HCRT

Summary

HCRT (hypocretin neuropeptide precursor, HGNC:4847) is a protein-coding gene on chromosome 17q21.2, encoding Hypocretin neuropeptide precursor (O43612). Neuropeptides that play a significant role in the regulation of food intake and sleep-wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions.

This gene encodes a hypothalamic neuropeptide precursor protein that gives rise to two mature neuropeptides, orexin A and orexin B, by proteolytic processing. Orexin A and orexin B, which bind to orphan G-protein coupled receptors HCRTR1 and HCRTR2, function in the regulation of sleep and arousal. This neuropeptide arrangement may also play a role in feeding behavior, metabolism, and homeostasis.

Source: NCBI Gene 3060 — RefSeq curated summary.

At a glance

• Gene–disease (curated): narcolepsy 1 (Limited, GenCC)
• Clinical variants (ClinVar): 27 total — 1 pathogenic
• Phenotypes (HPO): 101
• MANE Select transcript: NM_001524

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4847
Approved symbol	HCRT
Name	hypocretin neuropeptide precursor
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	PPOX, OX
Ensembl gene	ENSG00000161610
Ensembl biotype	protein_coding
OMIM	602358
Entrez	3060

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000293330

RefSeq mRNA: 1 — MANE Select: NM_001524 NM_001524

CCDS: CCDS11421

Canonical transcript exons

ENST00000293330 — 2 exons

Exon	Start	End
ENSE00001059071	42185345	42185452
ENSE00001059073	42184060	42184528

Expression profiles

Bgee: expression breadth broad, 90 present calls, max score 80.57.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hypothalamus	UBERON:0001898	80.57	gold quality
pancreatic ductal cell	CL:0002079	75.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	60.41	gold quality
granulocyte	CL:0000094	59.34	gold quality
tibialis anterior	UBERON:0001385	56.60	silver quality
decidua	UBERON:0002450	56.55	gold quality
skin of hip	UBERON:0001554	54.48	silver quality
epithelial cell of pancreas	CL:0000083	53.95	silver quality
ileal mucosa	UBERON:0000331	53.72	silver quality
hair follicle	UBERON:0002073	52.43	gold quality
deltoid	UBERON:0001476	52.28	silver quality
thymus	UBERON:0002370	51.32	gold quality
tendon of biceps brachii	UBERON:0008188	51.17	gold quality
quadriceps femoris	UBERON:0001377	50.62	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
metanephric glomerulus	UBERON:0004736	49.61	gold quality
vastus lateralis	UBERON:0001379	49.45	gold quality
nucleus accumbens	UBERON:0001882	49.38	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
putamen	UBERON:0001874	48.87	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8894	yes	1679.74
E-GEOD-93593	yes	6.66
E-ANND-3	no	0.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPB, NFKB, NR6A1, PAX8, TFAP2A, TTF1

Literature-anchored findings (GeneRIF, showing 40)

• The human prepro-orexin gene regulatory region that activates gene expression in the lateral region and represses it in the medial regions of the hypothalamus. (PMID:11854267)
• reduced ACTH secretion and the diminished secretory process regularity of the ACTH/cortisol ensemble conjointly suggest that hypocretin deficiency induces changes in the interplay between pituitary-adrenal hormones in narcolepsy (PMID:12414876)
• plasma concentrations of orexin-A-like immunoreactivity (orexin-A-LI) in 156 patients with sleep apnea hypopnea syndrome were significantly decreased. (PMID:12732338)
• results are consistent with previous physiologic findings in depressed patients indicating dampened diurnal variations in hypocretin-1; results also indicate a serotonergic influence on hypocretin levels in CSF (PMID:12873798)
• Prepro-OR was expressed only in the epididymis and penis. (PMID:15070969)
• Decrease in the number of hypocretin neurons does not play a major role in the occurrence of narcolepsy-like symptoms in Prader-Willi syndrome. (PMID:15985489)
• The plasma orexin-A levels in obstructive sleep apnea-hypopnea syndrome patients are elevated. (PMID:16008971)
• orexin A, NPY, leptin play an important role in the regulation of energy metabolism in humans; in obesity the activity of these peptides is disturbed (PMID:16135994)
• Hypocretin enhanced cyclic-AMP production from cultured adrenal cortex cells, and did not alter inositol-3-phosphate release. (PMID:16157481)
• orexin-A is produced by the renal tubular cells and secreted into urine and may act on the kidney in the autocrine or paracrine fashion, or via the urine (urocrine fashion). (PMID:16202475)
• Point mutations in the prion protein, period 2, and the prepro-hypocretin/orexin gene have been found as the cause of a few sleep disorders. (PMID:16338760)
• Orexin-A had a compact conformation in the N-terminal half region, which contained a short helix and was fixed by the two disulfide bonds, and a helix-turn-helix conformation in the remaining C-terminal half region. (PMID:16429482)
• the genes (hypocretin/orexin ligand and its receptor) involved in the pathogenesis of narcolepsy have been identified–REVIEW (PMID:17376528)
• This result supports existing evidence which indicates that mutations of the prepro-orexin gene are rare and that the genetic contribution to the aetiology of human narcolepsy is likely to be complex. (PMID:17576097)
• orexin-A/hypocretin-1 may therefore play an important role in the various physiological responses including sleep, feeding, and the overall metabolism in intracerebral hemorrhage patients (PMID:17868933)
• Orexin stimulates HIF-1 activity. (PMID:18006690)
• Orexin effects on StAR were primarily, but not exclusively, acting through the orexin receptor type 1. (PMID:18450961)
• We found a specific reduction in hypocretin signaling in patients with HD as MCH cell number was not significantly affected. It remains to be shown whether the moderate decrease in hypocretin neurotransmission could contribute to clinical symptoms. (PMID:18498421)
• the hypocretin system is intact and sleepiness is not typical in relapsing remitting multiple sclerosis and optic neuritis without hypothalamic lesions on MRI (PMID:18505777)
• IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence (PMID:19158946)
• Hypocretin modulates the median eminence-projecting proopiomelanocortin neurons identified by selective green fluorescent protein expression and antidromic stimulation or retrograde dye tracing in transgenic mice. (PMID:19193897)
• These results confirm previous studies demonstrating lower levels of plasma orexin-A in obstructive sleep apnoea patients and indicate that smoking may affect orexin-A levels and apnoea-hypopnoea index. (PMID:19383226)
• Multiple roles for orexin-mediated MAPK activation in adrenal cell-line. This complexity may help explain diverse biological actions of orexins with wide-ranging consequences for our understanding of mechanisms initiated by these steroidogenic molecules. (PMID:19460850)
• Findings in this review suggest that the orexin system interacts with systems that regulate emotion, reward, and energy homeostasis to maintain proper vigilance states. (PMID:19549926)
• Extensive loss of hypothalamic neurons that produce wake-promoting neuropeptide hypocretin (orexin) causes severe sleepiness of narcolepsy, and partial loss of these cells may contribute to the sleepiness of Parkinson’s and other disorders. (PMID:19847903)
• Results suggest that it is unlikely that hypocretin-1 is involved in the degenerative process of ALS. (PMID:19922146)
• hPPO-overexpressing mice show small reduction in REM sleep, in addition to differences in vigilance state amounts in the light/dark transition periods, but overall the sleep-wake patterns of hPPO-overexpressing mice do not significantly differ. (PMID:20003098)
• Posttraumatic stress disorder patients had significantly lower CSF and plasma orexin-A concentrations than those in healthy controls. The CSF orexin-A concentrations were strongly negatively correlated with the severity of posttraumatic stress disorder. (PMID:20116928)
• Rapid eye movement sleep behavior disorder coexists with cataplexy in narcolepsy due to hypocretin deficiency. (PMID:20129934)
• A positive correlation between hypocretin-1 level and fatigue may indicate involvement of some compensatory mechanisms stimulating the production of the neuropeptide in MS patients. (PMID:20193740)
• Individual neuroluminescence signals produced by transgenic HCRT neurons fall into two distinct amplitude categories easily classified into large or small signals differing from the continuous distribution of green fluorescent protein neuroluminescence. (PMID:20305645)
• These results suggest the involvement of hypocretin in sleep disorders in dementia with Lewy bodies. (PMID:20531237)
• The orexin peptides may differentially affect arousal in the two stocks tested; orexin-A causes a stock dependant increase whereas orexin-B does not affect either. (PMID:20595012)
• In the present study, for the first time hcrt-1 levels in manic patients were investigated but did not reveal significant differences neither compared to age-matched patients with MDD nor healthy controls without any psychiatric or neurological disorder. (PMID:20655364)
• Data indicate that the hypocretin deficit in drug-free narcolepsy patients and their altered wake-sleep cycle couple with an intact modulation of body core temperature. (PMID:20854137)
• These experiments confirmed that NR6A1 works as a regulator for hypocretin transcription. (PMID:21056546)
• both OXA and OXR2 may be involved in the pathogenesis and/or maintenance of BPH. (PMID:21186399)
• Our results suggest that the prepro-orexin gene polymorphism g1182C>T is associated with susceptibility to OSAHS in Han Chinese. (PMID:21371780)
• Mutations of orexin are not usually involved in the etiology of autosomal dominant nocturnal frontal lobe epilepsy. (PMID:21464433)
• We conclude that the hypocretin system is affected in advanced AD (PMID:21546124)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hcrt	ENSDARG00000070932
mus_musculus	Hcrt	ENSMUSG00000045471
rattus_norvegicus	Hcrt	ENSRNOG00000018892

