NR0B2

Summary

NR0B2 (nuclear receptor subfamily 0 group B member 2, HGNC:7961) is a protein-coding gene on chromosome 1p36.11, encoding Nuclear receptor subfamily 0 group B member 2 (Q15466). Transcriptional regulator that acts as a negative regulator of receptor-dependent signaling pathways.

The protein encoded by this gene is an unusual orphan receptor that contains a putative ligand-binding domain but lacks a conventional DNA-binding domain. The gene product is a member of the nuclear hormone receptor family, a group of transcription factors regulated by small hydrophobic hormones, a subset of which do not have known ligands and are referred to as orphan nuclear receptors. The protein has been shown to interact with retinoid and thyroid hormone receptors, inhibiting their ligand-dependent transcriptional activation. In addition, interaction with estrogen receptors has been demonstrated, leading to inhibition of function. Studies suggest that the protein represses nuclear hormone receptor-mediated transactivation via two separate steps: competition with coactivators and the direct effects of its transcriptional repressor function.

Source: NCBI Gene 8431 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited obesity (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 114 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 6
• Druggable target: yes
• Transcription factor: yes — 130 downstream targets (CollecTRI)
• MANE Select transcript: NM_021969

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7961
Approved symbol	NR0B2
Name	nuclear receptor subfamily 0 group B member 2
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	SHP
Ensembl gene	ENSG00000131910
Ensembl biotype	protein_coding
OMIM	604630
Entrez	8431

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000254227

RefSeq mRNA: 1 — MANE Select: NM_021969 NM_021969

CCDS: CCDS291

Canonical transcript exons

ENST00000254227 — 2 exons

Exon	Start	End
ENSE00000761012	26913409	26913975
ENSE00001065528	26911489	26912086

Expression profiles

Bgee: expression breadth broad, 87 present calls, max score 95.12.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.5218 / max 311.1250, expressed in 65 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11204	1.4614	61
11203	0.0371	17
11202	0.0087	4
11205	0.0081	6
11201	0.0065	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	95.12	gold quality
duodenum	UBERON:0002114	93.72	gold quality
liver	UBERON:0002107	92.92	gold quality
jejunal mucosa	UBERON:0000399	92.70	gold quality
body of pancreas	UBERON:0001150	87.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.31	gold quality
right adrenal gland	UBERON:0001233	83.83	gold quality
left adrenal gland	UBERON:0001234	83.63	gold quality
left adrenal gland cortex	UBERON:0035825	82.95	gold quality
right adrenal gland cortex	UBERON:0035827	82.11	gold quality
pancreas	UBERON:0001264	82.06	gold quality
adrenal cortex	UBERON:0001235	81.62	gold quality
gall bladder	UBERON:0002110	81.33	gold quality
apex of heart	UBERON:0002098	80.88	gold quality
adrenal gland	UBERON:0002369	80.02	gold quality
sperm	CL:0000019	79.96	gold quality
right atrium auricular region	UBERON:0006631	79.37	gold quality
male germ cell	CL:0000015	79.06	gold quality
cardiac atrium	UBERON:0002081	78.64	gold quality
body of stomach	UBERON:0001161	77.60	gold quality
jejunum	UBERON:0002115	77.58	gold quality
pancreatic ductal cell	CL:0002079	77.07	silver quality
epithelial cell of pancreas	CL:0000083	76.76	gold quality
spleen	UBERON:0002106	76.28	gold quality
heart left ventricle	UBERON:0002084	75.81	gold quality
cardiac ventricle	UBERON:0002082	75.50	gold quality
stomach	UBERON:0000945	75.24	gold quality
adult mammalian kidney	UBERON:0000082	75.04	gold quality
islet of Langerhans	UBERON:0000006	72.62	gold quality
metanephros cortex	UBERON:0010533	72.43	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

130 targets.

