GeneBe

NR0B1

protein-coding

nuclear receptor subfamily 0 group B member 1, the group of Nuclear receptor subfamily 0 group B

Gene summary

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. [provided by RefSeq, Jul 2008]

Previous symbols:
  • AHC
  • DSS

MANE transcript

NM_000475.5

Inheritance

XL, XLR

ClinVar variants

P:133U:120B:183

Top phenotype

Adrenal hypoplasia, congenital; 46,XY sex reversal 2

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:30,304,206-30,309,390

External References & Databases

Ensembl (ENSG00000169297)NCBI Gene (190)OMIM (300473)HGNC:7960GenCCUniProt (P51843)AlphaFoldClinVar (NR0B1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~5.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked adrenal hypoplasia congenitaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010264

Submitter: G2P

46,XY sex reversal 2MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010226

Submitter: Ambry Genetics

X-linked adrenal hypoplasia congenitaSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010264

Submitter: Orphanet

X-linked adrenal hypoplasia congenitaSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010264

Submitter: PanelApp Australia

X-linked adrenal hypoplasia congenitaSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010264

Submitter: Labcorp Genetics (formerly Invitae)

X-linked adrenal hypoplasia congenitaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010264

Submitter: Ambry Genetics

X-linked adrenal hypoplasia congenitaDEFINITIVE

Inheritance Pattern: XLR

Disease ID:MONDO:0010264

Submitter: Natera

X-linked adrenal hypoplasia congenitaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010264

Submitter: Myriad Women's Health

Clinical Genomic Database (CGD)

Adrenal hypoplasia, congenital; 46,XY sex reversal 2XL

Manifestation: Endocrine; Genitourinary; Obstetric; Oncologic

Intervention: Endocrine; Genitourinary; Obstetric; Oncologic

Rationale: Affected individuals typically present in infancy with acute-onset adrenal insufficiency, which can be lethal, and preventive and treatment measures can be effective

Comments: Digenic inheritance (with GNRH1) has been reported; Dosage-sensitive sex reversal has been described due to duplications

Refs: 6891556; 7951319; 7990958; 9003500; 9529340; 10022408; 11549627; 11788621; 12519885; 17503084; 17164309; 20301604; 20301714; 21408189; 21632081; 21739173; 21925982; 22456342; 22570964Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NR0B1 variants in ClinVar

8 Conditions Cataloged
Congenital adrenal hypoplasia, X-linkedTotal: 361
46,XY sex reversal 2Total: 285
not providedTotal: 51
Inborn genetic diseasesTotal: 48
NR0B1-related disorderTotal: 26
not specifiedTotal: 15
Differences in sex developmentTotal: 1
Mineralocorticoid deficiency, isolatedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000475.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
139
clinvar
12
clinvar
 153
missense
11
clinvar
10
clinvar
116
clinvar
24
clinvar
8
clinvar
 169
nonsense
40
clinvar
6
clinvar
1
clinvar
 47
start loss
1
clinvar
1
clinvar
 2
frameshift
49
clinvar
7
clinvar
1
clinvar
 57
splice donor/acceptor (+/-2bp)
7
clinvar
1
clinvar
 8
Total1082512016320436

Highest pathogenic variant AF is 9.1685666e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000475.5RefSeqNP_000466.22MANE Select
ENST00000378970.5EnsemblENSP00000368253.42MANE Select
ENST00000378963.1EnsemblENSP00000368246.12Standard
ENST00000378963.2EnsemblENSP00000368246.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
nr0b1Danio rerio

Structure: somatic cell

Quality: decreased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • NHR
  • Nuclear Receptors
  • Gene expression (Transcription)
  • Generic Transcription Pathway
  • Nuclear Receptor transcription pathway

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • transcription initiation from RNA polymerase II promoter
  • steroid biosynthetic process
  • spermatogenesis
  • protein localization

Molecular Function

  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA binding
  • steroid hormone receptor activity
  • transcription corepressor activity
  • RNA binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • microtubule organizing center
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000378970
Coding exons
2
Length
5393
Individuals with no LoFs
123291
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
123292
p
0.00000406
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.081501920.7800.00001323013
Missense (PolyPhen)3058.750.510631073
Synonymous-0.8419988.91.110.00000644986
Loss of Function3.06010.90.006.93e-7165

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000370.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Orphan nuclear receptor. Component of a cascade required for the development of the hypothalamic-pituitary-adrenal-gonadal axis. Acts as a coregulatory protein that inhibits the transcriptional activity of other nuclear receptors through heterodimeric interactions. May also have a role in the development of the embryo and in the maintenance of embryonic stem cell pluripotency (By similarity). {ECO:0000250}.;
Disease
DISEASE: 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. {ECO:0000269|PubMed:10323730, ECO:0000269|PubMed:10341858, ECO:0000269|PubMed:10675358, ECO:0000269|PubMed:10848616, ECO:0000269|PubMed:11113848, ECO:0000269|PubMed:11443184, ECO:0000269|PubMed:11748852, ECO:0000269|PubMed:11788621, ECO:0000269|PubMed:12629128, ECO:0000269|PubMed:15800903, ECO:0000269|PubMed:7990958, ECO:0000269|PubMed:9003500, ECO:0000269|PubMed:9063431, ECO:0000269|PubMed:9360549, ECO:0000269|PubMed:9415399, ECO:0000269|PubMed:9529340}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:9486644}. Note=The disease is caused by mutations 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.;

Recessive Scores

pRec
0.610

Intolerance Scores

LoFtool
0.0263
RVIS EVS
-0.49
RVIS percentile EVS
22.09

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.787

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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