NR0B1

Summary

NR0B1 (nuclear receptor subfamily 0 group B member 1, HGNC:7960) is a protein-coding gene on chromosome Xp21.2, encoding Nuclear receptor subfamily 0 group B member 1 (P51843). Nuclear receptor that lacks a DNA-binding domain and acts as a corepressor that inhibits the transcriptional activity of other nuclear receptors through heterodimeric interactions. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein that contains a DNA-binding domain. The encoded protein acts as a dominant-negative regulator of transcription which is mediated by the retinoic acid receptor. This protein also functions as an anti-testis gene by acting antagonistically to Sry. Mutations in this gene result in both X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism.

Source: NCBI Gene 190 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked adrenal hypoplasia congenita (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 432 total — 111 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 83
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 63 downstream targets (CollecTRI)
• MANE Select transcript: NM_000475

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7960
Approved symbol	NR0B1
Name	nuclear receptor subfamily 0 group B member 1
Location	Xp21.2
Locus type	gene with protein product
Status	Approved
Aliases	DAX1, AHCH
Ensembl gene	ENSG00000169297
Ensembl biotype	protein_coding
OMIM	300473
Entrez	190

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000378963, ENST00000378970

RefSeq mRNA: 1 — MANE Select: NM_000475 NM_000475

CCDS: CCDS14223

Canonical transcript exons

ENST00000378970 — 2 exons

Exon	Start	End
ENSE00001479408	30304206	30304823
ENSE00001819343	30308196	30309390

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 93.47.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3117 / max 294.5868, expressed in 193 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198770	1.2122	168
198769	0.0995	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	93.47	gold quality
left adrenal gland	UBERON:0001234	92.92	gold quality
adrenal tissue	UBERON:0018303	92.36	gold quality
right adrenal gland cortex	UBERON:0035827	92.17	gold quality
left adrenal gland cortex	UBERON:0035825	91.32	gold quality
adrenal cortex	UBERON:0001235	90.93	gold quality
adrenal gland	UBERON:0002369	89.96	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.36	gold quality
right testis	UBERON:0004534	88.35	gold quality
left testis	UBERON:0004533	87.97	gold quality
testis	UBERON:0000473	86.65	gold quality
islet of Langerhans	UBERON:0000006	82.86	gold quality
germinal epithelium of ovary	UBERON:0001304	76.10	gold quality
type B pancreatic cell	CL:0000169	75.07	gold quality
left ovary	UBERON:0002119	73.13	gold quality
adult organism	UBERON:0007023	73.13	gold quality
ovary	UBERON:0000992	70.02	gold quality
right ovary	UBERON:0002118	67.49	gold quality
pancreatic ductal cell	CL:0002079	66.85	silver quality
pituitary gland	UBERON:0000007	66.64	gold quality
buccal mucosa cell	CL:0002336	65.04	gold quality
pancreas	UBERON:0001264	64.51	gold quality
amygdala	UBERON:0001876	64.11	gold quality
ectocervix	UBERON:0012249	63.85	gold quality
adenohypophysis	UBERON:0002196	63.36	gold quality
hypothalamus	UBERON:0001898	62.67	gold quality
mammalian vulva	UBERON:0000997	61.32	gold quality
cranial nerve II	UBERON:0000941	60.87	gold quality
cingulate cortex	UBERON:0003027	60.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	6.00
E-HCAD-31	yes	4.77
E-ANND-3	no	1.46

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

63 targets.

Target	Regulation
ABCD2
ABCD3
ADAM2
AKR1C4
AMH	Repression
APOC3
CAMP	Repression
CCND1	Repression
CNOT2
CYP11A1	Activation
CYP17A1	Repression
CYP19A1	Repression
CYP21A1P
CYP2B6
DHH
DR1
EGF
EPO
ESRRB
ESRRG	Repression
EWSR1
FDFT1
FLI1
FSHR
G6PC1	Repression
GATA4
GLB1
HSD3B1	Repression
IL2
LBP

Upstream regulators (CollecTRI, top): AR, ESRRA, ESRRB, ESRRG, EWSR1, FLI1, NANOG, NCOR2, NR0B1, NR1H4, NR2F1, NR3C1, NR4A1, NR5A1, NR5A2, POU5F1, SF1, SOX2, STAT3, TOX, WT1

miRNA regulators (miRDB)

12 targeting NR0B1, 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-548C-3P	99.99	74.01	7587
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-5585-3P	98.25	67.41	941
HSA-MIR-509-3-5P	97.21	67.74	1517
HSA-MIR-509-5P	97.21	67.90	1512
HSA-MIR-4714-5P	97.04	67.76	955
HSA-MIR-514A-5P	96.94	65.49	801
HSA-MIR-3664-5P	96.74	66.56	770
HSA-MIR-4793-3P	94.87	65.85	896

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• describe phenotypic spectrum of disorders associated with mutations and reveal how the discovery of naturally occurring mutations is helping to unravel the role in development and disease [review] (PMID:11738790)
• Identified nine novel NR0B1 mutations in X-linked AHC patients (Y81X, 343delG, 457delT, 629delG, L295P, 926-927delTG, 1130delA, 1141-1155del15, and E428X). (PMID:11748852)
• potently inhibits ligand-dependent transcriptional activation as well as the interaction between the N- and C-terminal activation domains of the androgen receptor (PMID:11875111)
• X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein (PMID:12034880)
• adrenal hypoplasia congenita and multiple pituitary hormone deficiency without mutations in the DAX1 or SF1 genes (PMID:12083815)
• WT1 and this protein inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells (PMID:12213901)
• An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation (Q37X) leading to a mild form of X-linked adrenal hypoplasia congenita. (PMID:12519885)
• missense mutations and deletions in dax1 protein is associated with persistent hypertriglyceridemia (PMID:12636049)
• modulation of DAX-1 and steroidogenic factor-1 intracellular levels in granulosa cells suggests that these transcription factors could be involved in mitogen-activated protein kinase suppression of steroidogenic acute regulatory protein expression (PMID:12727988)
• SMRT and DAX-1 repress agonist-dependent activity of both androgen and progesterone receptors (PMID:12771131)
• DAX-1 and COUP-TFII may play a role in the modulation of Ad4BP/SF-1-dependent transcription of steroidogenic enzymes in different cell types and follicular stages in normal cycling human ovaries. (PMID:12843196)
• DAX-1alpha can bind to steroidogenic factor 1 and to DNA but is unable to repress steroidogenic factor 1-mediated transcriptional activation of the reporter gene and acts as an antagonist of DAX-1 under certain conditions (PMID:15044589)
• DAX-1 might modify the AR & ER-beta intracellular location. Because a direct positive relation between the expression of these three receptors was found, the presence of DAX-1 in neoplastic cells might indicate a possible failure of endocrine therapies. (PMID:15084237)
• It remains probable that this unusual patient has either a DAX1 or SF1 mutation defect. A Wnt-4 defect was not evaluated. (PMID:15379426)
• determined the presence of an alternatively spliced form of NR0B1, NR0B1A; NR0B1A is encoded by NR0B1 exon 1 & exon 2A located within the 3385 nt intron between NR0B1 exons 1 and 2; detected expression of NR0B1A in adrenal gland, testis, ovary & pancreas (PMID:15589120)
• 13 novel mutations in the DAX1 protein associated with adrenal hypoplasia gongenita are described. (PMID:15841486)
• DAX-1 is a major repressor of ACTH-R gene expression in vitro and in vivo. (PMID:15879363)
• *mutated in adrenal gland and reproduction disorderse (REVIEW) (PMID:15988384)
• The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression. (PMID:16206264)
• DAX-1 may inhibit the proliferation and progression of endometrial carcinoma through inhibition of estrogenic actions, possibly by interacting with estrogen receptors present in carcinoma cells, rather than regulating in situ steroidogenesis (PMID:16232195)
• Somatic abnormalities in DAX1 are absent or uncommon in patients with idiopathic nonobstructive azoospermia (PMID:16275267)
• Two Taiwanese patients with adrenal hypoplasia congenita were detected to have novel mutations of the DAX1 (NR0B1) gene. (PMID:16355812)
• Three known and two novel mutations were detected in the DAX1 coding sequence in X-linked adrenal hypoplasia congenita patients (PMID:16645015)
• nuclear receptor DAX1 mutations are a relatively frequent cause of adrenal failure in this group of boys (PMID:16684822)
• 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)
• DAX-1 plays a critical role in spermatogenesis in the human testis (PMID:16834661)
• The gene that was most reproducibly up-regulated by EWS/FLI was NR0B1. (PMID:17114343)
• Novel features of this family include a novel DAX1 mutation, marked variability in age of presentation, hypertension on ‘standard’ doses of 9alpha-fludrocortisone and mild testicular enlargement. (PMID:17308433)
• Study describes 3 siblings with adrenal hypoplasia congenita, with different phenotypes; molecular analysis detected a novel mutation, a transition of C to T at position 359 in exon 1 of the DAX1 gene, determining a stop codon. (PMID:17573657)
• novel DAX-1 mutation was detected in two family members with different phenotype: one live infant with adrenal hypoplasia, his mother, and probably his dead brother (PMID:18038713)
• study reported patients with adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by the loss of function mutations of the DAX-1 gene (PMID:18202527)
• DAX-1 acts as a corepressor of PPARgamma and performs a potential function in the regulation of PPARgamma-mediated cellular differentiation. (PMID:18381063)
• DAX-1 directly modulates GR signaling in addition to affecting glucocorticoid hormone levels (PMID:18417736)
• DAX1 is important in the pathogenesis of the Ewing’s family of tumors, and is a cell-cycle progression regulator. (PMID:18591936)
• In comparison to DAX-1A, DAX-1 is, by far, the predominant mRNA isoform found in human adrenal glands and gonads. (PMID:18819054)
• Ad4BP/SF-1 and DAX-1 are expressed not only in benign adrenal adenoma but also malignant adrenocortical carcinoma, it is useful to distinguish from other retroperitoneal tumors (PMID:18824868)
• DAX1 immunoreactivity is considered a new biological modulator of human prostate cancer, but independent to the status of sex steroid receptors in human prostate cancer tissues. (PMID:18827407)
• three unrelated cases with variable clinical presentations of congenital adrenal hypoplasia, all with novel mutations in the DAX-1 gene (PMID:18941128)
• The positive interaction between DAX1 and SF-1 in regulating PBX1 may be an important mechanism in adrenal gland development and diseases. (PMID:18984668)
• structure of the Dax-1:LRH-1 complex provides the molecular mechanism for the function of Dax-1 as a potent transcriptional repressor (PMID:19015525)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nr0b1	ENSDARG00000056541
mus_musculus	Nr0b1	ENSMUSG00000025056
rattus_norvegicus	Nr0b1	ENSRNOG00000003765