Target	Regulation
ABCA1	Repression
ABCG1
ACAT2	Repression
ACTG2	Repression
ADIPOQ	Repression
AGT	Repression
AHR
ANG	Unknown
APOA2
APOB	Repression
APOC3	Unknown
APOM
BGLAP	Unknown
BMAL1
CASP1
CCND1	Unknown
CDKN1A	Repression
CDX1	Unknown
CEL
CES2
CETP
CLOCK
CRTC2
CSN2
CYP19A1	Repression
CYP1A1	Repression
CYP27A1	Unknown
CYP2D6
CYP3A4
CYP7A1	Unknown

Upstream regulators (CollecTRI, top): ATF6, BMAL1, CLOCK, DNMT1, EP300, ESR1, ESRRA, ESRRG, FOXA2, FOXM1, FOXO1, GATA1, HNF4A, JUN, NCOA1, NEUROD1, NFE2L2, NR0B2, NR1H3, NR1H4, NR1I2, NR5A1, NR5A2, RELA, RXRA, SIRT1, SREBF1, SREBF2, TBP, TCF3, USF1

miRNA regulators (miRDB)

29 targeting NR0B2, 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-340-5P	100.00	72.50	4437
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-4796-5P	99.34	70.06	810
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-6876-3P	98.97	65.69	765
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-626	98.89	66.21	762
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-4277	98.34	67.17	1323
HSA-MIR-6870-3P	98.08	65.10	692
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-6782-3P	97.60	67.75	931
HSA-MIR-505-5P	97.01	65.54	778
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-8083	95.93	67.55	694
HSA-MIR-6796-5P	95.37	66.08	1120

Literature-anchored findings (GeneRIF, showing 40)

