OTOP1

Summary

OTOP1 (otopetrin 1, HGNC:19656) is a protein-coding gene on chromosome 4p16.3, encoding Proton channel OTOP1 (Q7RTM1). Proton-selective ion channel. It is a selective cancer dependency (DepMap: 32.6% of cell lines).

This gene encodes a transmembrane protein which belongs to the otopetrin domain protein family and is required for the formation of otoconia and otoliths, calcium carbonate biominerals within the inner ear of mammals that are required for the detection of linear acceleration and gravity. This gene modulates purinergic control of intracellular calcium in vestibular supporting cells. Naturally occurring mutations in the orthologous mouse gene are associated with nonsyndromic otoconia agenesis and a consequent balance defect. The orthologous mouse gene is also induced in white adipose tissue during obesity. The encoded protein is a component of a counterinflammatory pathway that attenuates obesity-induced adipose tissue inflammation and plays an adaptive role in maintaining metabolic homeostasis in obesity.

Source: NCBI Gene 133060 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 120 total — 1 pathogenic
• Cancer dependency (DepMap): dependent in 32.6% of screened cell lines
• MANE Select transcript: NM_177998

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19656
Approved symbol	OTOP1
Name	otopetrin 1
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000163982
Ensembl biotype	protein_coding
OMIM	607806
Entrez	133060

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000296358

RefSeq mRNA: 1 — MANE Select: NM_177998 NM_177998

CCDS: CCDS3372

Canonical transcript exons

ENST00000296358 — 6 exons

Exon	Start	End
ENSE00001080243	4202448	4202578
ENSE00001080246	4226462	4226929
ENSE00001080248	4206072	4206130
ENSE00001080249	4197166	4198103
ENSE00001080250	4212868	4213004
ENSE00001531002	4188726	4188973

Expression profiles

Bgee: expression breadth broad, 11 present calls, max score 74.78.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.78	silver quality
colonic epithelium	UBERON:0000397	42.10	gold quality
skin of abdomen	UBERON:0001416	40.96	gold quality
zone of skin	UBERON:0000014	40.51	gold quality
skin of leg	UBERON:0001511	40.02	gold quality
stromal cell of endometrium	CL:0002255	39.81	gold quality
esophagus mucosa	UBERON:0002469	39.25	silver quality
bone marrow cell	CL:0002092	38.05	gold quality
lower esophagus mucosa	UBERON:0035834	37.68	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
sural nerve	UBERON:0015488	36.22	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
granulocyte	CL:0000094	35.06	gold quality
mucosa of stomach	UBERON:0001199	33.47	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
vagina	UBERON:0000996	32.86	silver quality
bone marrow	UBERON:0002371	32.71	gold quality
left uterine tube	UBERON:0001303	32.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	31.95	gold quality
esophagus	UBERON:0001043	31.54	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
prefrontal cortex	UBERON:0000451	30.34	gold quality
primary visual cortex	UBERON:0002436	30.24	gold quality
liver	UBERON:0002107	29.07	gold quality
tonsil	UBERON:0002372	28.55	gold quality
leukocyte	CL:0000738	28.25	gold quality
duodenum	UBERON:0002114	28.14	gold quality
monocyte	CL:0000576	27.76	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.80

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 32.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 1)

• The roles of two extracellular loops in proton sensing and permeation in human Otop1 proton channel. (PMID:36266567)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	OTOP1	ENSDARG00000021566
mus_musculus	Otop1	ENSMUSG00000051596
rattus_norvegicus	Otop1	ENSRNOG00000028423
caenorhabditis_elegans		WBGENE00010403
caenorhabditis_elegans		WBGENE00017034
caenorhabditis_elegans		WBGENE00017449
caenorhabditis_elegans		WBGENE00018478
caenorhabditis_elegans		WBGENE00018479
caenorhabditis_elegans		WBGENE00018480

Paralogs (2): OTOP3 (ENSG00000182938), OTOP2 (ENSG00000183034)

Protein

Protein identifiers

Proton channel OTOP1 — Q7RTM1 (reviewed: Q7RTM1)

Alternative names: Otopetrin-1

All UniProt accessions (1): Q7RTM1

UniProt curated annotations — full annotation on UniProt →

Function. Proton-selective ion channel. Biphasically modulated by acid and alkali, mediating proton influx and efflux in response to extracellular acid and base stimulation, respectively. Sour taste receptor, which carries inward currents in response to extracellular acidification. Sensor for ammonium chloride (NH(4)Cl) in taste receptor cells. NH(4)Cl acts by increasing the intracellular pH, thereby generating a driving force for proton entry through OTOP1 channel. Might also participate in alkaline sensation. Plays a role in the regulation of Ca(2+) flux in response to purigenic (ATP, ADP and UDP) stimuli, leading to increase in cytosolic Ca(2+) due to influx of extracellular calcium. May play this role by inhibiting P2Y purinoceptor-mediated Ca(2+) release in a Ca(2+)-dependent manner and promote an influx of Ca(2+) in response to ATP. Through this mechanism and possibly others, plays a role in the formation and function of calcium carbonate-based structures in the vestibular system of the inner ear, called otoconia, that sense gravity and linear acceleration. In obesity, may attenuate adipose tissue inflammation, through the negative regulation of IFNG signaling, hence may play an adaptive role in the maintainance of metabolic homeostasis. Following alkali activation, may also be permeable Na(+), K(+), Cs(+) and Li(+).

