OTP

Summary

OTP (orthopedia homeobox, HGNC:8518) is a protein-coding gene on chromosome 5q14.1, encoding Homeobox protein orthopedia (Q5XKR4). Probably involved in the differentiation of hypothalamic neuroendocrine cells.

This gene encodes a member of the homeodomain (HD) family. HD family proteins are helix-turn-helix transcription factors that play key roles in the specification of cell fates. This protein may function during brain development.

Source: NCBI Gene 23440 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 38 total
• MANE Select transcript: NM_032109

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8518
Approved symbol	OTP
Name	orthopedia homeobox
Location	5q14.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000171540
Ensembl biotype	protein_coding
OMIM	604529
Entrez	23440

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000306422, ENST00000515716

RefSeq mRNA: 1 — MANE Select: NM_032109 NM_032109

CCDS: CCDS4039

Canonical transcript exons

ENST00000306422 — 3 exons

Exon	Start	End
ENSE00001163048	77636821	77637230
ENSE00001169222	77628712	77630794
ENSE00001169228	77638513	77638713

Expression profiles

Bgee: expression breadth broad, 27 present calls, max score 72.42.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	72.42	silver quality
tibialis anterior	UBERON:0001385	71.58	silver quality
hypothalamus	UBERON:0001898	70.42	gold quality
ileal mucosa	UBERON:0000331	64.93	gold quality
superior vestibular nucleus	UBERON:0007227	64.02	gold quality
deltoid	UBERON:0001476	58.98	silver quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	54.33	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
lateral nuclear group of thalamus	UBERON:0002736	53.39	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	52.71	gold quality
seminal vesicle	UBERON:0000998	50.56	gold quality
myocardium	UBERON:0002349	50.25	gold quality
lower lobe of lung	UBERON:0008949	49.49	silver quality
buccal mucosa cell	CL:0002336	49.33	gold quality
medulla oblongata	UBERON:0001896	49.31	silver quality
quadriceps femoris	UBERON:0001377	48.44	gold quality
lateral globus pallidus	UBERON:0002476	47.99	gold quality
nasal cavity epithelium	UBERON:0005384	47.03	gold quality
vastus lateralis	UBERON:0001379	45.74	gold quality
colonic epithelium	UBERON:0000397	44.91	gold quality
upper leg skin	UBERON:0004262	44.77	silver quality
biceps brachii	UBERON:0001507	44.76	gold quality
amniotic fluid	UBERON:0000173	44.72	gold quality
ventricular zone	UBERON:0003053	44.68	gold quality
layer of synovial tissue	UBERON:0007616	43.55	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-8894	yes	1572.01
E-ANND-3	no	1.47

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
SLC6A3	Activation
TH	Activation

Upstream regulators (CollecTRI, top): TBXT

miRNA regulators (miRDB)

65 targeting OTP, 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-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-6766-5P	99.68	67.70	2325

Literature-anchored findings (GeneRIF, showing 6)

• we successfully identified a novel gene OTP frequently methylated in breast cancer by genome-wide screening. Our results suggest that the OTP gene may play a crucial role in breast carcinogenesis. (PMID:22366991)
• Data indicate that low mRNA expression levels of CD44 and orthopedia homeobox (OTP) and high levels of RET, were strongly associated with a low 20-year survival of carcinoid patients. (PMID:23444222)
• Our results suggest that OTP may serve as a useful diagnostic marker for lung carcinoid tumors. (PMID:26927888)
• We tested the functional consequences of the novel human OTP mutations and Q83K as well as the mouse R108W mutant; all affect residues that are highly conserved across species. On a single site response element, wild-type OTP was found to act as a repressor; both R108W and Q153R abolished this repression (PMID:29107289)
• Orthopedia protein (OTP) is specific for lung carcinoids because well-differentiated nonlung neuroendocrine tumors are negative for OTP. OTP preferentially stains typical carcinoids over atypical carcinoids (PMID:29316326)
• Half of the pulmonary TC tumors expressed OTP. (PMID:30284410)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	otpa	ENSDARG00000014201
danio_rerio	otpb	ENSDARG00000058379
mus_musculus	Otp	ENSMUSG00000021685
rattus_norvegicus	Otp	ENSRNOG00000010560

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Homeobox protein orthopedia — Q5XKR4 (reviewed: Q5XKR4)

All UniProt accessions (1): Q5XKR4

UniProt curated annotations — full annotation on UniProt →

Function. Probably involved in the differentiation of hypothalamic neuroendocrine cells.

Subcellular location. Nucleus.

Similarity. Belongs to the paired homeobox family. Bicoid subfamily.

RefSeq proteins (1): NP_115485* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000047	HTH_motif	Conserved_site
IPR001356	HD	Domain
IPR003654	OAR_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR051895	OTP_Homeobox	Family

Pfam: PF00046, PF03826

UniProt features (6 total): compositionally biased region 2, chain 1, DNA-binding region 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5XKR4-F1	62.73	0.19

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 190 (showing top): YAATNRNNNYNATT_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, HNF3ALPHA_Q6, NKX25_02, GCANCTGNY_MYOD_Q6, GOBP_PITUITARY_GLAND_DEVELOPMENT, GOBP_NEUROGENESIS, RACCACAR_AML_Q6, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, CHX10_01, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NEUROBLAST_PROLIFERATION, GCGCTTT_MIR518B_MIR518C_MIR518D, GOBP_FOREBRAIN_DEVELOPMENT, SHEPARD_BMYB_MORPHOLINO_DN

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), positive regulation of neuroblast proliferation (GO:0002052), neuroblast proliferation (GO:0007405), forebrain neuron differentiation (GO:0021879), hypothalamus cell differentiation (GO:0021979), neurohypophysis development (GO:0021985), neuron differentiation (GO:0030182), neuroendocrine cell differentiation (GO:0061101), dopaminergic neuron differentiation (GO:0071542), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), cell differentiation (GO:0030154)

GO Molecular Function (5): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), fibrillar center (GO:0001650), nucleoplasm (GO:0005654), nuclear body (GO:0016604), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
generation of neurons	2
cell differentiation	2
neuron differentiation	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
neural precursor cell proliferation	1
forebrain generation of neurons	1
central nervous system neuron differentiation	1
hypothalamus development	1
pituitary gland development	1
gland development	1
neuroepithelial cell differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
system development	1
cellular developmental process	1
transcription cis-regulatory region binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
nucleic acid binding	1
binding	1
chromosome	1
nucleolus	1
nuclear lumen	1
nucleoplasm	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTP	SIM1	P81133	859
OTP	POU3F2	P20265	774
OTP	OXT	P01178	742
OTP	ACTR1B	P42025	665
OTP	ACTR1A	P42024	656
OTP	SIX3	O95343	625
OTP	ARNT2	Q9HBZ2	619
OTP	SIM2	Q14190	568
OTP	TRH	P20396	562
OTP	PAX2	Q02962	544
OTP	FOXB1	Q99853	511
OTP	ONECUT1	Q9UBC0	478
OTP	CRH	P06850	463
OTP	NHLH2	Q02577	446
OTP	FEZF2	Q8TBJ5	438
OTP	TBR1	Q16650	438

IntAct

26 interactions, top by confidence:

A	B	Type	Score
EOMES	OTP	psi-mi:“MI:0915”(physical association)	0.560
OTP	CPNE7	psi-mi:“MI:0915”(physical association)	0.560
OTP	BEX1	psi-mi:“MI:0915”(physical association)	0.560
CCL21	OTP	psi-mi:“MI:0915”(physical association)	0.560
OTP	TPGS2	psi-mi:“MI:0915”(physical association)	0.560
PDE6D	OTP	psi-mi:“MI:0915”(physical association)	0.560
CDK6	OTP	psi-mi:“MI:0915”(physical association)	0.560
OTP	SLC12A7	psi-mi:“MI:0915”(physical association)	0.560
OTP	FLAD1	psi-mi:“MI:0915”(physical association)	0.400
OTP	EOMES	psi-mi:“MI:0915”(physical association)	0.000
CPNE7	OTP	psi-mi:“MI:0915”(physical association)	0.000
BEX1	OTP	psi-mi:“MI:0915”(physical association)	0.000
CDK6	OTP	psi-mi:“MI:0915”(physical association)	0.000
CCL21	OTP	psi-mi:“MI:0915”(physical association)	0.000
TPGS2	OTP	psi-mi:“MI:0915”(physical association)	0.000
PDE6D	OTP	psi-mi:“MI:0915”(physical association)	0.000
SLC12A7	OTP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): OTP (Two-hybrid), OTP (Two-hybrid), OTP (Two-hybrid), OTP (Two-hybrid), OTP (Two-hybrid), OTP (Two-hybrid), OTP (Two-hybrid), CPNE7 (Two-hybrid), FLAD1 (Affinity Capture-MS), OTP (Negative Genetic)

ESM2 similar proteins: A3RK74, A3RK75, A4L7N3, B3LYS5, B3P0K6, B4HF64, B4MB78, E1BPQ1, F1R8Z9, G3V7R4, O09113, O43524, O93385, P23512, P32183, P35582, P35584, P41161, P55317, P56673, P70314, P78337, P97474, Q00939, Q05826, Q12778, Q28EM1, Q32NP8, Q3BJS1, Q5XKR4, Q60987, Q66JJ0, Q68EZ2, Q68F77, Q6EUW1, Q6EUW2, Q810W5, Q8K3Q3, Q8R5I7, Q969V6

Diamond homologs: A1A546, A1YEV8, A1YG25, A2T711, A6NJT0, A6NNA5, A6YP92, G5EC89, G5EDS1, L8E946, O08934, O09113, O14813, O15266, O18381, O35085, O35137, O35602, O35690, O35750, O42115, O42201, O42250, O42356, O42357, O42358, O42477, O42567, O60902, O70137, O73917, O95076, O97039, P0DMV5, P23759, P23760, P24610, P26367, P26630, P29506

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

622 predictions. Top by Δscore:

Variant	Effect	Δscore
5:77630801:C:CT	acceptor_gain	1.0000
5:77630802:G:T	acceptor_gain	1.0000
5:77630805:C:CT	acceptor_gain	1.0000
5:77630806:G:T	acceptor_gain	1.0000
5:77630790:CAGAC:C	acceptor_gain	0.9900
5:77630791:AGAC:A	acceptor_gain	0.9900
5:77630792:GAC:G	acceptor_gain	0.9900
5:77630793:AC:A	acceptor_gain	0.9900
5:77630794:CC:C	acceptor_gain	0.9900
5:77630795:C:CC	acceptor_gain	0.9900
5:77630795:CTG:C	acceptor_loss	0.9900
5:77630796:T:A	acceptor_loss	0.9900
5:77630810:C:CT	acceptor_gain	0.9900
5:77630811:G:T	acceptor_gain	0.9900
5:77636815:TCGTA:T	donor_loss	0.9800
5:77636816:CGTAC:C	donor_loss	0.9800
5:77636817:GTACC:G	donor_loss	0.9800
5:77636818:TACC:T	donor_loss	0.9800
5:77636819:ACCT:A	donor_loss	0.9800
5:77636820:C:T	donor_loss	0.9800
5:77637920:T:A	donor_gain	0.9700
5:77630795:C:T	acceptor_gain	0.9600
5:77630793:ACC:A	acceptor_gain	0.9400
5:77630794:CCT:C	acceptor_gain	0.9400
5:77630795:CT:C	acceptor_gain	0.9400
5:77630796:T:G	acceptor_gain	0.9400
5:77630791:AGACC:A	acceptor_gain	0.9300
5:77630792:GACC:G	acceptor_gain	0.9300
5:77637942:T:A	donor_gain	0.9300
5:77636669:C:CT	acceptor_gain	0.9200

AlphaMissense

2094 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:77630289:T:G	H318P	1.000
5:77630299:C:G	A315P	1.000
5:77630304:C:G	R313P	1.000
5:77630307:C:G	R312P	1.000
5:77630308:G:T	R312S	1.000
5:77630310:A:G	L311P	1.000
5:77630310:A:T	L311H	1.000
5:77630319:A:C	I308S	1.000
5:77630319:A:G	I308T	1.000
5:77630319:A:T	I308N	1.000
5:77630321:G:C	S307R	1.000
5:77630321:G:T	S307R	1.000
5:77630322:C:A	S307I	1.000
5:77630323:T:G	S307R	1.000
5:77630759:C:A	K161N	1.000
5:77630759:C:G	K161N	1.000
5:77630761:T:C	K161E	1.000
5:77630762:C:A	K160N	1.000
5:77630762:C:G	K160N	1.000
5:77630763:T:A	K160M	1.000
5:77630764:T:C	K160E	1.000
5:77630765:C:A	W159C	1.000
5:77630765:C:G	W159C	1.000
5:77630766:C:G	W159S	1.000
5:77630767:A:G	W159R	1.000
5:77630767:A:T	W159R	1.000
5:77630768:C:A	K158N	1.000
5:77630768:C:G	K158N	1.000
5:77630769:T:A	K158M	1.000
5:77630770:T:C	K158E	1.000

dbSNP variants (sampled 300 via entrez): RS1000572659 (5:77628648 T>A,C), RS1000922471 (5:77628254 G>A,C,T), RS1000997008 (5:77633915 A>G), RS1001049638 (5:77639707 C>A), RS1001050227 (5:77629319 C>T), RS1001109921 (5:77634195 A>G), RS1001503960 (5:77629641 G>A), RS1001660491 (5:77631338 C>G,T), RS1001773519 (5:77631551 C>A,T), RS1002002542 (5:77632532 G>A), RS1002118567 (5:77632884 A>G), RS1002212757 (5:77639282 C>A,G,T), RS1002423611 (5:77638665 G>A), RS1002524223 (5:77630312 G>A,C), RS1002665047 (5:77629711 C>T)

Disease associations

OMIM: gene MIM:604529 | 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
GCST90000047_102	Age at first sexual intercourse	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression	1
arsenite	increases methylation	1
CGP 52608	affects binding, increases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases abundance, increases expression	1
Demecolcine	increases expression	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression, increases expression	1
Methyl Methanesulfonate	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Theophylline	increases expression, affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Vincristine	increases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Cadmium Chloride	increases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5A8	SEES3-1V human OTP, clone1	Embryonic stem cell	Male
CVCL_A5A9	SEES3-1V human OTP, clone2	Embryonic stem cell	Male
CVCL_A5B0	SEES3-1V human OTP, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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