Protein

Protein identifiers

Hypocretin neuropeptide precursor — O43612 (reviewed: O43612)

Alternative names: Hypocretin, Orexin precursor, Prepro-orexin, Preprohypocretin

All UniProt accessions (1): O43612

UniProt curated annotations — full annotation on UniProt →

Function. Neuropeptides that play a significant role in the regulation of food intake and sleep-wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. A broader role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids, is also suggested. Binds to orexin receptors HCRTR1/OX1R and HCRTR2/OX2R with a high affinity. Stimulates food intake. Modulates pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner. Binds to orexin receptor HCRTR2/OX2R only. Stimulates food intake. Modulates pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner.

Subcellular location. Rough endoplasmic reticulum. Cytoplasmic vesicle. Synapse.

Tissue specificity. Abundantly expressed in subthalamic nucleus but undetectable in other brain regions tested (hypothalamus was not tested) and in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. Specific enzymatic cleavages at paired basic residues yield the different active peptides.

Disease relevance. Narcolepsy 1 (NRCLP1) [MIM:161400] Neurological disabling sleep disorder, characterized by excessive daytime sleepiness, sleep fragmentation, symptoms of abnormal rapid-eye-movement (REM) sleep, cataplexy, hypnagogic hallucinations, and sleep paralysis. Cataplexy is a sudden loss of muscle tone triggered by emotions, which is the most valuable clinical feature used to diagnose narcolepsy. Human narcolepsy is primarily a sporadically occurring disorder but familial clustering has been observed. The disease is caused by variants affecting the gene represented in this entry. Human narcolepsy is associated with a deficient orexin system. Orexins are absent and/or greatly diminished in the brain and cerebrospinal fluid (CSF) of most narcoleptic patients.

Similarity. Belongs to the orexin family.

RefSeq proteins (1): NP_001515* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001704	Orexin	Family

Pfam: PF02072

UniProt features (17 total): helix 4, modified residue 3, peptide 2, turn 2, disulfide bond 2, signal peptide 1, strand 1, propeptide 1, sequence variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
1UVQ	X-RAY DIFFRACTION	1.8
7L1U	ELECTRON MICROSCOPY	3.2
1CQ0	SOLUTION NMR
1R02	SOLUTION NMR
1WSO	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43612-F1	61.41	0.00

Antibody-complex structures (SAbDab): 1 — 7L1U

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 (3): 34, 66, 97

Disulfide bonds (2): 39–45, 40–47

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-389397	Orexin and neuropeptides FF and QRFP bind to their respective receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 220 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_ETHANOL, MORF_FLT1, MODULE_274, GOBP_BEHAVIOR, MORF_MSH3, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GOBP_ADULT_BEHAVIOR, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_PROCESS, GOBP_NEUROTRANSMITTER_TRANSPORT, CHX10_01, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING

GO Biological Process (21): temperature homeostasis (GO:0001659), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), positive regulation of cytosolic calcium ion concentration (GO:0007204), neuropeptide signaling pathway (GO:0007218), chemical synaptic transmission (GO:0007268), negative regulation of DNA replication (GO:0008156), sleep (GO:0030431), response to starvation (GO:0042594), eating behavior (GO:0042755), drinking behavior (GO:0042756), negative regulation of potassium ion transport (GO:0043267), regulation of neurotransmitter secretion (GO:0046928), behavioral response to ethanol (GO:0048149), positive regulation of calcium ion transport (GO:0051928), negative regulation of transmission of nerve impulse (GO:0051970), positive regulation of transmission of nerve impulse (GO:0051971), excitatory postsynaptic potential (GO:0060079), positive regulation of cold-induced thermogenesis (GO:0120162), response to peptide (GO:1901652), feeding behavior (GO:0007631), response to alcohol (GO:0097305)

GO Molecular Function (3): neuropeptide hormone activity (GO:0005184), type 1 orexin receptor binding (GO:0031771), type 2 orexin receptor binding (GO:0031772)

GO Cellular Component (10): extracellular region (GO:0005576), rough endoplasmic reticulum (GO:0005791), synaptic vesicle (GO:0008021), perinuclear region of cytoplasm (GO:0048471), postsynapse (GO:0098794), neuronal dense core vesicle lumen (GO:0099013), endoplasmic reticulum (GO:0005783), secretory granule (GO:0030141), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
G protein-coupled receptor signaling pathway	2
feeding behavior	2
transmission of nerve impulse	2
regulation of transmission of nerve impulse	2
orexin receptor binding	2
endomembrane system	2
multicellular organismal-level homeostasis	1
phospholipase C activator activity	1
regulation of biological quality	1
anterograde trans-synaptic signaling	1
DNA replication	1
regulation of DNA replication	1
negative regulation of DNA metabolic process	1
multicellular organismal process	1
response to stress	1
response to nutrient levels	1
potassium ion transport	1
regulation of potassium ion transport	1
negative regulation of monoatomic ion transport	1
neurotransmitter secretion	1
modulation of chemical synaptic transmission	1
regulation of neurotransmitter transport	1
regulation of secretion by cell	1
adult behavior	1
response to ethanol	1
calcium ion transport	1
positive regulation of monoatomic ion transport	1
regulation of calcium ion transport	1
negative regulation of cell communication	1
negative regulation of nervous system process	1
positive regulation of cell communication	1
positive regulation of nervous system process	1
regulation of postsynaptic membrane potential	1
chemical synaptic transmission, postsynaptic	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
response to chemical	1

Protein interactions and networks

STRING

1614 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCRT	HCRTR1	O43613	999
HCRT	HCRTR2	O43614	996
HCRT	PMCH	P20382	983
HCRT	LEP	P41159	930
HCRT	NPY	P01303	928
HCRT	OXR1	Q8N573	926
HCRT	POMC	P01189	921
HCRT	AGRP	O00253	877
HCRT	HLA-DQB1	P01917	871
HCRT	CRH	P06850	867
HCRT	GHRL	Q9UBU3	854
HCRT	GAL	P22466	845
HCRT	INS	P01308	830
HCRT	FOS	P01100	794
HCRT	NTS	P30990	792

IntAct

5 interactions, top by confidence:

A	B	Type	Score
HLA-DQA1	HCRT	psi-mi:“MI:0915”(physical association)	0.560
HCRT	CNR1	psi-mi:“MI:0403”(colocalization)	0.380
HCRT	CNR1	psi-mi:“MI:2364”(proximity)	0.380
HCRT	PMPCB	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): HCRT (Negative Genetic), KCNQ4 (Negative Genetic), PMPCB (Affinity Capture-MS), HLA-DQA1 (Affinity Capture-MS)

ESM2 similar proteins: D3YZZ2, E7ERA6, F2Z333, H3BV60, O00292, O18796, O43508, O43612, O54907, O55232, O55241, O60391, O75462, O75610, O77668, O95633, O95685, P13224, P41155, P56717, Q02833, Q06643, Q14626, Q1LZB9, Q2TBM7, Q4V892, Q5RF19, Q5TM22, Q6IA17, Q6UXT9, Q6ZMM2, Q862Z7, Q86VR8, Q86YD3, Q8BQB4, Q8NBV8, Q8TAD2, Q99640, Q99MF4, Q9BZR6

Diamond homologs: O43612, O55232, O55241, O77668, P56717, Q9GLF6

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
HCRT	up-regulates	HCRTR1	binding
HCRT	up-regulates	HCRTR2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	20
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
7303	NM_001524.1(HCRT):c.47T>G (p.Leu16Arg)	Pathogenic

SpliceAI

3266 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42185340:TTTAC:T	donor_loss	1.0000
17:42185341:TTAC:T	donor_loss	1.0000
17:42185342:TAC:T	donor_loss	1.0000
17:42185344:C:CG	donor_loss	1.0000
1:161166931:TAAGG:T	donor_loss	1.0000
1:161166932:AAGGT:A	donor_loss	1.0000
1:161166933:AGG:A	donor_loss	1.0000
1:161170490:G:GT	donor_gain	1.0000
1:161170520:G:GG	donor_gain	1.0000
1:161170525:G:GT	donor_gain	1.0000
1:161170528:G:GT	donor_gain	1.0000
1:161170531:G:GT	donor_gain	1.0000
1:161170532:A:T	donor_gain	1.0000
1:161172328:CACC:C	acceptor_gain	1.0000
1:161172330:CC:C	acceptor_gain	1.0000
1:161172331:CC:C	acceptor_gain	1.0000
1:161172332:C:CC	acceptor_gain	1.0000
1:161173728:C:CC	acceptor_gain	1.0000
1:161175225:CCCA:C	acceptor_gain	1.0000
1:161175226:CCA:C	acceptor_gain	1.0000
1:161175226:CCAC:C	acceptor_gain	1.0000
1:161175227:CAC:C	acceptor_gain	1.0000
1:161175229:C:CC	acceptor_gain	1.0000
1:161175230:T:A	acceptor_loss	1.0000
1:161175259:C:CT	acceptor_gain	1.0000
1:161175260:A:T	acceptor_gain	1.0000
1:161177419:ATACC:A	donor_loss	1.0000
1:161177420:TACC:T	donor_loss	1.0000
1:161177421:AC:A	donor_loss	1.0000
17:42184526:GACCT:G	acceptor_loss	0.9900

AlphaMissense

800 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:42184269:A:G	I94T	0.998
17:42184362:A:G	I63T	0.998
17:42184359:A:T	L64H	0.995
17:42184362:A:C	I63S	0.994
17:42184359:A:G	L64P	0.993
17:42184269:A:C	I94S	0.992
17:42184362:A:T	I63N	0.991
17:42184365:C:T	G62D	0.989
17:42184366:C:G	G62R	0.989
17:42184269:A:T	I94N	0.988
17:42184258:C:A	G98C	0.987
17:42184263:G:A	T96I	0.986
17:42184266:A:G	L95P	0.986
17:42184350:C:A	G67V	0.986
17:42184350:C:T	G67D	0.986
17:42184351:C:A	G67C	0.985
17:42184366:C:A	G62C	0.985
17:42184431:C:T	C40Y	0.985
17:42184346:C:A	K68N	0.984
17:42184346:C:G	K68N	0.984
17:42184410:C:T	C47Y	0.983
17:42184411:A:G	C47R	0.982
17:42184431:C:G	C40S	0.982
17:42184432:A:T	C40S	0.982
17:42184351:C:G	G67R	0.981
17:42184410:C:G	C47S	0.979
17:42184411:A:T	C47S	0.979
17:42184258:C:G	G98R	0.978
17:42184266:A:T	L95Q	0.978
17:42184376:A:C	N58K	0.978

dbSNP variants (sampled 300 via entrez): RS1000249432 (17:42184867 A>G), RS1000855419 (17:42184337 G>A,C), RS1001729743 (17:42186087 C>T), RS1002003152 (17:42186766 G>A,C), RS1002262981 (17:42185638 C>G,T), RS1002362203 (17:42187029 A>C), RS1004878408 (17:42186371 GC>G,GCC), RS1004887933 (17:42186638 A>G), RS1007173139 (17:42184966 C>T), RS1007210598 (17:42184214 C>A,T), RS1007289298 (17:42185569 G>C), RS1007886523 (17:42187234 G>T), RS1009106899 (17:42186290 T>G), RS1009244774 (17:42185825 TG>T,TGG), RS1010027499 (17:42184425 T>C)

Disease associations

OMIM: gene MIM:602358 | disease phenotypes: MIM:161400

GenCC curated gene-disease

Disease	Classification	Inheritance
narcolepsy 1	Limited	Autosomal dominant

Mondo (1): narcolepsy 1 (MONDO:0008062)

Orphanet (1): Narcolepsy type 1 (Orphanet:2073)

HPO phenotypes

101 total (30 of 101 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000017	Nocturia
HP:0000707	Abnormality of the nervous system
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000711	Restlessness
HP:0000716	Depression
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000763	Sensory neuropathy
HP:0000822	Hypertension
HP:0000826	Precocious puberty
HP:0000953	Hyperpigmentation of the skin
HP:0000962	Hyperkeratosis
HP:0000975	Hyperhidrosis
HP:0000992	Cutaneous photosensitivity
HP:0000998	Hypertrichosis
HP:0001010	Hypopigmentation of the skin
HP:0001030	Fragile skin
HP:0001047	Atopic dermatitis
HP:0001056	Milia
HP:0001072	Thickened skin
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001259	Coma
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563534	Narcolepsy 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects expression, affects methylation	2
Triclosan	decreases expression, increases methylation	2
CGP 52608	increases reaction, affects binding	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression, increases abundance	1
Methotrexate	decreases expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03356938	Not specified	COMPLETED	The Role of the Circadian System in Neurological Sleep-wake Disorders
NCT03754348	Not specified	COMPLETED	Microglial Activation in Narcolepsy Type 1 and Kleine-Levin Syndrome: Positron Emission Tomography (PET) Study in [18F] DPA-714
NCT04419792	Not specified	SUSPENDED	‘A Profile of Physical Performance Variables in an Out-patient Adult Population With Narcolepsy’