Subunit / interactions. Homodimer. Interacts with STAT1, independently of STAT1 phosphorylation status.

Subcellular location. Cell membrane. Cell projection. Microvillus.

Activity regulation. Activated by both acid and alkali, with proton influx in response to extracellular acid and proton efflux during alkali stimulation. Inhibited by Zn(2+); this inhibition is thought to be pH-sensitive. Currents evoked in response to mild acid (pH 6.0) stimulus may also be mildly potentiated by exposure to Zn(2+). Activated by NH(4)Cl.

Domain organisation. Residues involved in the gating by extracellular Zn (2+) and pH are located in the extracellular loops between transmembrane domain 5-6 and transmembrane domain 11-12.

Similarity. Belongs to the otopetrin family.

RefSeq proteins (1): NP_819056* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004878	Otopetrin	Family

Pfam: PF03189

Catalyzed reactions (Rhea), 1 shown:

• H(+)(in) = H(+)(out) (RHEA:34979)

UniProt features (41 total): topological domain 13, transmembrane region 12, sequence variant 5, mutagenesis site 5, region of interest 2, compositionally biased region 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7RTM1-F1	76.44	0.40

Functional residue map

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

Mutagenesis-validated functional residues (5):

Position	Phenotype
229	complete loss of h(+) current at ph 5 and 4.5.
229	abolishes proton channel activity at ph 5 and 4.5.
570	does not affect cell membrane localization. reduction of proton channel activity.
570	does not affect proton channel activity.
570	does not affect cell membrane localization. strong reduction of proton channel activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9729555	Sensory perception of sour taste

MSigDB gene sets: 92 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GOBP_RESPONSE_TO_PEPTIDE, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_RESPONSE_TO_GRAVITY, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_EAR_DEVELOPMENT, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_INSULIN

GO Biological Process (10): detection of gravity (GO:0009590), otolith formation (GO:0032475), cellular response to insulin stimulus (GO:0032869), otolith mineralization (GO:0045299), negative regulation of type II interferon-mediated signaling pathway (GO:0060336), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811), biomineral tissue development (GO:0031214), monoatomic ion transmembrane transport (GO:0034220), inner ear morphogenesis (GO:0042472)

GO Molecular Function (2): proton channel activity (GO:0015252), identical protein binding (GO:0042802)

GO Cellular Component (4): plasma membrane (GO:0005886), microvillus (GO:0005902), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory perception of taste	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
detection of external stimulus	1
detection of abiotic stimulus	1
response to gravity	1
otolith morphogenesis	1
anatomical structure formation involved in morphogenesis	1
response to insulin	1
cellular response to peptide hormone stimulus	1
biomineral tissue development	1
otolith development	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of response to type II interferon	1
type II interferon-mediated signaling pathway	1
regulation of type II interferon-mediated signaling pathway	1
monoatomic cation transmembrane transport	1
transport	1
tissue development	1
animal organ development	1
monoatomic ion transport	1
transmembrane transport	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
monoatomic cation channel activity	1
proton transmembrane transporter activity	1
protein binding	1
membrane	1
cell periphery	1
actin filament bundle	1
actin-based cell projection	1

Protein interactions and networks

STRING

616 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTOP1	OC90	Q02509	904
OTOP1	ATP2B2	Q01814	759
OTOP1	PKD2L1	Q9P0L9	718
OTOP1	ATP2B4	P23634	703
OTOP1	SLC26A4	O43511	661
OTOP1	TMEM128	Q5BJH2	647
OTOP1	CALHM3	Q86XJ0	626
OTOP1	OTOL1	A6NHN0	622
OTOP1	CALHM1	Q8IU99	609
OTOP1	TAS1R2	Q8TE23	605
OTOP1	ELOVL3	Q9HB03	573
OTOP1	PLCB2	Q00722	572
OTOP1	TAS1R1	Q7RTX1	541
OTOP1	CIDEA	O60543	525
OTOP1	COX7A1	P24310	523

IntAct

2 interactions, top by confidence:

A	B	Type	Score
OTOP1	SEMG1	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): OTOP1 (Proximity Label-MS), SEMG2 (Affinity Capture-MS), SEMG1 (Affinity Capture-MS), OSBPL8 (Affinity Capture-MS)