Paralogs (1): NR0B2 (ENSG00000131910)

Protein

Protein identifiers

Nuclear receptor subfamily 0 group B member 1 — P51843 (reviewed: P51843)

Alternative names: DSS-AHC critical region on the X chromosome protein 1, Nuclear receptor DAX-1

All UniProt accessions (3): A6NNU8, P51843, F1D8P4

UniProt curated annotations — full annotation on UniProt →

Function. Nuclear receptor that lacks a DNA-binding domain and acts as a corepressor that inhibits the transcriptional activity of other nuclear receptors through heterodimeric interactions. Component of a cascade required for the development of the hypothalamic-pituitary-adrenal-gonadal axis. May also have a role in the development of the embryo and in the maintenance of embryonic stem cell pluripotency.

Subunit / interactions. Homodimer. Interacts with NR5A1, NR5A2, NR0B2 and with COPS2. Interacts with ESRRB; represses ESRRB activity at the GATA6 promoter.

Subcellular location. Nucleus. Cytoplasm.

Disease relevance. Adrenal hypoplasia, congenital (AHC) [MIM:300200] A disorder of adrenal gland development characterized by absence of the permanent zone of the adrenal cortex, structural disorganization of the adrenal glands, adrenal insufficiency and profound hormonal deficiencies. AHC patients manifest primary adrenal failure usually in early infancy, and hypogonadotropic hypogonadism leading to absent or incomplete sexual maturation. AHC can be inherited in an X-linked or autosomal recessive pattern. The disease is caused by variants affecting the gene represented in this entry. 46,XY sex reversal 2 (SRXY2) [MIM:300018] A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype. The disease is caused by variants affecting the gene represented in this entry. XY individuals with a duplication of part of the short arm of the X chromosome and an intact SRY gene develop as females. The single X chromosome in these individuals does not undergo X-chromosome inactivation; therefore, these individuals presumably carry 2 active copies of genes, including the NR0B1 gene, in the duplicated region. Individuals with deletion of this region develop as males. Genes within the dosage-sensitive sex reversal region are, therefore, not essential for testis development, but, when present in a double dose, interfere with testis formation.

Domain organisation. Homodimerization involved an interaction between amino and carboxy termini involving LXXLL motifs and steroid binding domain (AF-2 motif). Heterodimerizes with NR5A1 and NROB2 through its N-terminal LXXLL motifs.

Miscellaneous. More abundant than isoform 1 in all tissues tested except testis where they are nearly equal.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P51843-1	1	yes
P51843-2	2, NR0B1A

RefSeq proteins (1): NP_000466* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR025900	Nuclear_receptor_repeat	Repeat
IPR033544	NR0B1/2	Family
IPR035500	NHR-like_dom_sf	Homologous_superfamily

Pfam: PF00104, PF14046

UniProt features (38 total): sequence variant 19, repeat 4, short sequence motif 4, mutagenesis site 4, splice variant 2, chain 1, sequence conflict 1, helix 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4RWV	X-RAY DIFFRACTION	1.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51843-F1	60.48	0.25

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 (4):

Position	Phenotype
16–17	strongly reduces homodimerization and interaction with nr0b2.
83–84	strongly reduces homodimerization and interaction with nr0b2.
149–150	strongly reduces homodimerization and interaction with nr0b2.
461–462	strongly reduces homodimerization and interaction with nr0b2.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway

MSigDB gene sets: 344 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_RESPONSE_TO_IMMOBILIZATION_STRESS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_MALE_SEX_DETERMINATION, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_SEX_DETERMINATION, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_PITUITARY_GLAND_DEVELOPMENT, TGACCTY_ERR1_Q2, GOBP_MALE_GAMETE_GENERATION, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_FOREBRAIN_DEVELOPMENT, PID_ERB_GENOMIC_PATHWAY

GO Biological Process (20): negative regulation of transcription by RNA polymerase II (GO:0000122), spermatogenesis (GO:0007283), sex determination (GO:0007530), intracellular protein localization (GO:0008104), gonad development (GO:0008406), male gonad development (GO:0008584), negative regulation of steroid biosynthetic process (GO:0010894), hypothalamus development (GO:0021854), pituitary gland development (GO:0021983), male sex determination (GO:0030238), adrenal gland development (GO:0030325), negative regulation of intracellular steroid hormone receptor signaling pathway (GO:0033144), Leydig cell differentiation (GO:0033327), response to immobilization stress (GO:0035902), endodermal cell differentiation (GO:0035987), negative regulation of gluconeogenesis (GO:0045721), negative regulation of DNA-templated transcription (GO:0045892), Sertoli cell differentiation (GO:0060008), developmental process involved in reproduction (GO:0003006), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (10): transcription corepressor activity (GO:0003714), RNA binding (GO:0003723), nuclear receptor binding (GO:0016922), protein domain specific binding (GO:0019904), DNA hairpin binding (GO:0032448), protein homodimerization activity (GO:0042803), AF-2 domain binding (GO:0050682), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), ribosome (GO:0005840), membrane (GO:0016020), nuclear speck (GO:0016607), centriolar satellite (GO:0034451)

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
cellular anatomical structure	5
developmental process involved in reproduction	4
negative regulation of DNA-templated transcription	2
diencephalon development	2
endocrine system development	2
gland development	2
male gonad development	2
cell differentiation	2
DNA-templated transcription	2
binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
male gamete generation	1
macromolecule localization	1
development of primary sexual characteristics	1
animal organ development	1
reproductive structure development	1
gonad development	1
development of primary male sexual characteristics	1
steroid biosynthetic process	1
negative regulation of steroid metabolic process	1
regulation of steroid biosynthetic process	1
negative regulation of lipid biosynthetic process	1
limbic system development	1
anatomical structure development	1
multicellular organism development	1
sex determination	1
nuclear receptor-mediated steroid hormone signaling pathway	1
regulation of intracellular steroid hormone receptor signaling pathway	1
negative regulation of intracellular signal transduction	1
response to stress	1
endoderm formation	1
gluconeogenesis	1
regulation of gluconeogenesis	1
negative regulation of biosynthetic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of small molecule metabolic process	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
epithelial cell differentiation	1

Protein interactions and networks

STRING

1678 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NR0B1	NR5A1	Q13285	986
NR0B1	WT1	P19544	904
NR0B1	SALL4	Q9UJQ4	888
NR0B1	SRY	Q05066	886
NR0B1	STAR	P49675	874
NR0B1	SOX9	P48436	865
NR0B1	CYP11A1	P05108	840
NR0B1	AMH	P03971	829
NR0B1	GATA4	P43694	818
NR0B1	ESRRB	O95718	813
NR0B1	NANOG	Q9H9S0	807
NR0B1	CYP17A1	P05093	764
NR0B1	CYP19A1	P11511	759
NR0B1	CYP11B2	P19099	757
NR0B1	WNT4	P56705	751
NR0B1	MC2R	Q01718	751

IntAct

26 interactions, top by confidence:

A	B	Type	Score
NR0B1	NR5A1	psi-mi:“MI:0915”(physical association)	0.810
NR0B1	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
EEF2KMT	NR0B1	psi-mi:“MI:0915”(physical association)	0.560
NR0B1	EEF2KMT	psi-mi:“MI:0915”(physical association)	0.560
RORA	NR0B1	psi-mi:“MI:0915”(physical association)	0.510
	TTC8	psi-mi:“MI:0914”(association)	0.350
	NFIB	psi-mi:“MI:0914”(association)	0.350
NR0B1	NR5A1	psi-mi:“MI:0915”(physical association)	0.000
ESRRG	NR0B1	psi-mi:“MI:0915”(physical association)	0.000
NR0B1	ESRRG	psi-mi:“MI:0915”(physical association)	0.000
NR0B1	RORA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (49): ESRRG (Two-hybrid), NR5A1 (Two-hybrid), PPARG (Affinity Capture-Western), PPARG (Reconstituted Complex), NR0B1 (Reconstituted Complex), PPARG (Affinity Capture-Western), NR0B1 (Protein-peptide), NR0B1 (Reconstituted Complex), NR0B1 (Affinity Capture-Western), NR5A1 (Two-hybrid), NR0B1 (PCA), NR0B1 (Two-hybrid), NR0B1 (Two-hybrid), NR0B1 (Two-hybrid), ESRRG (Two-hybrid)

ESM2 similar proteins: A0A0J9YWL9, A0A0J9YY54, A5D7L8, A6NEF3, A6NI86, B2KFW1, B4DH59, D3YZV8, E9Q6E9, F1LWT0, F6QRE9, H0YKK7, O15069, P17040, P17564, P21263, P51843, P62521, P79386, Q0P6D6, Q13342, Q2EG98, Q2KI51, Q3BBV2, Q4VC44, Q5F378, Q5QGU6, Q63560, Q6ITT4, Q6P5H2, Q6ZQX7, Q86T75, Q8CHD8, Q8IWY8, Q8N660, Q8N693, Q99PG2, Q9BE18, Q9BG93, Q9BG94

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

4 interactions.

A	Effect	B	Mechanism
NR0B1	“down-regulates activity”	NR5A1	binding
NR0B1	“up-regulates activity”	NCOR2	binding
RNF31	“up-regulates quantity by stabilization”	NR0B1	monoubiquitination
ESRRB	down-regulates	NR0B1

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	111
Likely pathogenic	14
Uncertain significance	108
Likely benign	144
Benign	28

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075657	NM_000475.5(NR0B1):c.226C>T (p.Gln76Ter)	Pathogenic
10949	NM_000475.5(NR0B1):c.847C>T (p.Gln283Ter)	Pathogenic
10950	NM_000475.5(NR0B1):c.1107G>A (p.Trp369Ter)	Pathogenic
10951	NM_000475.5(NR0B1):c.788T>A (p.Leu263Ter)	Pathogenic
10953	NM_000475.5(NR0B1):c.704G>A (p.Trp235Ter)	Pathogenic
10954	NM_000475.5(NR0B1):c.513G>A (p.Trp171Ter)	Pathogenic
10955	NM_000475.5(NR0B1):c.839del (p.Leu280fs)	Pathogenic
10956	NM_000475.5(NR0B1):c.273C>A (p.Tyr91Ter)	Pathogenic
10957	NM_000475.5(NR0B1):c.1319A>T (p.Asn440Ile)	Pathogenic
10958	NM_000475.5(NR0B1):c.1183C>T (p.Gln395Ter)	Pathogenic
10959	NM_000475.5(NR0B1):c.813C>G (p.Tyr271Ter)	Pathogenic
10960	NM_000475.5(NR0B1):c.1376_1377delinsG (p.Asp459fs)	Pathogenic
10961	NM_000475.5(NR0B1):c.765del (p.Cys255fs)	Pathogenic
10962	NC_000023.11:g.(?30304206_30309390?)dup	Pathogenic
10964	NM_000475.5(NR0B1):c.1146G>T (p.Lys382Asn)	Pathogenic
10965	NM_000475.5(NR0B1):c.873G>C (p.Trp291Cys)	Pathogenic
10966	NG_009814.1:g.(?4989)(10173_?)del	Pathogenic
10967	NM_000475.5(NR0B1):c.1231_1234del (p.Leu411fs)	Pathogenic
10968	NM_000475.5(NR0B1):c.591C>A (p.Tyr197Ter)	Pathogenic
10969	NM_000475.5(NR0B1):c.1316T>G (p.Ile439Ser)	Pathogenic
10970	NM_000475.5(NR0B1):c.501del (p.Gly169fs)	Pathogenic
10971	NM_000475.5(NR0B1):c.1142T>A (p.Leu381His)	Pathogenic
10972	NR0B1, 1-BP INS, 430G	Pathogenic
10973	NM_000475.5(NR0B1):c.1138T>G (p.Tyr380Asp)	Pathogenic
10974	NC_000023.11:g.30304157_30306387delinsTGGAAATTATATATATTTCCAAATAAA	Pathogenic
10975	NM_000475.5(NR0B1):c.1197C>A (p.Tyr399Ter)	Pathogenic
10977	NM_000475.5(NR0B1):c.109C>T (p.Gln37Ter)	Pathogenic
1186881	NM_000475.5(NR0B1):c.1168+1G>T	Pathogenic
1208006	NM_000475.5(NR0B1):c.343del (p.Val115fs)	Pathogenic
1342040	NM_000475.5(NR0B1):c.155_156del (p.Glu52fs)	Pathogenic

SpliceAI

302 predictions. Top by Δscore:

Variant	Effect	Δscore
X:30304821:CGT:C	acceptor_gain	1.0000
X:30305731:T:TA	donor_gain	1.0000
X:30308194:AC:A	donor_gain	1.0000
X:30308195:CC:C	donor_gain	1.0000
X:30308313:T:A	donor_gain	1.0000
X:30304824:C:CC	acceptor_gain	0.9900
X:30305742:T:TA	donor_gain	0.9900
X:30308189:CCCTT:C	donor_loss	0.9900
X:30308190:CCTTA:C	donor_loss	0.9900
X:30308191:CTTAC:C	donor_loss	0.9900
X:30308192:TTA:T	donor_loss	0.9900
X:30308194:A:AT	donor_loss	0.9900
X:30308232:ACT:A	donor_gain	0.9900
X:30308233:CTC:C	donor_gain	0.9900
X:30304819:CACGT:C	acceptor_gain	0.9800
X:30308235:C:CA	donor_gain	0.9800
X:30308288:TGG:T	donor_gain	0.9800
X:30304822:GTCT:G	acceptor_loss	0.9700
X:30304823:TCTG:T	acceptor_loss	0.9700
X:30304824:C:T	acceptor_loss	0.9700
X:30304825:T:A	acceptor_loss	0.9700
X:30308232:A:AC	donor_gain	0.9700
X:30308233:C:CC	donor_gain	0.9700
X:30304820:ACGT:A	acceptor_gain	0.9600
X:30304821:CGTC:C	acceptor_gain	0.9600
X:30308191:C:T	donor_gain	0.9600
X:30304822:GT:G	acceptor_gain	0.9500
X:30308194:A:AC	donor_gain	0.9500
X:30308195:C:CC	donor_gain	0.9500
X:30308185:A:AC	donor_gain	0.9300

AlphaMissense

3053 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:30308218:C:A	K382N	0.998
X:30308218:C:G	K382N	0.998
X:30308560:G:C	F268L	0.997
X:30308560:G:T	F268L	0.997
X:30308562:A:G	F268L	0.997
X:30308203:A:C	F387L	0.996
X:30308203:A:T	F387L	0.996
X:30308204:A:G	F387S	0.996
X:30308205:A:G	F387L	0.996
X:30308539:G:C	F275L	0.996
X:30308539:G:T	F275L	0.996
X:30308541:A:G	F275L	0.996
X:30308222:A:G	L381P	0.995
X:30308540:A:G	F275S	0.995
X:30308591:G:T	A258D	0.995
X:30308205:A:T	F387I	0.994
X:30308207:A:T	L386H	0.994
X:30308561:A:G	F268S	0.994
X:30308558:A:T	V269D	0.993
X:30308205:A:C	F387V	0.992
X:30308217:C:G	G383R	0.992
X:30308217:C:T	G383R	0.992
X:30308493:A:G	W291R	0.992
X:30308493:A:T	W291R	0.992
X:30308561:A:C	F268C	0.992
X:30308207:A:G	L386P	0.991
X:30308465:G:T	A300D	0.991
X:30308531:A:G	L278P	0.991
X:30308207:A:C	L386R	0.990
X:30308217:C:A	G383W	0.990

dbSNP variants (sampled 300 via entrez): RS1000166922 (X:30308064 C>A,G), RS1000369780 (X:30307373 C>A), RS1001710892 (X:30308600 C>A), RS1002656643 (X:30310121 G>A), RS1003762245 (X:30305293 T>C), RS1004282171 (X:30311378 T>C), RS1005051557 (X:30303731 A>G), RS1005773940 (X:30304036 C>T), RS1005935319 (X:30305541 G>A), RS1006108699 (X:30307511 C>T), RS1006568894 (X:30306859 T>C), RS1007238338 (X:30307266 C>A), RS1007811778 (X:30309492 G>A,C,T), RS1008196351 (X:30309969 T>C), RS1008653182 (X:30309496 G>A,C)

Disease associations

OMIM: gene MIM:300473 | disease phenotypes: MIM:300018, MIM:300200

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked adrenal hypoplasia congenita	Definitive	X-linked
46,XY sex reversal 2	Moderate	X-linked

Mondo (2): 46,XY sex reversal 2 (MONDO:0010226), X-linked adrenal hypoplasia congenita (MONDO:0010264)

Orphanet (1): X-linked adrenal hypoplasia congenita (Orphanet:95702)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000030	Testicular gonadoblastoma
HP:0000037	Male pseudohermaphroditism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000045	Abnormal scrotum morphology
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000058	Abnormal labia morphology
HP:0000062	Ambiguous genitalia
HP:0000100	Nephrotic syndrome
HP:0000127	Renal salt wasting
HP:0000133	Gonadal dysgenesis
HP:0000142	Abnormal vagina morphology
HP:0000147	Polycystic ovaries
HP:0000149	Ovarian gonadoblastoma
HP:0000150	Gonadoblastoma
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000798	Oligozoospermia
HP:0000812	Abnormal internal genitalia
HP:0000815	Hypergonadotropic hypogonadism
HP:0000823	Delayed puberty
HP:0000826	Precocious puberty
HP:0000835	Adrenal hypoplasia
HP:0000837	Increased circulating gonadotropin level
HP:0000846	Adrenal insufficiency
HP:0000868	Decreased fertility in females
HP:0000939	Osteoporosis

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535601	Dosage-sensitive sex reversal (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795094 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 128,600 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL61	PODOFILOX	4	37,640
CHEMBL98	VORINOSTAT	4	50,361
CHEMBL52606	COLFORSIN	2	40,599

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

Binding affinities (BindingDB)

43 measured of 242 human assays (247 total across all organisms); most potent 43 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2-methylpropyl 6-(furan-2-yl)-3-methyl-4-oxidanylidene-1,5,6,7-tetrahydroindole-2-carboxylate	EC50	0.00157 nM
2-[[5-cyano-2-keto-4-(5-methyl-2-furyl)-3,4-dihydro-1H-pyridin-6-yl]thio]acetic acid ethyl ester	EC50	0.0249 nM
PODOFILOX	IC50	81 nM
(Z)-1-(1,3-benzodioxol-5-yl)-3-(2-bromoanilino)-2-propen-1-one	EC50	96 nM
MLS001074108	IC50	134 nM
cid_426728	IC50	212 nM
[7-(2-ethoxyethanoylamino)-1,2-dimethoxy-10-methylsulfanyl-9-oxidanylidene-6,7-dihydro-5H-benzo[a]heptalen-3-yl] 2-ethoxyethanoate	IC50	244 nM
(6E)-6-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,2-dihydropyrazol-3-ylidene]-1-cyclohexa-2,4-dienone	EC50	639 nM
1,4,5,6-Tetrahydro-cyclopentapyrazole-3-carboxylic acid (2-bromo-3-phenyl-allylidene)-hydrazide	EC50	1090 nM
cid_722352	IC50	1430 nM
MLS000565810	EC50	1700 nM
colforsinum	IC50	1730 nM
MLS000533118	EC50	1730 nM
3-chloranyl-4-fluoranyl-N-pyridin-2-yl-1-benzothiophene-2-carboxamide	EC50	1760 nM
(Z)-1-phenyl-3-(2-pyridinylamino)-2-propen-1-one	EC50	2010 nM
5-[(1,3-benzoxazol-2-ylhydrazinylidene)methyl]-2-methoxy-phenol	EC50	2140 nM
MLS000069706	IC50	2370 nM
SMR001565305	IC50	2720 nM
2-(4-methoxyphenyl)-6,7-dihydropyrrolo[1,2-a]thieno[3,2-d]pyrimidin-9(5H)-one	IC50	2920 nM
(E)-3-(3,4-dimethoxyphenyl)-N-[4-(3-hydroxy-1-adamantyl)phenyl]-2-propenamide	EC50	3120 nM
MLS000738042	IC50	3480 nM
2-phenyl-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazole	IC50	3720 nM
1-(4-chlorophenyl)-N-propan-2-yl-4-pyrazolo[3,4-d]pyrimidinamine	EC50	3850 nM
6-methoxy-2-(4-methoxyphenyl)-1-benzopyran-4-one	EC50	3920 nM
9-(1,3-benzodioxol-5-yl)-4-hydroxy-6,7-dimethoxy-3H-benzo[f][2]benzofuran-1-one	EC50	4420 nM
cid_1321268	IC50	4800 nM
(Z)-1-(1,3-benzodioxol-5-yl)-3-(3-fluoroanilino)-2-propen-1-one	IC50	5540 nM
3-chloro-N-(5-methyl-1,3-thiazol-2-yl)-1-benzothiophene-2-carboxamide	IC50	6670 nM
5-(4-methylphenyl)-3-(1-pyrrolidinylcarbonyl)isoxazole	IC50	9010 nM
2-[2-(1H-indol-3-yl)ethenyl]quinoline	IC50	10300 nM
MLS000419199	EC50	13400 nM
SMR003082527	IC50	14000 nM
(3Z)-3-(1-anilinoethylidene)-5-benzylpyrrolidine-2,4-dione	IC50	15800 nM
N-(5-methoxy-1,3-benzothiazol-2-yl)-2-furancarboxamide	IC50	17300 nM
5-[(2,4-dichlorophenoxy)methyl]-3-phenyl-1,2-oxazole	IC50	17800 nM
cid_5051334	IC50	23100 nM
cid_6056275	IC50	23400 nM
SMR000710071	IC50	24700 nM
MLS001160626	IC50	31700 nM
5,7-Dihydroxy-2-(3-hydroxy-4-methoxy-phenyl)-3,6-dimethoxy-chromen-4-one	IC50	35000 nM
(Z)-3-(1,3-benzodioxol-5-ylamino)-1-(2-thienyl)prop-2-en-1-one	EC50	35100 nM
(7-methyl-2-sulfanylidene-[1,2,4]triazolo[1,5-a]pyridin-3-yl)-phenylmethanone	IC50	46500 nM
4-methoxy-N-(3-methoxyphenyl)benzamide	EC50	1.11e+06 nM

ChEMBL bioactivities

12 potent at pChembl≥5 of 20 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.87	IC50	134.3	nM	BREFELDIN A
6.67	IC50	212	nM	CHEMBL434976
6.61	IC50	244.2	nM	CHEMBL1706279
6.41	IC50	386.1	nM	CHEMBL1734496
6.13	IC50	747.2	nM	VORINOSTAT
5.84	IC50	1432	nM	CHEMBL1524921
5.76	IC50	1729	nM	COLFORSIN
5.68	IC50	2094	nM	CHEMBL3199267
5.67	IC50	2145	nM	PODOFILOX
5.57	IC50	2715	nM	CHEMBL1707859
5.34	IC50	4569	nM	CHEMBL1446542
5.10	IC50	7904	nM	CHEMBL1506679

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, affects binding, increases reaction, increases expression	4
Valproic Acid	decreases expression, decreases reaction, increases expression, increases methylation	3
arsenite	decreases expression, increases methylation, decreases reaction	2
bisphenol S	decreases reaction, increases reaction, affects binding, affects folding	2
bisphenol AF	affects binding, affects folding, decreases reaction	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
alternariol	decreases expression	1
propionaldehyde	decreases expression	1
bisphenol A	affects binding, affects folding, decreases reaction	1
ethyl-p-hydroxybenzoate	increases expression	1
butyraldehyde	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
CGP 52608	affects binding, increases reaction	1
JP8 aviation fuel	decreases expression	1
enniatins	increases expression	1
dihydroxy-vitamin D3	affects binding, increases reaction	1
monomethylarsonous acid	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime	increases expression, affects binding, increases reaction, decreases reaction	1
abrine	increases expression	1
quinocetone	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
fatostatin	decreases expression	1
eldecalcitol	affects binding, increases reaction	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Fulvestrant	decreases expression, decreases reaction, increases expression	1

ChEMBL screening assays

3 unique, capped per target: 2 functional, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1794556	Functional	PUBCHEM_BIOASSAY: Luminescence-based cell-based high throughput dose response assay for inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1). (Class of assay: confirmatory) [Related pubchem assays (deposito	PubChem BioAssay data set
CHEMBL1961869	Binding	Effect on DAX1(NR0B1) dependent reporter activity in HEK293 cells at 20 uM	Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. — Nature

Cellosaurus cell lines

14 cell lines: 14 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_5T35	GM23908	Transformed cell line	Male
CVCL_5T36	GM23909	Transformed cell line	Male
CVCL_AZ34	GM24519	Transformed cell line	Male
CVCL_AZ35	GM24520	Transformed cell line	Male
CVCL_AZ36	GM24521	Transformed cell line	Female
CVCL_D2YM	GM25202	Transformed cell line	Male
CVCL_D2YP	GM25205	Transformed cell line	Male
CVCL_D2YR	GM25207	Transformed cell line	Male
CVCL_D2YS	GM25221	Transformed cell line	Male
CVCL_D2YT	GM25222	Transformed cell line	Male

Clinical trials (associated diseases)

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