• polymorphisms in the human SHP1 gene; found no rare SHP1 coding sequence variants that were exclusive to patients with lipodystrophy (PMID:12181644)
• SHP is able to interact with LXR and to modulate its transcriptional activity. (PMID:12198243)
• SHP has a role in modulating hepatic glucocorticoid action (PMID:12324453)
• the relation between genetic variation in SHP and birth weight, adiposity, and insulin levels in three independent populations (PMID:12716767)
• orphan receptor small heterodimer partner expression is regulated by estrogen receptor alpha (PMID:12842887)
• Modulation of SHP expression and/or activity in adipose tissue may therefore have significant effects on aromatase expression and estrogen production in breast adipose tissue. (PMID:14593077)
• basic helix-loop-helix (bHLH) transcription factors, the E2A proteins (E47, E12 and E2/5), activated the human but not the mouse SHP promoter (PMID:14627819)
• results suggest that bile acids negatively regulate the human angiotensinogen gene through the inhibitory effect of small heterodimer partner on hepatocyte nuclear factor-4 (PMID:14672953)
• Acts as a novel corepressor for basic helix-loop-helix transcription factor BETA2/NeuroD (PMID:14752053)
• At diagnosis, methylation of SHP1 occurred more frequently in acute myeloid leukaemia than acute lymphoblastic leukaemia. Frequent methylation of SHP1, but not SOCS1, may be important in the pathogenesis, but not prognosis, of acute leukaemias (PMID:14762685)
• orphan nuclear receptor small heterodimer partner promoter is regulated by sterol regulatory element binding protein-1 (PMID:15123650)
• PGC-1alpha mediates the ligand-dependent activation of FXR and transcription of SHP gene. (PMID:15202934)
• SHP-1 tyrosine phosphatase is regulated in human platelets by serine phosphorylation at its C terminus (PMID:15269224)
• c-Jun works to activate the expression of SHP genes associated with the cascade regulation of monocytic differentiation. (PMID:15292277)
• Results suggest that SHP mediates recruitment of mSin3A-Swi/Snf to the CYP7A1 promoter, resulting in chromatin remodeling and gene repression. (PMID:15314177)
• NR0B2 is involved in the regulation of G6Pase, CYP7A1, and PEPCK gene expression via novel mechanism of inhibition of HNF3 activity and expand the role of NR0B2 as a coregulator of other family of transcription factors in addition to nuclear receptors. (PMID:15358835)
• SHP mutations found in obese Danish men (PMID:15459958)
• crystal structure at 1.9 A resoluation of the ligand-binding domain of hLRH-1 in complex with the NR box 1 motif of human SHP, which contacts the AF-2 region of hLRH-1 using selective structural motifs (PMID:15723037)
• SHP affects genes involved in diverse biological pathways, e.g., several key genes involved in consecutive steps of cholesterol degradation, bile acid conjugation, transport and lipogenic pathways. (PMID:15973435)
• The GR/dexamethasone activation of the hNTCP promoter is counteracted by bile acids and small heterodimer partner, providing a negative feedback mechanism for bile acid uptake in human hepatocytes. (PMID:16123152)
• LRH-1 and SHP1 regulate 3-hydroxy-3-methylglutaryl coenzyme A reductase promoter and have a role in regulation of cholesterol synthesis and uptake (PMID:16282330)
• DAX1 and small heterodimer partner (SHP) form homodimers individually, as well as DAX1-SHP heterodimers suggesting the possibility of novel functions independent of their coregulator roles. (PMID:16709599)
• both SHP-1 and SHP-2 have a positive role in epidermal growth factor-induced ERK1/2 activation and they act cooperatively rather than antagonistically. (PMID:16762922)
• Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma. (PMID:16825495)
• SHP is a novel co-regulator of Smad3 that regulates TGF-beta signaling (PMID:17074765)
• results suggest that SHP might regulate a level of hepatic gluconeogenesis driven by C/EBPalpha activation (PMID:17094771)
• These studies establish a critical role for G9a methyltransferase, histone deacetylases, and the Swi/Snf-Brm complex in the SHP-mediated inhibition of hepatic bile acid synthesis via coordinated chromatin modification at target genes. (PMID:17145766)
• New roles for SHP in testicular androgen and retinoic acid metabolism, making SHP a testicular gatekeeper of the timing of male sexual maturation. (PMID:17289919)
• LRH-1 stimulation of the FAS LXR response is blocked by the addition of small heterodimer partner (SHP) and that FAS mRNA (PMID:17522048)
• Metformin inhibits hepatic gluconeogenesis through AMPK-dependent regulation of SHP. (PMID:17909097)
• LRH-1/phospholipid and LRH-1/SHP (fragments) interactions are analyzed by counting atomic contact number, identifying hydrogen bonds, and estimating binding free energies (PMID:17910058)
• Small heterodimer partner (SHP), an orphan nuclear hormone receptor lacking a DNA binding domain, inhibits nuclear hormone receptor-mediated hepatitis B viral transcription and replication. (PMID:18234786)
• SHP-1 acts as a sensor for hydroxynonenal and is responsible for an adaptive response to oxidative stress in respiratory epithetlium. (PMID:18276794)
• These results indicate that bile acid performs a critical function in the regulation of the induction of inflammatory-related genes in gastric cells (PMID:18307978)
• Propose that SHP functions as a novel tumor suppressor in the development of heptaocellular carcinoma. (PMID:18325392)
• PGC-1alpha is an important co-activator for LRH-1 and that SHP targets the interaction between LRH-1 and PGC-1alpha to inhibit CYP7A1 expression. (PMID:18385139)
• Data have shown that SHP represses the transcriptional activity of hepatocyte nuclear factor-6 that serves as a novel target in the regulation of gluconeogenesis. (PMID:18459945)
• These results indicate that SMILE isoforms regulate the inhibition of estrogen receptor transactivation by SHP in a cell-type-specific manner and act as a novel transcriptional co-regulator in ER signalling. (PMID:18657049)
• bile acid induces an increase in the gene expression of COX-2 via the sequential transcriptional induction of SHP and CDX1 in precancerous lesions of human gastric cancer. (PMID:18775915)
• Mutations in SHP associated with mild obesity in childhood increase susceptibility to type 2 diabetes in later life in Japanese patients. (PMID:18781616)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nr0b2a	ENSDARG00000044685
danio_rerio	nr0b2b	ENSDARG00000102756
mus_musculus	Nr0b2	ENSMUSG00000037583
rattus_norvegicus	Nr0b2	ENSRNOG00000007229

Paralogs (1): NR0B1 (ENSG00000169297)

Protein

Protein identifiers

Nuclear receptor subfamily 0 group B member 2 — Q15466 (reviewed: Q15466)

Alternative names: Orphan nuclear receptor SHP, Small heterodimer partner

All UniProt accessions (1): Q15466

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator that acts as a negative regulator of receptor-dependent signaling pathways. Specifically inhibits transactivation of the nuclear receptor with which it interacts. Inhibits transcriptional activity of NEUROD1 on E-box-containing promoter by interfering with the coactivation function of the p300/CBP-mediated transcription complex for NEUROD1. Essential component of the liver circadian clock which via its interaction with NR1D1 and RORG regulates NPAS2-mediated hepatic lipid metabolism. Regulates the circadian expression of cytochrome P450 (CYP) enzymes. Represses: NR5A2 and HNF4A to down-regulate CYP2C38, NFLI3 to up-regulate CYP2A5, BHLHE41/HNF1A axis to up-regulate CYP1A2, CYP2E1 and CYP3A11, and NR1D1 to up-regulate CYP2B10, CYP4A10 and CYP4A14.

Subunit / interactions. Interacts (via N-terminus) with NEUROD1 (via N-terminus and C-terminus). Interacts with ID2. Interacts with RORG, NFIL3, NR1D1 and BHLHE41. Heterodimer; efficient DNA binding requires dimerization with another bHLH protein. Interacts with RARA, RXRA, THRB, NR5A1, NR5A2, NR1I3, PPARA, PPARG and EID1. Interacts with HNF4A; the resulting heterodimer is transcriptionally inactive. Interacts with DDX3X; this interaction disrupts the interaction between HNF4 and NR0B2/SHP that forms inactive heterodimers and enhances the formation of active HNF4 homodimers.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Liver. Low levels of expression were detected in heart and pancreas.

Post-translational modifications. Arginine methylation by PRMT5 enhances repression activity of metabolic genes in liver in response to bile acid signaling, by increasing interaction with cofactors.

Disease relevance. Obesity (OBESITY) [MIM:601665] A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the nuclear hormone receptor family. NR0 subfamily.

RefSeq proteins (1): NP_068804* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR033544	NR0B1/2	Family
IPR035500	NHR-like_dom_sf	Homologous_superfamily

Pfam: PF00104

UniProt features (12 total): sequence variant 6, helix 3, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
6W9M	X-RAY DIFFRACTION	1.59
4ONI	X-RAY DIFFRACTION	1.8
1YUC	X-RAY DIFFRACTION	1.9
4DOR	X-RAY DIFFRACTION	1.9
5UFS	X-RAY DIFFRACTION	2.12
7YXC	X-RAY DIFFRACTION	2.25
7YXD	X-RAY DIFFRACTION	2.3
2Q3Y	X-RAY DIFFRACTION	2.4
7YXN	X-RAY DIFFRACTION	2.46
7YXR	X-RAY DIFFRACTION	2.5
2Z4J	X-RAY DIFFRACTION	2.6
9HDF	X-RAY DIFFRACTION	2.78
7YXO	X-RAY DIFFRACTION	2.99
7YXP	X-RAY DIFFRACTION	3.36

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15466-F1	82.42	0.65

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 (1): 57

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway

MSigDB gene sets: 221 (showing top): GOBP_CIRCADIAN_RHYTHM, FXR_IR1_Q6, GOBP_RESPONSE_TO_ETHANOL, PAX4_01, MODULE_64, GOBP_INSULIN_SECRETION, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, MAZ_Q6, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_REGENERATION, MEF2_02, GOBP_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION, SHEPARD_BMYB_MORPHOLINO_DN

GO Biological Process (15): negative regulation of transcription by RNA polymerase II (GO:0000122), Notch signaling pathway (GO:0007219), circadian rhythm (GO:0007623), cholesterol metabolic process (GO:0008203), response to glucose (GO:0009749), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), animal organ regeneration (GO:0031100), positive regulation of insulin secretion (GO:0032024), circadian regulation of gene expression (GO:0032922), obsolete negative regulation of DNA-binding transcription factor activity (GO:0043433), response to ethanol (GO:0045471), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), rhythmic process (GO:0048511)

GO Molecular Function (11): transcription corepressor activity (GO:0003714), nuclear receptor binding (GO:0016922), protein domain specific binding (GO:0019904), protein homodimerization activity (GO:0042803), peroxisome proliferator activated receptor binding (GO:0042975), protein-containing complex binding (GO:0044877), nuclear retinoid X receptor binding (GO:0046965), nuclear thyroid hormone receptor binding (GO:0046966), transcription regulator inhibitor activity (GO:0140416), protein binding (GO:0005515), nuclear retinoic acid receptor binding (GO:0042974)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of gene expression	4
cellular anatomical structure	3
negative regulation of DNA-templated transcription	2
gene expression	2
DNA-templated transcription	2
regulation of DNA-templated transcription	2
binding	2
nuclear receptor binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
cell surface receptor signaling pathway	1
rhythmic process	1
sterol metabolic process	1
secondary alcohol metabolic process	1
response to hexose	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
regeneration	1
animal organ development	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
circadian rhythm	1
response to alcohol	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
biological_process	1
transcription coregulator activity	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
signaling receptor binding	1
nuclear retinoic acid receptor binding	1
transcription regulator activity	1
molecular function inhibitor activity	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

2092 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NR0B2	CREB3	O43889	988
NR0B2	NR5A2	O00482	983
NR0B2	NR1H4	Q96RI1	981
NR0B2	CYP7A1	P22680	969
NR0B2	HNF4A	P41235	963
NR0B2	CYP8B1	Q9UNU6	954
NR0B2	NR1I2	O75469	933
NR0B2	ABCB11	O95342	925
NR0B2	NR1I3	Q14994	888
NR0B2	NR1H3	Q13133	871
NR0B2	FABP6	P51161	852
NR0B2	SLC10A1	Q14973	837
NR0B2	SLC10A2	Q12908	819
NR0B2	CYP27A1	Q02318	816
NR0B2	XPR1	Q9UBH6	816

IntAct

57 interactions, top by confidence:

A	B	Type	Score
SIRT1	NR0B2	psi-mi:“MI:0915”(physical association)	0.610
NR0B2	SIRT1	psi-mi:“MI:0403”(colocalization)	0.610
NR5A2	NR0B2	psi-mi:“MI:0407”(direct interaction)	0.560
ESRRG	NR0B2	psi-mi:“MI:0915”(physical association)	0.560
NR0B2	CIDEC	psi-mi:“MI:0915”(physical association)	0.560
NR0B2	GPSM3	psi-mi:“MI:0915”(physical association)	0.560
NR0B2	DNM2	psi-mi:“MI:0915”(physical association)	0.560
ATXN3	NR0B2	psi-mi:“MI:0915”(physical association)	0.560
MDM2	NR0B2	psi-mi:“MI:0915”(physical association)	0.520
NR0B2	MDM2	psi-mi:“MI:0915”(physical association)	0.520
TP53	NR0B2	psi-mi:“MI:0915”(physical association)	0.520
NR0B2	TP53	psi-mi:“MI:0915”(physical association)	0.520
NR0B2	HDAC3	psi-mi:“MI:0915”(physical association)	0.500
NR0B2	HDAC3	psi-mi:“MI:0914”(association)	0.500
NR0B2	HDAC1	psi-mi:“MI:0915”(physical association)	0.500
GPS2	NR0B2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (152): NR0B2 (Protein-peptide), ICK (Affinity Capture-MS), NEUROD1 (Affinity Capture-Western), NEUROD1 (Two-hybrid), ID2 (Two-hybrid), NEUROD1 (Reconstituted Complex), ID2 (Reconstituted Complex), NR1I2 (Two-hybrid), NR1I2 (Reconstituted Complex), NR0B2 (Reconstituted Complex), NR0B2 (Two-hybrid), ICK (Affinity Capture-MS), VCPIP1 (Affinity Capture-MS), NR0B2 (Affinity Capture-MS), NR0B2 (Affinity Capture-Western)

