NR4A2

protein-coding

nuclear receptor subfamily 4 group A member 2, the group of Nuclear receptor subfamily 4 group A

Gene summary

This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. The encoded protein may act as a transcription factor. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson disease, schizophernia, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

Previous symbols:

NURR1

MANE transcript

NM_006186.4

Inheritance

ClinVar variants

P:57U:147B:40

Top phenotype

Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr2:156,324,437-156,342,348

External References & Databases

Ensembl (ENSG00000153234)

Transcript & Mutation Effects

hg38 • Region Span ~17.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859257

Submitter: PanelApp Australia

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Genomic loss of NR4A2 was first reported in relation to complex neurodevelopmental disorder in 2013 (PMID: 23554088). Affected individuals present with developmental delays, language impairment, intellectual disability, autism, epilepsy, and ataxia, with dystonia. Parkinsonism is also reported in early adulthood in some individuals (PMID: 31922365). To date, 8 unique de novo variants predicted to cause loss of function of the protein have been reported. Multiple de novo missense variants in the DNA binding domain of the protein have also been described in affected individuals in the literature (PMIDs: 30504930, 32366965). In addition to SNVs and indels, whole-gene deletions involving only NR4A2 have also been identified (PMIDs: 28544326, 29770430). This gene is intolerant to loss-of- function variants, as indicated by its pLI score of 1 in gnomAD (v2.1.1). This gene-disease relationship is supported by mouse models with conditional gene targeting showing loss of striatal dopamine neurons, neuron degeneration, and impaired motor function (PMID: 20016108). In summary, NR4A2 is definitively associated with complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel Expert Panel on 05/05/2021 (SOP Version 8).

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859257

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonismAD

Manifestation: Neurologic

Intervention: Neurologic

Rationale: The condition can include dystonia and movement abnormalities, which has been reported as responding to medical management (with L-dopa)

Refs: 28544326; 29770430; 31428396; 31922365; 32366965; 33585677

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NR4A2 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 88

Inborn genetic diseasesTotal: 64

Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonismTotal: 63

Parkinson disease, late-onsetTotal: 21

not specifiedTotal: 17

NR4A2-related disorderTotal: 8

Autism spectrum disorderTotal: 2

Complex neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006186.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	25 clinvar	2 clinvar	34
missense	6 clinvar	17 clinvar	133 clinvar	12 clinvar	1 clinvar	169
nonsense	4 clinvar	3 clinvar	2 clinvar			9
start loss	1 clinvar		1 clinvar			2
frameshift	13 clinvar	9 clinvar	3 clinvar			25
splice donor/acceptor (+/-2bp)	3 clinvar	1 clinvar	1 clinvar			5
Total	27	30	147	37	3	244

Highest pathogenic variant AF is 0.0000027363262

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006186.4	RefSeq	NP_006177.1	6	MANE Select
ENST00000339562.9	Ensembl	ENSP00000344479.4	6	MANE Select
NM_173173.3	RefSeq	NP_775265.1	6	Standard
ENST00000409108.6	Ensembl	ENSP00000386993.2	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nr4a2a	Danio rerio	Structure: caudal tuberculum Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

nr4a2a

Danio rerio

Structure: caudal tuberculum

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aldosterone synthesis and secretion - Homo sapiens (human)
NHR
Nuclear Receptors
Corticotropin-releasing hormone signaling pathway
Dopaminergic Neurogenesis

Biological Process

negative regulation of transcription by RNA polymerase II
response to hypoxia
neuron migration
response to amphetamine
transcription, DNA-templated

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding

Cellular Component

nucleus
nucleoplasm
transcription factor complex
cytoplasm
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000339562
Coding exons: 6
Length: 17917
Individuals with no LoFs: 113255
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 113256
p: 0.00000441

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.24	236	354	0.666	0.0000221	3936
Missense (PolyPhen)		58	138.82	0.41781		1595
Synonymous	0.0913	153	154	0.991	0.0000110	1183
Loss of Function	4.39	0	22.4	0.00	0.00000112	255

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000031	0.000010	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. It is crucial for expression of a set of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons (By similarity). {ECO:0000250, ECO:0000269|PubMed:17184956}.;

Recessive Scores

pRec: 0.607

Intolerance Scores

LoFtool: 0.0180
RVIS EVS: -0.63
RVIS percentile EVS: 17.03

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium