	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.07	gold quality
telencephalon	UBERON:0001893	96.91	gold quality
forebrain	UBERON:0001890	96.72	gold quality
putamen	UBERON:0001874	96.68	gold quality
temporal lobe	UBERON:0001871	96.65	gold quality
hypothalamus	UBERON:0001898	96.57	gold quality
nerve	UBERON:0001021	96.36	gold quality
tibial nerve	UBERON:0001323	96.36	gold quality
pituitary gland	UBERON:0000007	96.31	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.09

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, SP3

miRNA regulators (miRDB)

88 targeting NSMF, 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-4673	100.00	66.64	1490
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-1207-5P	99.49	69.11	2983

Literature-anchored findings (GeneRIF, showing 8)

• 12% of Kallman syndrome males have KAL1 deletions, but intragenic deletions of the FGFR1, GNRH1, GNRHR, GPR54 and NELF genes are uncommon in Idiopathic hypogonadotropic hypogonadism/Kallman syndrome. (PMID:18463157)
• our findings implicate NELF as a nuclear protein involved in the developmental function of the reproductive axis. (PMID:20025934)
• NELF is associated with normosmic idiopathic hypogonadotropic hypogonadism and Kallmann syndrome, either singly or in combination with a mutation in another gene. (PMID:21300340)
• a model in which NELF recruits Pcf11 and NCoR1-GPS2-HDAC3 to paused RNAP II, reinforcing repression of HIV transcription and establishing a critical checkpoint for HIV transcription and latency. (PMID:23884411)
• The nuclear and non-nuclear NELF variant transcripts and proteins were identified, explaining variable NELF cellular localization. (PMID:24316376)
• These findings suggest a role for NELF in the regulation of the JAK/STAT signaling pathway, which have important functions in GnRH neurons. (PMID:29050862)
• NSMF promotes the replication stress-induced DNA damage response for genome maintenance. (PMID:33963872)
• NELF and PAF1C complexes are core transcriptional machineries controlling colon cancer stemness. (PMID:38182897)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nsmfa	ENSDARG00000060025
danio_rerio	nsmfb	ENSDARG00000101234
mus_musculus	Nsmf	ENSMUSG00000006476
rattus_norvegicus	Nsmf	ENSRNOG00000008810

Protein

Protein identifiers

NMDA receptor synaptonuclear signaling and neuronal migration factor — Q6X4W1 (reviewed: Q6X4W1)

Alternative names: Nasal embryonic luteinizing hormone-releasing hormone factor

All UniProt accessions (2): A0A1B0GUJ1, Q6X4W1

UniProt curated annotations — full annotation on UniProt →

Function. Couples NMDA-sensitive glutamate receptor signaling to the nucleus and triggers long-lasting changes in the cytoarchitecture of dendrites and spine synapse processes. Part of the cAMP response element-binding protein (CREB) shut-off signaling pathway. Stimulates outgrowth of olfactory axons and migration of gonadotropin-releasing hormone (GnRH) and luteinizing-hormone-releasing hormone (LHRH) neuronal cells.

Subunit / interactions. Interacts with KPNA1; the interaction occurs in a calcium-independent manner after synaptic NMDA receptor stimulation and is required for nuclear import of NSMF but is competed by CABP1. Interacts (via the central NLS-containing motif region) with CABP1 (via EF-hands 1 and 2); the interaction occurs in a calcium-dependent manner after synaptic NMDA receptor stimulation and prevents the nuclear import of NSMF. Cannot be competed by calmodulin.

Subcellular location. Nucleus. Nucleus envelope. Nucleus membrane. Nucleus matrix. Cytoplasm. Cell cortex. Cytoskeleton. Cell membrane. Cell projection. Dendrite. Synapse. Synaptosome. Postsynaptic density. Membrane.

Tissue specificity. Highly expressed in adult and fetal brain. Weakly expressed in heart, liver, spleen, testis, small intestine, skeletal muscle, peripheral white blood cells and kidney.

Post-translational modifications. Proteolytically processed after NMDA receptor activation. Cleaved in a calcium-dependent and calpain-sensitive manner. Calpain cleavage is essential for the translocation process from dendrites to the nucleus.

Disease relevance. Hypogonadotropic hypogonadism 9 with or without anosmia (HH9) [MIM:614838] 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. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in NSMF as well as in other HH-associated genes including FGFR1.

Miscellaneous. NSMF mRNAs expressed in the hippocampus exhibit a prominent dendritic localization which is mediated by a dendritic targeting element (DTE) residing in the 3’-untranslated region (3’UTR). Transport from dendrites to the nucleus is induced by NMDA receptor activation and results in a rapid stripping of synaptic contacts and a reduction of dendritic complexity.

Similarity. Belongs to the NSMF family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q6X4W1-1	1, NELF-v1	yes
Q6X4W1-2	2, NELF-v2
Q6X4W1-3	3, NELF-v3
Q6X4W1-4	4, NELF-v4
Q6X4W1-5	5, NELF-v5
Q6X4W1-6	6

RefSeq proteins (5): NP_001124441, NP_001124442, NP_001124443, NP_001171535, NP_056352 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033374	NSMF	Family
IPR058542	IQ_SCN5A_C	Domain

Pfam: PF24609

UniProt features (25 total): splice variant 5, compositionally biased region 4, region of interest 4, modified residue 3, sequence variant 3, mutagenesis site 2, initiator methionine 1, chain 1, lipid moiety-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6X4W1-F1	65.71	0.33

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 (4): 204, 290, 292, 2

Mutagenesis-validated functional residues (2):

Position	Phenotype
247–250	localizes predominantly in the cytoplasm.
263–264	localizes both in the cytoplasm and the nucleus.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 334 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, GOBP_NEUROGENESIS, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, CACCAGC_MIR138, GOBP_CELL_CELL_SIGNALING, GOBP_CELLULAR_RESPONSE_TO_ELECTRICAL_STIMULUS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPTIC_PLASTICITY, ONKEN_UVEAL_MELANOMA_UP, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_DENDRITE_MORPHOGENESIS

GO Biological Process (8): regulation of neuron apoptotic process (GO:0043523), regulation of neuronal synaptic plasticity (GO:0048168), regulation of dendrite morphogenesis (GO:0048814), cellular response to amino acid stimulus (GO:0071230), cellular response to electrical stimulus (GO:0071257), cellular response to gonadotropin stimulus (GO:0071371), positive regulation of neuron migration (GO:2001224), regulation of neuron migration (GO:2001222)

GO Molecular Function (2): calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515)

GO Cellular Component (19): euchromatin (GO:0000791), nucleus (GO:0005634), nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), membrane (GO:0016020), nuclear matrix (GO:0016363), dendrite (GO:0030425), cortical cytoskeleton (GO:0030863), nuclear membrane (GO:0031965), neuron projection (GO:0043005), perikaryon (GO:0043204), synapse (GO:0045202), apical dendrite (GO:0097440), cytoskeleton (GO:0005856), cell cortex (GO:0005938), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
neuron migration	2
nucleus	2
nuclear lumen	2
cell periphery	2
regulation of apoptotic process	1
neuron apoptotic process	1
regulation of synaptic plasticity	1
regulation of anatomical structure morphogenesis	1
dendrite morphogenesis	1
regulation of dendrite development	1
response to amino acid	1
cellular response to acid chemical	1
response to electrical stimulus	1
cellular response to abiotic stimulus	1
cellular response to hormone stimulus	1
response to gonadotropin	1
positive regulation of cell migration	1
regulation of neuron migration	1
regulation of cell migration	1
calcium ion binding	1
protein binding	1
binding	1
chromatin	1
intracellular membrane-bounded organelle	1
endomembrane system	1
organelle envelope	1
intracellular anatomical structure	1
membrane	1
asymmetric synapse	1
postsynaptic specialization	1
neuron projection	1
dendritic tree	1
cytoskeleton	1
cell cortex	1
nuclear envelope	1
organelle membrane	1
plasma membrane bounded cell projection	1
neuronal cell body	1
cell junction	1

Protein interactions and networks

STRING

572 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NSMF	TACR3	P29371	887
NSMF	KISS1R	Q969F8	873
NSMF	PROK2	Q9HC23	868
NSMF	TAC3	Q9UHF0	853
NSMF	CHD7	Q9P2D1	847
NSMF	GNRHR	P30968	818
NSMF	FGFR1	P11362	804
NSMF	GNRH1	P01148	748
NSMF	PROKR2	Q8NFJ6	738
NSMF	ANOS1	P23352	712
NSMF	HS6ST1	O60243	710
NSMF	KISS1	Q15726	685
NSMF	FGF8	P55075	626
NSMF	IL17RD	Q8NFM7	593
NSMF	FEZF1	A0PJY2	556

IntAct

4 interactions, top by confidence:

A	B	Type	Score
NSMF	RBPJ	psi-mi:“MI:0914”(association)	0.350
VPS26C	NSMF	psi-mi:“MI:0915”(physical association)	0.000
GFI1B	NSMF	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): KCTD15 (Affinity Capture-MS), RBPJ (Affinity Capture-MS), RNF123 (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), NSMF (Two-hybrid), NSMF (Two-hybrid), NSMF (Two-hybrid), NSMF (Two-hybrid), NSMF (Two-hybrid), NSMF (Two-hybrid), NSMF (Two-hybrid), NSMF (Two-hybrid), NSMF (Two-hybrid), NSMF (Two-hybrid), NSMF (Two-hybrid)

ESM2 similar proteins: A0A0K3AXH1, A0A125YYR0, A0A7J6K9S4, B5SNZ6, B8PYG1, B9EHT4, C5E2E7, D0Z5N4, F1RD40, F4I2J8, F4IIZ9, F4J6F6, F4KFS5, F5HB62, G5EG86, O04064, O19132, O48767, O48791, O64953, P23915, P26358, P32351, P34335, P49584, Q0WUY1, Q2PAY3, Q5R4R7, Q60JJ0, Q66654, Q6NUM6, Q6X4W1, Q6XL73, Q755A9, Q75QN6, Q80TL4, Q86ME2, Q8BFX3, Q8GX05, Q8SVC0

Diamond homologs: B8PYG1, Q6X4W1, Q99NF2, Q9EPI6

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	1
Uncertain significance	85
Likely benign	52
Benign	25

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2690963	NM_001130969.3(NSMF):c.710+1G>A	Likely pathogenic

SpliceAI

2487 predictions. Top by Δscore:

Variant	Effect	Δscore
9:137449458:C:CT	acceptor_gain	1.0000
9:137449594:CTCA:C	donor_loss	1.0000
9:137449595:TCACC:T	donor_loss	1.0000
9:137449596:CACCT:C	donor_loss	1.0000
9:137449918:TGTA:T	donor_loss	1.0000
9:137449919:GTAC:G	donor_loss	1.0000
9:137449920:TACC:T	donor_loss	1.0000
9:137449922:C:CT	donor_loss	1.0000
9:137449922:CCTT:C	donor_gain	1.0000
9:137450024:AG:A	acceptor_gain	1.0000
9:137450026:C:CC	acceptor_gain	1.0000
9:137450174:A:AC	donor_gain	1.0000
9:137450175:C:CC	donor_gain	1.0000
9:137450191:T:TA	donor_gain	1.0000
9:137452431:CTCCT:C	acceptor_gain	1.0000
9:137452436:C:CC	acceptor_gain	1.0000
9:137452734:A:AC	donor_gain	1.0000
9:137452735:C:CC	donor_gain	1.0000
9:137452815:ATGAG:A	acceptor_gain	1.0000
9:137452816:TGAG:T	acceptor_gain	1.0000
9:137452817:GAG:G	acceptor_gain	1.0000
9:137452818:AG:A	acceptor_gain	1.0000
9:137452820:C:A	acceptor_loss	1.0000
9:137452820:C:CC	acceptor_gain	1.0000
9:137453050:CCTCA:C	donor_loss	1.0000
9:137453054:A:T	donor_loss	1.0000
9:137453177:CTGC:C	acceptor_gain	1.0000
9:137453178:TGC:T	acceptor_gain	1.0000
9:137453178:TGCCT:T	acceptor_loss	1.0000
9:137453180:CCT:C	acceptor_loss	1.0000

AlphaMissense

3494 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:137449444:A:G	W515R	1.000
9:137449444:A:T	W515R	1.000
9:137450215:G:T	A426D	1.000
9:137450245:C:T	G416E	1.000
9:137449599:C:A	G499W	0.999
9:137449673:A:G	L474P	0.999
9:137449930:C:T	G471E	0.999
9:137449958:C:G	G462R	0.999
9:137450021:A:G	W441R	0.999
9:137450021:A:T	W441R	0.999
9:137450202:T:A	K430N	0.999
9:137450202:T:G	K430N	0.999
9:137450203:T:A	K430I	0.999
9:137450206:G:T	A429D	0.999
9:137450226:C:A	K422N	0.999
9:137450226:C:G	K422N	0.999
9:137450227:T:A	K422M	0.999
9:137450228:T:C	K422E	0.999
9:137450230:A:G	L421P	0.999
9:137450239:A:G	L418P	0.999
9:137450246:C:G	G416R	0.999
9:137450246:C:T	G416R	0.999
9:137450251:C:T	G414D	0.999
9:137450254:C:T	G413E	0.999
9:137450255:C:G	G413R	0.999
9:137450255:C:T	G413R	0.999
9:137452368:G:C	C411W	0.999
9:137452370:A:G	C411R	0.999
9:137452378:A:G	L408P	0.999
9:137452818:A:G	L350P	0.999

dbSNP variants (sampled 300 via entrez): RS1000030352 (9:137458867 A>G), RS1000082371 (9:137458716 T>C), RS1000390302 (9:137447239 C>G,T), RS1000503412 (9:137448936 G>A), RS1000783252 (9:137455444 A>G), RS1000821471 (9:137447076 G>A), RS1001163671 (9:137447109 C>T), RS1001524970 (9:137457168 T>C), RS1001609622 (9:137456848 C>A), RS1001618777 (9:137457844 G>A,C), RS1001853864 (9:137455921 T>C,G), RS1002859158 (9:137454460 G>A,C), RS1002985939 (9:137448164 CCAGAAGCTGGGCA>C), RS1003060213 (9:137450109 G>A), RS1003498207 (9:137455264 T>G)

Disease associations

OMIM: gene MIM:608137 | disease phenotypes: MIM:614838

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 9 with or without anosmia	Strong	Autosomal dominant
hypogonadotropic hypogonadism	Supportive	Autosomal dominant

Mondo (2): hypogonadotropic hypogonadism 9 with or without anosmia (MONDO:0013911), hypogonadotropic hypogonadism (MONDO:0018555)

Orphanet (2): Kallmann syndrome (Orphanet:478), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000006	Autosomal dominant inheritance
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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	2
Valproic Acid	increases methylation, increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
diallyl trisulfide	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects methylation	1
Carcinogens	decreases expression	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Hydrogen Peroxide	increases expression	1
Plant Extracts	decreases expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	decreases expression	1
Palmitic Acid	decreases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	decreases expression, increases abundance	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