ESM2 similar proteins: A2ARJ3, A2YD22, A5WVU6, A8X0L4, A9RA88, B0CMA4, F1QYC4, F1RAX4, G5EBX4, O17386, O22752, O22757, O22815, O59802, O80580, P28233, P51916, P93766, Q02739, Q05005, Q0DC45, Q0V947, Q19337, Q3UP23, Q5GH77, Q5R687, Q5RBT7, Q5U4Q2, Q5W0B7, Q5XV67, Q641M3, Q6NZ21, Q6PQZ3, Q6S5G4, Q6ZUK4, Q7M734, Q7RTM1, Q91WG1, Q921C1, Q94KB1

Diamond homologs: Q7M734, Q7RTM1, Q7RTS5, Q7RTS6, Q7ZWK8, Q80SX5, Q80UF9, Q80VM9, A9JTM7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	110
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3062781	GRCh37/hg19 4p16.3-15.33(chr4:68345-14083766)x1	Pathogenic

SpliceAI

1063 predictions. Top by Δscore:

Variant	Effect	Δscore
4:4188969:CAAAG:C	acceptor_gain	1.0000
4:4188974:C:CC	acceptor_gain	1.0000
4:4188970:AAAG:A	acceptor_gain	0.9900
4:4188971:AAG:A	acceptor_gain	0.9900
4:4188972:AG:A	acceptor_gain	0.9900
4:4188972:AGC:A	acceptor_loss	0.9900
4:4188973:GC:G	acceptor_loss	0.9900
4:4188974:C:CA	acceptor_loss	0.9900
4:4188975:T:A	acceptor_loss	0.9900
4:4202443:CT:C	donor_loss	0.9900
4:4202447:C:CA	donor_loss	0.9900
4:4202486:T:A	donor_gain	0.9900
4:4202574:CAAAC:C	acceptor_gain	0.9900
4:4202576:AAC:A	acceptor_gain	0.9900
4:4202577:AC:A	acceptor_gain	0.9900
4:4202578:CC:C	acceptor_gain	0.9900
4:4202578:CCTG:C	acceptor_loss	0.9900
4:4202579:C:A	acceptor_loss	0.9900
4:4202579:C:CC	acceptor_gain	0.9900
4:4226461:CCG:C	donor_gain	0.9900
4:4226461:CCGCG:C	donor_gain	0.9900
4:4226454:GGACT:G	donor_loss	0.9800
4:4226455:GACTC:G	donor_loss	0.9800
4:4226456:ACTC:A	donor_loss	0.9800
4:4226457:CTCAC:C	donor_loss	0.9800
4:4226458:TCA:T	donor_loss	0.9800
4:4226459:CAC:C	donor_loss	0.9800
4:4226460:A:AC	donor_gain	0.9800
4:4226460:A:AG	donor_loss	0.9800
4:4226461:C:CC	donor_gain	0.9800

AlphaMissense

3954 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:4202538:A:G	W214R	0.995
4:4202538:A:T	W214R	0.995
4:4188895:A:G	W583R	0.993
4:4188895:A:T	W583R	0.993
4:4188970:A:G	W558R	0.993
4:4188970:A:T	W558R	0.993
4:4202548:G:C	N210K	0.989
4:4202548:G:T	N210K	0.989
4:4188902:A:C	F580L	0.986
4:4188902:A:T	F580L	0.986
4:4188904:A:G	F580L	0.986
4:4226648:C:G	G73R	0.986
4:4226648:C:T	G73R	0.986
4:4226679:G:C	S62R	0.985
4:4226679:G:T	S62R	0.985
4:4226681:T:G	S62R	0.985
4:4197172:A:C	N554K	0.984
4:4197172:A:T	N554K	0.984
4:4188893:C:A	W583C	0.983
4:4188893:C:G	W583C	0.983
4:4197969:A:G	W289R	0.983
4:4197969:A:T	W289R	0.983
4:4202546:A:G	L211P	0.983
4:4226549:A:G	W106R	0.983
4:4226549:A:T	W106R	0.983
4:4188867:G:C	P592R	0.982
4:4226668:C:T	G66E	0.982
4:4202483:C:G	R232P	0.981
4:4202514:A:G	S222P	0.981
4:4188908:A:C	F578L	0.980

dbSNP variants (sampled 300 via entrez): RS10000020 (4:4215724 A>G), RS1000044445 (4:4205069 G>A), RS10001663 (4:4217436 C>A), RS1000178118 (4:4216174 A>G), RS1000394203 (4:4204916 G>A), RS1000411037 (4:4188442 T>C), RS1000597820 (4:4209683 G>A), RS1000639505 (4:4225658 C>A), RS1000830477 (4:4198309 A>C), RS1001007591 (4:4203576 A>G), RS1001175376 (4:4204752 G>A,C), RS1001191203 (4:4215252 G>A,T), RS1001439103 (4:4210382 A>G), RS1001461372 (4:4203855 G>A), RS1001520984 (4:4193848 C>T)

Disease associations

OMIM: gene MIM:607806 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009442_5	Age-related cognitive decline (executive function) (slope of z-scores)	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	decreases expression, affects cotreatment	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	decreases methylation	1

Clinical trials (associated diseases)

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