ESM2 similar proteins: A1L3T7, A4FU01, C9JE40, E9Q6X9, O08580, O09017, O94812, O95398, P10588, P11474, P33076, P33242, P43136, P50569, P62044, P79387, P79621, P97680, P97947, Q04752, Q13285, Q15466, Q2T9W1, Q3V3V9, Q562E7, Q58EX7, Q5BK61, Q5ND34, Q5QJV7, Q62227, Q68EF8, Q6QMY5, Q6ZNJ1, Q6ZQA0, Q76MJ5, Q7Z614, Q80TT2, Q80VA5, Q86XR2, Q8BGI5

Diamond homologs: P51843, P70503, P79386, P97947, Q15466, Q26622, Q61066, Q62227, Q9BG93, Q9BG94, Q9BG96, Q9BG97, P49116, P49117, P55094, A0JNE3, Q505F1, Q5RCZ5, Q8VIJ4, Q95K90, P10589, Q28CK1, Q60632, Q66J63, Q6GN21, Q9QXZ7, Q9TTF0, Q9TTR8, Q9Y5X4, Q9YGL3, O09017, P10588, P43136, Q06725, Q6PH18, Q91379, Q9PVE4, Q9Y466

SIGNOR signaling

25 interactions.

A	Effect	B	Mechanism
NR0B2	down-regulates	NR1I2	binding
NR0B2	“down-regulates quantity by repression”	THRA	“transcriptional regulation”
NR0B2	up-regulates	PPARA	binding
NR0B2	“down-regulates quantity by repression”	ESRRG	“transcriptional regulation”
NR0B2	down-regulates	AR	binding
NR0B2	down-regulates	ESR1	binding
NR0B2	down-regulates	NR1I3	binding
NR0B2	down-regulates	NR5A2	binding
metformin	“up-regulates quantity by expression”	NR0B2
NR0B2	“up-regulates quantity by expression”	G6PC1	“transcriptional regulation”
PRKAA1	up-regulates	NR0B2
NR0B2	“down-regulates activity”	CEBPA	binding
NR0B2	“down-regulates quantity by repression”	PCK2	“transcriptional regulation”
NR0B2	“up-regulates quantity by expression”	G6P	“transcriptional regulation”
NR0B2	“down-regulates quantity by repression”	THR	“transcriptional regulation”
NR0B2	“down-regulates quantity by repression”	HNF4A	“transcriptional regulation”
ESR1	“down-regulates quantity by repression”	NR0B2	“transcriptional regulation”
NR0B2	“down-regulates quantity by repression”	ESR2	“transcriptional regulation”
NR0B2	“down-regulates quantity by repression”	NR1H2	“transcriptional regulation”
NR0B2	“down-regulates quantity by repression”	NR1H3	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	NR0B2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 31 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	6	21.6×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
cholesterol homeostasis	5	26.9×	3e-04
positive regulation of gene expression	6	8.0×	5e-03
negative regulation of apoptotic process	6	7.2×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	80
Likely benign	23
Benign	3

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
5426	NM_021969.3(NR0B2):c.100C>T (p.Arg34Ter)	Pathogenic
636300	NM_021969.3(NR0B2):c.227del (p.Phe76fs)	Pathogenic
2432311	NM_021969.3(NR0B2):c.253_254dup (p.Arg86fs)	Likely pathogenic
2634784	NM_021969.3(NR0B2):c.265C>T (p.Gln89Ter)	Likely pathogenic
636298	NM_021969.3(NR0B2):c.293_301delinsAC (p.Leu98fs)	Likely pathogenic

SpliceAI

156 predictions. Top by Δscore:

Variant	Effect	Δscore
1:26912320:T:TA	donor_gain	1.0000
1:26912084:CAT:C	acceptor_gain	0.9900
1:26912086:TC:T	acceptor_loss	0.9900
1:26912087:C:CC	acceptor_gain	0.9900
1:26912087:C:G	acceptor_loss	0.9900
1:26912088:T:C	acceptor_loss	0.9900
1:26912095:A:T	acceptor_gain	0.9900
1:26913403:GCTCA:G	donor_loss	0.9900
1:26913404:CTCAC:C	donor_loss	0.9900
1:26913405:TCA:T	donor_loss	0.9900
1:26913406:CAC:C	donor_loss	0.9900
1:26913407:A:AC	donor_gain	0.9900
1:26913407:ACC:A	donor_loss	0.9900
1:26913408:C:CC	donor_gain	0.9900
1:26913408:C:CT	donor_loss	0.9900
1:26912082:CACAT:C	acceptor_gain	0.9800
1:26912083:ACAT:A	acceptor_gain	0.9800
1:26912084:CATC:C	acceptor_gain	0.9800
1:26912094:C:CT	acceptor_gain	0.9800
1:26913408:CCG:C	donor_gain	0.9800
1:26913408:CCGG:C	donor_gain	0.9800
1:26913447:T:TA	donor_gain	0.9800
1:26912085:AT:A	acceptor_gain	0.9700
1:26913407:AC:A	donor_gain	0.9700
1:26913408:CC:C	donor_gain	0.9700
1:26913408:CCGGG:C	donor_gain	0.9700
1:26913445:ATT:A	donor_gain	0.9700
1:26912341:CTG:C	donor_gain	0.9500
1:26912342:TGT:T	donor_gain	0.9500
1:26912350:A:AC	donor_gain	0.9500

AlphaMissense

1650 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:26913431:T:A	K170N	0.986
1:26913431:T:G	K170N	0.986
1:26913734:G:C	F69L	0.979
1:26913734:G:T	F69L	0.979
1:26913736:A:G	F69L	0.979
1:26913579:A:G	I121T	0.968
1:26913416:G:C	F175L	0.965
1:26913416:G:T	F175L	0.965
1:26913418:A:G	F175L	0.965
1:26913654:A:G	F96S	0.964
1:26913417:A:G	F175S	0.962
1:26913432:T:A	K170I	0.962
1:26913435:A:G	L169P	0.957
1:26911912:A:G	F236S	0.952
1:26913639:G:T	A101D	0.950
1:26913620:A:C	F107L	0.946
1:26913620:A:T	F107L	0.946
1:26913622:A:G	F107L	0.946
1:26911911:G:C	F236L	0.944
1:26911911:G:T	F236L	0.944
1:26911913:A:G	F236L	0.944
1:26913713:G:C	F76L	0.942
1:26913713:G:T	F76L	0.942
1:26913715:A:G	F76L	0.942
1:26913418:A:T	F175I	0.941
1:26913588:A:T	L118H	0.936
1:26913642:A:G	L100S	0.934
1:26913495:A:G	L149P	0.929
1:26913418:A:C	F175V	0.928
1:26913591:A:G	I117T	0.926

dbSNP variants (sampled 300 via entrez): RS1000312201 (1:26915871 T>A,C), RS1000697256 (1:26915188 G>A), RS1002708800 (1:26912008 T>C), RS1003083219 (1:26913071 G>A), RS1003596314 (1:26911340 T>C,G), RS1005767822 (1:26914639 G>A,C), RS1005827093 (1:26914239 G>A), RS1005958652 (1:26913965 A>G), RS1005999342 (1:26914975 A>G), RS1006549945 (1:26912498 G>T), RS1007778864 (1:26911774 T>A,C), RS1009573425 (1:26915067 A>G), RS1009675088 (1:26915810 G>A), RS1010006455 (1:26914020 G>A), RS1011681780 (1:26912651 G>A,T)

Disease associations

OMIM: gene MIM:604630 | disease phenotypes: MIM:601665

GenCC curated gene-disease

Disease	Classification	Inheritance
inherited obesity	Limited	Autosomal dominant
schizophrenia	No Known Disease Relationship	Unknown

Mondo (3): obesity disorder (MONDO:0011122), inherited obesity (MONDO:0019182), schizophrenia (MONDO:0005090)

Orphanet (3): Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Genetic obesity (Orphanet:77828), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0001513	Obesity
HP:0010982	Polygenic inheritance
HP:0012340	Decreased resting energy expenditure
HP:0031819	Increased waist to hip ratio

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002216_1	Triglycerides	1.000000e-09
GCST002222_44	LDL cholesterol	3.000000e-12
GCST002223_69	HDL cholesterol	1.000000e-15
GCST007611_16	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	6.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5603 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: nhr — 0B. DAX-like receptors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 10 [PMID: 18759424]	Binding	6.3	pIC50

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.30	IC50	500	nM	CHEMBL461415
6.00	IC50	1000	nM	CHEMBL459497
5.60	IC50	2500	nM	CHEMBL176252
5.10	IC50	8000	nM	CHEMBL460351

PubChem BioAssay actives

4 with measured affinity, of 25 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(E)-3-[3-chloro-4-[3-(3,5-dimethyl-1-adamantyl)-4-hydroxyphenyl]phenyl]prop-2-enoic acid	364173: Displacement of [5,5’-3H2]AHPN from human recombinant GST-SHP by liquid scintillation counting relative to 3-Cl-AHPC	ic50	0.5000	uM
(E)-3-[4-[3-(1-adamantyl)-4-fluorophenyl]-3-chlorophenyl]prop-2-enoic acid	364173: Displacement of [5,5’-3H2]AHPN from human recombinant GST-SHP by liquid scintillation counting relative to 3-Cl-AHPC	ic50	1.0000	uM
(E)-3-[4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorophenyl]prop-2-enoic acid	364173: Displacement of [5,5’-3H2]AHPN from human recombinant GST-SHP by liquid scintillation counting relative to 3-Cl-AHPC	ic50	2.5000	uM
(E)-3-[3-chloro-4-[3-(3-ethylpentan-3-yl)-4-hydroxyphenyl]phenyl]prop-2-enoic acid	364173: Displacement of [5,5’-3H2]AHPN from human recombinant GST-SHP by liquid scintillation counting relative to 3-Cl-AHPC	ic50	8.0000	uM

CTD chemical–gene interactions

139 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Chenodeoxycholic Acid	affects cotreatment, decreases expression, affects reaction, decreases reaction, increases expression (+2 more)	14
GW 4064	decreases reaction, increases expression, affects binding, increases activity, affects cotreatment	8
Lithocholic Acid	increases activity, increases expression, affects binding	5
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
Cyclosporine	affects cotreatment, affects expression, decreases expression	4
perfluorooctane sulfonic acid	decreases expression, increases expression	3
obeticholic acid	affects binding, increases reaction, increases expression	3
Deoxycholic Acid	increases expression, affects cotreatment, decreases expression	3
Estradiol	decreases reaction, increases reaction, affects binding, affects reaction, decreases expression	3
Tamoxifen	affects binding, decreases reaction, increases expression	3
Tetrachlorodibenzodioxin	decreases reaction, increases expression, decreases expression	3
Aflatoxin B1	affects expression, decreases expression, increases expression	3
lasiocarpine	decreases expression	2
bisphenol A	affects binding, affects reaction, affects folding, decreases reaction	2
perfluorooctanoic acid	decreases expression	2
pregna-4,17-diene-3,16-dione	decreases reaction, increases expression	2
bisphenol AF	affects binding, affects folding, decreases reaction	2
Resveratrol	affects cotreatment, decreases expression, decreases reaction, increases expression	2
Amitriptyline	increases expression	2
trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride	increases expression	2
Clozapine	increases expression	2
Fluoxetine	increases expression	2
Ketoconazole	increases expression	2
Perhexiline	increases expression	2
Quercetin	affects cotreatment, decreases reaction, increases expression, decreases expression	2
Rifampin	decreases expression, increases expression	2
Sotalol	increases expression, decreases expression	2
Tretinoin	increases expression	2
Triclosan	affects cotreatment, increases expression, decreases expression	2
Ursodeoxycholic Acid	increases expression	2

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1953096	Binding	Binding affinity to GST-tagged human recombinant SHP at 100 uM by NMR spectroscopy	Analogues of orphan nuclear receptor small heterodimer partner ligand and apoptosis inducer (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid. 2. Impact of 3-chloro group replacement on inhibition of proliferation and induction of apoptosis of leukemia and cancer cell lines. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4S1	SEES3-1V human NR0B2, clone1	Embryonic stem cell	Male
CVCL_A4S2	SEES3-1V human NR0B2, clone2	Embryonic stem cell	Male
CVCL_A4S3	SEES3-1V human NR0B2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety